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The molecular mechanism underlying the functional interaction between H1R and TRPV1 remains unclear. We show here that H1R directly binds to the carboxy-terminal region of TRPV1 at residues 715-725 and 736-749. Cell-penetrating peptides containing these sequences suppress histamine-induced scratching behavior in a cheek injection model. The H1R-TRPV1 binding is kept at a minimum at rest in mouse trigeminal neurons due to TRPV1 SUMOylation and it is enhanced upon histamine treatment through a transient TRPV1 deSUMOylation. The knockin of the SUMOylation-deficient TRPV1 mutant in mice leads to constitutive enhancement of H1R-TRPV1 binding, which exacerbates scratching behaviors induced by histamine. Conversely, SENP1 conditional knockout in sensory neurons enhances TRPV1 SUMOylation and suppresses the histamine-induced scratching response. In addition to interfering with binding, TRPV1 SUMOylation promotes H1R degradation through ubiquitination. Our work unveils the molecular mechanism of histaminergic itch by which H1R directly binds to deSUMOylated TRPV1 to facilitate the transduction of the pruritogen signal to the scratching response.
Learn More >Itch is an unpleasant sensation that often accompanies chronic dermatological conditions. Although many of the itch receptors and the neural pathways underlying this sensation are known, the identity of endogenous ligands is still not fully appreciated. Using an unbiased bioinformatic approach, we identified GPR15L as a candidate pruritogen whose expression is robustly up-regulated in psoriasis and atopic dermatitis. Although GPR15L was previously shown to be a cognate ligand of the receptor GPR15, expressed in dermal T cells, here we show that it also contributes to pruritogenesis by activating Mas-related G protein-coupled receptors (MRGPRs). GPR15L can selectively stimulate mouse dorsal root ganglion neurons that express Mrgpra3 and evokes intense itch responses. GPR15L causes mast cell degranulation through stimulation of MRGPRX2 and Mrgprb2. Genetic disruption of GPR15L expression attenuates scratch responses in a mouse model of psoriasis. Our study reveals unrecognized features of GRP15L, showing that it is a potent itch-inducing agent.
Learn More >Repeated application of noxious stimuli leads to a progressively increased pain perception; this temporal summation is enhanced in and predictive of clinical pain disorders. Its electrophysiological correlate is "wind-up," in which dorsal horn spinal neurons increase their response to repeated nociceptor stimulation. To understand the genetic basis of temporal summation, we undertook a GWAS of wind-up in healthy human volunteers and found significant association with SLC8A3 encoding sodium-calcium exchanger type 3 (NCX3). NCX3 was expressed in mouse dorsal horn neurons, and mice lacking NCX3 showed normal, acute pain but hypersensitivity to the second phase of the formalin test and chronic constriction injury. Dorsal horn neurons lacking NCX3 showed increased intracellular calcium following repetitive stimulation, slowed calcium clearance, and increased wind-up. Moreover, virally mediated enhanced spinal expression of NCX3 reduced central sensitization. Our study highlights Ca efflux as a pathway underlying temporal summation and persistent pain, which may be amenable to therapeutic targeting.
Learn More >Following tissue injury, latent sensitization (LS) of nociceptive signaling can persist indefinitely, kept in remission by compensatory µ-opioid receptor constitutive activity (MOR) in the dorsal horn of the spinal cord. To demonstrate LS, we conducted plantar incision in mice and then waited 3-4 weeks for hypersensitivity to resolve. At this time (remission), systemic administration of the opioid receptor antagonist/inverse agonist naltrexone reinstated mechanical and heat hypersensitivity. We first tested the hypothesis that LS extends to serotonergic neurons in the rostral ventral medulla (RVM) that convey pronociceptive input to the spinal cord. We report that in male and female mice, hypersensitivity was accompanied by increased Fos expression in serotonergic neurons of the RVM, abolished upon chemogenetic inhibition of RVM 5-HT neurons, and blocked by intrathecal injection of the 5-HTR antagonist ondansetron; the 5-HTR antagonist MDL-11,939 had no effect. Second, to test for MOR, we microinjected the MOR inverse agonist CTAP and/or neutral opioid receptor antagonist 6β-naltrexol. Intra-RVM CTAP produced mechanical hypersensitivity at both hindpaws. 6β-naltrexol had no effect by itself, but blocked CTAP-induced hypersensitivity. This indicates that MOR, rather than an opioid ligand-dependent mechanism, maintains LS in remission. We conclude that incision establishes LS in descending RVM 5-HT neurons that drives pronociceptive 5-HTR signaling in the dorsal horn, and this LS is tonically opposed by MOR in the RVM. The 5-HT receptor is a promising therapeutic target for the development of drugs to prevent the transition from acute to chronic post-surgical pain.Surgery leads to latent pain sensitization and a compensatory state of endogenous pain control that is maintained long after tissue healing. Here we show that either chemogenetic inhibition of serotonergic neuron activity in the rostral ventromedial medulla (RVM), or pharmacological inhibition of 5-HT receptor signaling at the spinal cord blocks behavioral signs of post-surgical latent sensitization. We conclude that µ-opioid receptor constitutive activity (MOR) in the RVM opposes descending serotonergic facilitation of LS, and that the 5-HT receptor is a promising therapeutic target for the development of drugs to prevent the transition from acute to chronic post-surgical pain.
Learn More >Chronic triptan exposurein rodents recapitulates medication overuse headache (MOH), causing cephalic pain sensitization and trigeminal ganglion overexpression of pronociceptive proteins including CGRP. Because of these transcriptional derangements, as well as the emerging role of epigenetics in chronic pain, in the present study, we evaluated the effects of the histone deacetylase inhibitors (HDACis) panobinostat and givinostat, in rats chronically exposed to eletriptan for one month. Both panobinostat and givinostat counteracted overexpression of genes coding for CGRP and its receptor subunit RAMP1, having no effects on CLR and RCP receptor subunits in the trigeminal ganglion (TG) of eletriptan-exposed rats. Within the trigeminal nucleus caudalis (TNc), transcripts for these genes were neither upregulated by eletriptan nor altered by concomitant treatment with panobinostat or givinostat. HDACis counteracted hypersensitivity to capsaicin-induced vasodilatation in the trigeminal territory, as well as photophobic behavior and cephalic allodyniain eletriptan-exposed rats. Eletriptan did not affect CGRP, CLR, and RAMP1 expression in cultured trigeminal ganglia, whereas both inhibitors reduced transcripts for CLR and RAMP-1. The drugs, however, increased luciferase expression driven by CGRP promoter in cultured cells. Our findings provide evidence for a key role of HDACs and epigenetics in MOH pathogenesis, highlighting the therapeutic potential of HDAC inhibition in the prevention of migraine chronification.
Learn More >People with chronic pain report experiencing stigma, but few studies have explored this in detail. This mixed-methods study aimed to investigate factors that contribute to chronic pain stigma, the effects of stigma, and to explore the stigma experiences of people with chronic pain. Participants were 215 adults with chronic pain who completed questionnaires assessing chronic pain stigma, opioid use, mental health conditions, pain, depression, disability and social support, and 179 also answered open-ended questions about stigma experiences. Linear regression and path analysis showed that greater stigma was experienced by those who used more opioids, had a mental health condition, viewed their pain as organic, and were unemployed. Stigma was associated with greater disability, depression and lower social support. Qualitative results supported quantitative findings, with 3 themes: 1. "Faking It": Others disbelieve pain and attribute it to drug seeking, laziness, or mental health problems, 2. A spectrum of stigma: Experiences of stigma vary from none to widespread, and 3. "I hide it well": Concealing pain and avoiding stigmatizing situations lead to isolation & disability. This study demonstrates the negative influence of stigma and presents a novel integrated model of chronic pain stigma which may be used to develop interventions.
Learn More >Recent studies have shown that the incidence of chronic primary pain (CPP) including temporomandibular disorders (TMD) and fibromyalgia syndrome (FMS) often exhibit comorbidities. We recently reported that central sensitization and descending facilitation system contributed to the development of somatic pain hypersensitivity induced by orofacial inflammation combined with stress. The purpose of this study was to explore whether TMD caused by unilateral anterior crossbite (UAC) can induce somatic pain hypersensitivity, and whether the cholecystokinin (CCK) receptor-mediated descending facilitation system promotes hypersensitivity through neuron-glia cell cascade signaling. UAC evoked thermal and mechanical pain hypersensitivity of the hind paws from day 5 to 70 that peaked at week 4 post UAC. The expression levels of CCK1 receptors, IL-18 and IL-18 receptors (IL-18R) were significantly up-regulated in the L4-L5 spinal dorsal horn at 4 weeks post UAC. Intrathecal injection of CCK1 and IL-18 receptor antagonists blocked somatic pain hypersensitivity. IL-18 mainly co-localized with microglia, while IL-18R mainly co-localized with astrocytes and to a lesser extent with neurons. These findings indicate that the signaling transduction between neurons and glia at the spinal cord level contributes to the descending pain facilitation through CCK1 receptors during the development of the comorbidity of TMD and FMS. Perspective: CCK1 receptor-dependent descending facilitation may mediate central mechanisms underlying the development of widespread somatic pain via a reciprocal neuron-glial signaling cascade, providing novel therapeutic targets for the clinical treatment of TMD and FMS comorbidities.
Learn More >Mutations in the peroxisomal half-transporter ABCD1 cause X-linked adrenoleukodystrophy, resulting in elevated very long-chain fatty acids (VLCFA), progressive neurodegeneration and an associated pain syndrome that is poorly understood. In the nervous system of mice, we found ABCD1 expression to be highest in dorsal root ganglia (DRG), with satellite glial cells (SGCs) displaying higher expression than neurons. We subsequently examined sensory behavior and DRG pathophysiology in mice deficient in ABCD1 compared to wild-type mice. Beginning at 8 months of age, mice developed persistent mechanical allodynia. DRG had a greater number of IB4-positive nociceptive neurons expressing PIEZO2, the mechanosensitive ion channel. Blocking PIEZO2 partially rescued the mechanical allodynia. Beyond affecting neurons, ABCD1 deficiency impacted SGCs, as demonstrated by high levels of VLCFA, increased glial fibrillary acidic protein (GFAP), as well as genes disrupting neuron-SGC connectivity. These findings suggest that lack of the peroxisomal half-transporter ABCD1 leads to PIEZO2-mediated mechanical allodynia as well as SGC dysfunction. Given the known supportive role of SGCs to neurons, this elucidates a novel mechanism underlying pain in X-linked adrenoleukodystrophy.
Learn More >The development of a high-end cannabinoid-based therapy is the result of intense translational research, aiming to convert recent discoveries in the laboratory into better treatments for patients. Novel compounds and new regimes for drug treatment are emerging. Given that previously unreported signaling mechanisms for cannabinoids have been uncovered, clinical studies detailing their high therapeutic potential are mandatory. The advent of novel genomic, optogenetic, and viral tracing and imaging techniques will help to further detail therapeutically relevant functional and structural features. An evolutionarily highly conserved group of neuromodulatory lipids, their receptors, and anabolic and catabolic enzymes are involved in a remarkable variety of physiological and pathological processes and has been termed the endocannabinoid system (ECS). A large body of data has emerged in recent years, pointing to a crucial role of this system in the regulation of the behavioral domains of acquired fear, anxiety, and stress-coping. Besides neurons, also glia cells and components of the immune system can differentially fine-tune patterns of neuronal activity. Dysregulation of ECS signaling can lead to a lowering of stress resilience and increased incidence of psychiatric disorders. Chronic pain may be understood as a disease process evoked by fear-conditioned nociceptive input and appears as the dark side of neuronal plasticity. By taking a toll on every part of your life, this abnormal persistent memory of an aversive state can be more damaging than its initial experience. All strategies for the treatment of chronic pain conditions must consider stress-related comorbid conditions since cognitive factors such as beliefs, expectations, and prior experience (memory of pain) are key modulators of the perception of pain. The anxiolytic and anti-stress effects of medical cannabinoids can substantially modulate the efficacy and tolerability of therapeutic interventions and will help to pave the way to a successful multimodal therapy. Why some individuals are more susceptible to the effects of stress remains to be uncovered. The development of personalized prevention or treatment strategies for anxiety and depression related to chronic pain must also consider gender differences. An emotional basis of chronic pain opens a new horizon of opportunities for developing treatment strategies beyond the repeated sole use of acutely acting analgesics. A phase I trial to determine the pharmacokinetics, psychotropic effects, and safety profile of a novel nanoparticle-based cannabinoid spray for oromucosal delivery highlights a remarkable innovation in galenic technology and urges clinical studies further detailing the huge therapeutic potential of medical cannabis (Lorenzl et al.; this issue).
Learn More >Chronic pelvic pain (CPP) and infertility are the common characteristics of endometriosis. Macrophages and related inflammation play important roles in endometriosis pain. TRPV1 and TRPA1 form a heteromeric channel which is related to endometriosis pain. In the present study, the inflammation-mediated macrophage polarization along with TRPV1/TRPA1 heteromers in endometriosis was investigated and . Macrophage polarization and TRPV1/TRPA1 heteromers in endometriosis tissue of patients were assayed, and was further investigated in endometriosis mice by co-culturing macrophages derived from mice in different groups with human endometrium cells. Our results indicated that macrophage polarization, as CD86 and CD206 positive macrophages, were accompanied by TRPV1/TRPA1 heteromers in endometriosis tissues of patients with pain. Inflammatory factors in peritoneal lavage fluid and serum of mice were correlated with TRPV1/TRPA1 expression in endometriosis tissues of mice as well as macrophage polarization which tended to be consistent with TRPV1/TRPA1 heteromers in endometriosis tissue. Moreover, macrophage polarization in enterocoelia induced ectopic endometrial cells migration with the increase in TRPV1/TRPA1 heteromers. Our results suggest that endometriosis-induced celiac inflammation might mediate macrophage polarization along with the increase of TRPV1/TRPA1 heteromers, which may play a key role in endometriosis pain.
Learn More >Spinal cord stimulation (SCS) is a treatment for chronic neuropathic pain. It is based on the delivery of electric impulses to the spinal cord, traditionally in a regular square-wave pattern ("tonic" stimulation) and, more recently, in a rhythmic train-of-five "BurstDR" pattern. The safety of active SCS therapy in pregnancy is not established, and recommendations are based on limited casuistic evidence. We present in this study clinical data on a case series of six women treated with burst SCS during pregnancy. In addition, we present the ultrasonographic flow measurements of fetal and uteroplacental blood flow in a pregnant patient.
Learn More >Chronic musculoskeletal pain (CMP) is a significant burden for Persian Gulf War Veterans (GWV), yet the causes are poorly understood. Brain structure abnormalities are observed in GWV, however relationships with modifiable lifestyle factors such as physical activity (PA) are unknown. We evaluated gray matter volumes and associations with symptoms, PA, and sedentary time in GWV with and without CMP. Ninety-eight GWV (10 females) with CMP and 56 GWV (7 females) controls completed T1 weighted magnetic resonance imaging, pain and fatigue symptom questionnaires, and PA measurement via actigraphy. Regional gray matter volumes were analyzed using voxel-based morphometry and were compared across groups using analysis of covariance. Separate multiple linear regression models were used to test associations between PA intensities, sedentary time, symptoms, and gray matter volumes. Family-wise cluster error rates were used to control for multiple comparisons (α=0.05). GWV with CMP reported greater pain and fatigue symptoms, worse mood, and engaged in less moderate-to-vigorous PA and more sedentary time than healthy GWV (all <0.05). GWV with CMP had smaller gray matter volumes in the bilateral insula and larger volumes in the frontal pole (<0.05). Gray matter volumes in the left insula were associated with pain symptoms (r=0.26, -0.29; <0.05). No significant associations were observed for either PA or sedentary time (>0.05). GWV with CMP had smaller gray matter volumes within a critical brain region of the descending pain processing network and larger volumes within brain regions associated with pain sensation and affective processing which may reflect pain chronification.The pathophysiology of chronic pain in Gulf War Veterans is understudied and not well understood. In a large sample of Gulf War Veterans, we report Veterans with chronic musculoskeletal pain have smaller gray matter volumes in brain regions associated with pain regulation and larger volumes in regions associated with pain sensitivity compared to otherwise healthy Gulf War Veterans. Gray matter volumes in regions of pain regulation were significantly associated with pain symptoms and encompassed the observed group brain volume differences. These results are suggestive of deficient pain modulation that may contribute to pain chronification.
Learn More >There is evidence of altered corticolimbic circuitry in adults with chronic pain, but relatively little is known of functional brain mechanisms in adolescents with neuropathic pain (NeuP). Pediatric NeuP is etiologically and phenotypically different from NeuP in adults, highlighting the need for pediatric-focused research. The amygdala is a key limbic region with important roles in the emotional-affective dimension of pain and in pain modulation.
Learn More >Nociplastic pain arises from altered nociception despite no clear evidence of tissue or somatosensory system damage, and fibromyalgia syndrome can be highlighted as a prototype of this chronic pain subtype. Currently, there is a lack of effective treatments to alleviate both reflexive and nonreflexive pain responses associated with fibromyalgia condition, and suitable preclinical models are needed to assess new pharmacological strategies. In this context, although in recent years some remarkable animal models have been developed to mimic the main characteristics of human fibromyalgia, most of them show pain responses in the short term. Considering the chronicity of this condition, the present work aimed to develop two mouse models showing long-lasting reflexive and nonreflexive pain responses after several reserpine (RIM) or intramuscular acid saline solution (ASI) injections. To our knowledge, this is the first study showing that RIM6 and ASI mouse models show reflexive and nonreflexive responses up to 5-6 weeks, accompanied by either astro- or microgliosis in the spinal cord as pivotal physiopathology processes related to such condition development. In addition, acute treatment with pregabalin resulted in reflexive pain response alleviation in both the RIM6 and ASI models. Consequently, both may be considered suitable experimental models of fibromyalgia-like condition, especially RIM6.
Learn More >Neuropathic pain, a heterogeneous condition, affects 7%-10% of the general population. To date, efficacious and safe therapeutic approaches remain limited. Antisense oligonucleotide (ASO) therapy has opened the door to treat spinal muscular atrophy, with many ongoing clinical studies determining its therapeutic utility. ASO therapy for neuropathic pain and peripheral nerve disease requires efficient gene delivery and knockdown in both the dorsal root ganglion (DRG) and sciatic nerve, key tissues for pain signaling. We previously developed a new DNA/RNA heteroduplex oligonucleotide (HDO) technology that achieves highly efficient gene knockdown in the liver. Here, we demonstrated that intravenous injection of HDO, comprising an ASO and its complementary RNA conjugated to α-tocopherol, silences endogenous gene expression more than 2-fold in the DRG, and sciatic nerve with higher potency, efficacy, and broader distribution than ASO alone. Of note, we observed drastic target suppression in all sizes of neuronal DRG populations by hybridization. Our findings establish HDO delivery as an investigative and potentially therapeutic platform for neuropathic pain and peripheral nerve disease.
Learn More >Well-established efficacy of botulinum neurotoxin type A (BoNT/A) in aesthetic dermatology and neuromuscular hyperactivity disorders relies on canonical interruption of acetylcholine neurotransmission at the neuromuscular junction at the site of the injection. The mechanisms and the site of activity of BoNT/A in pain, on the other hand, remain elusive. Here, we explored analgesic activity of recombinant BoNT/A1 (rBoNT/A1; IPN10260) in a mouse model of inflammatory pain to investigate the potential role of peripheral sensory afferents in this activity. After confirming analgesic efficacy of rBoNT/A1 on CFA-induced mechanical hypersensitivity in C57Bl6J mice, we used GCaMP6s to perform calcium imaging in the ipsilateral dorsal root ganglion (DRG) neurons in rBoNT/A1 vs. vehicle-treated mice at baseline and following administration of a range of mechanical and thermal stimuli. Additionally, immunohisochemical studies were performed to detect cleaved SNAP25 in the skin, DRGs and the spinal cord. Injection of CFA resulted in reduced mechanical sensitivity threshold and increased calcium fluctuations in the DRG neurons. While rBoNT/A1 reduced mechanical hypersensitivity, calcium fluctuations in the DRG of rBoNT/A1- and vehicle-treated animals were similar. Cleaved SNAP25 was largely absent in the skin and the DRG but present in the lumbar spinal cord of rBoNT/A1-treated animals. Taken together, rBoNT/A1 ameliorates mechanical hypersensitivity related to inflammation, while the signal transmission from the peripheral sensory afferents to the DRG remained unchanged. This strengthens the possibility that spinal, rather than peripheral, mechanisms play a role in the mediation of analgesic efficacy of BoNT/A in inflammatory pain.
Learn More >Peripheral nerve block (PNB) under echo guidance may not prevent intrafascicular anesthetic injection-induced nerve injury. This study investigated whether unintended needle piercing alone, or the intrafascicular nerve injectant could induce neuropathy. 120 adult male Sprague-Dawley rats were divided into four groups: 1) group S, only the left sciatic nerve was exposed; 2) group InF-P, the left sciatic nerve was exposed and pierced with a 30 G needle; 3) group InF-S, left sciatic nerve was exposed and injected with saline (0.9% NaCl 30 µL); 4) group InF-R, left sciatic nerve was exposed and injected with 0.5% (5 mg/mL, 30 µL) ropivacaine. Behaviors of thermal and mechanical stimuli responses from hindpaws, sciatic nerve vascular permeability and tight junction protein expression, and macrophage infiltration were assessed. Pro-inflammatory cytokine expression and TIMP-1 and MMP-9 activation at the injection site and the swollen, and distal sites of the sciatic nerve were measured by cytokine array, western blotting, and immunofluorescence of POh14 and POD3. Intrafascicular saline and ropivacaine into the sciatic nerve, but not needle piercing alone, significantly induced mechanical allodynia that lasted for seven days. In addition, the prior groups increased vascular permeability and macrophage infiltration, especially in the swollen site of the sciatic nerve. Thermal hypersensitivity was induced and lasted for only 3 days after intrafascicular saline injection. Obvious upregulation of TIMP-1 and MMP-9 on POh6 and POh14 occurred regardless of intrafascicular injection or needle piercing. Compared to the needle piercing group, the ratio of MMP-9/TIMP-1 was significantly higher in the intrafascicular injectant groups at the injected and swollen sites of the sciatic nerve. Although no gross changes in the expressions of tight junction proteins (TJPs) claudin-5 and ZO-1, the TJPs turned to apparent fragmentation and fenestration-like degenerative change in swollen endothelial cells and thickened microvessels. Intrafascicular nerve injection is a distinct mechanism that induces neuropathy. It is likely that the InF nerve injection-induced neuropathy was largely due to dramatic, but transient, increases in enzymatic activities of MMP-9 and activating TIMP-1 in the operated nerves. The changes in enzymatic activities then contributed to certain levels of extracellular matrix degradation, which leads to increases in endoneurial vascular permeability.
Learn More >Pre-clinical studies demonstrate opposing effects of long-chain polyunsaturated fatty acid (PUFA) metabolites on inflammation and nociception. Omega-6 (n-6) PUFAs amplify both processes while omega-3 (n-3) PUFAs inhibit them. This cross-sectional study examined relationships between PUFAs in circulating erythrocytes and two chronic idiopathic pain conditions: temporomandibular disorder (TMD) and low back pain in a community-based sample of 503 U.S. adults. Presence or absence of TMD and low back pain, respectively, were determined by clinical examination and by responses to established screening questions. Liquid chromatography tandem mass spectrometry quantified PUFAs. In multivariable logistic regression models, a higher ratio of n-6/n-3 long-chain PUFAs was associated with greater odds of TMD (odds ratio ((OR)=1.75, 95% confidence limits (CL): 1.16, 2.64) and low back pain (OR=1.63, 95% CL: 1.07, 2.49). Higher levels of the pronociceptive n-6 long-chain arachidonic acid were associated with greater probability of both pain conditions for women, but not men. Higher levels of the antinociceptive long-chain n-3 PUFAs eicosapentaenoic and docosahexaenoic acids were associated with lower probability of both pain conditions for men, but not women. As systemic inflammation is not a hallmark of these conditions, PUFAs may influence idiopathic pain through other mechanisms.
Learn More >The Parent Risk Screening Measure (PRISM) rapidly assesses parent distress, psychosocial function and behaviors associated with child pain-related dysfunction in parents of youth with chronic pain. Recognizing that importance of parent pain-related cognitions and responses to pain during the acute pain period, the current study examined the utility of the PRISM in screening parents of youth with acute pain.
Learn More >Behavioral pain treatments may improve postsurgical analgesia and recovery; however, effective and scalable options are not widely available. This study tested a digital perioperative behavioral medicine intervention in orthopedic trauma surgery patients for feasibility and efficacy for reducing pain intensity, pain catastrophizing, and opioid cessation up to 3 months after surgery.
Learn More >People living with complex regional pain syndrome (CRPS), a rare chronic pain disorder, must become experts in their own self-management. Listening to the voice of the patient is often advocated in the pain literature. However, the patient's option is rarely asked for or considered by clinicians, even when they live with a condition that health professionals have rarely heard of.
Learn More >A previous European Headache Federation (EHF) guideline addressed the use of monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway to prevent migraine. Since then, randomized controlled trials (RCTs) and real-world evidence have expanded the evidence and knowledge for those treatments. Therefore, the EHF panel decided to provide an updated guideline on the use of those treatments.
Learn More >Nerve injury affecting the upper limb is a leading cause of lifelong disability. Damage to the nerves in the arm often causes weakness and somatosensory dysfunction ranging from numbness to pain. Previous studies show that combining brief bursts of electrical vagus nerve stimulation (VNS) with motor or tactile rehabilitation can restore forelimb function after median and ulnar nerve injury, which causes hyposensitivity of the ventral forelimb. Here, we sought to determine whether this approach would be similarly effective in a model of radial nerve injury that produces allodynia in the ventral forelimb. To test this, rats underwent complete transection of the radial nerve proximal to the elbow followed by tubular repair. In the first experiment, beginning ten weeks after injury, rats received six weeks of tactile rehabilitation, consisting of mechanical stimulation of either the dorsal or ventral region of the forepaw in the injured limb, with or without concurrent VNS. In a second experiment, a separate cohort of rats underwent six weeks of forelimb motor rehabilitative training with or without paired VNS. Contrary to findings in previous models of hyposensitivity, VNS therapy fails to improve recovery of either somatosensory or motor function in the forelimb after radial nerve injury. These findings describe initial evidence that pain may limit the efficacy of VNS therapy and thus highlight a characteristic that should be considered in future studies that seek to develop this intervention.
Learn More >Metformin is a well-tolerated antidiabetic drug and has recently been repurposed for numerous diseases, including pain. However, a higher dose of metformin is required for effective analgesia, which can potentiate its dose-dependent gastrointestinal side effects. Curcumin is a natural polyphenol and has beneficial therapeutic effects on pain. Curcumin has been used as an analgesic adjuvant with several analgesic drugs, allowing synergistic antinociceptive effects. Nevertheless, whether curcumin can exert synergistic analgesia with metformin is still unknown. In the present study, the nature of curcumin-metformin anti-inflammatory interaction was evaluated in in vitro using lipopolysaccharide-induced RAW 264.7 macrophage and BV-2 microglia cells. In both macrophage and microglia, curcumin effectively potentiates the anti-inflammatory effects of metformin, indicating potential synergistic effects in both peripheral and central pathways of pain. The nature of the interaction between curcumin and metformin was further recapitulated using a mouse model of formalin-induced pain. Coadministration of curcumin and metformin at a 1:1 fixed ratio of their ED doses significantly reduced the dose required to produce a 50% effect compared to the theoretically required dose in phase II of the formalin test with a combination index value of 0.24. Besides, the synergistic interaction does not appear to involve severe CNS side effects indicated by no motor alterations, no alterations in short-term and long-term locomotive behaviors, and the general well-being of mice. Our findings suggest that curcumin exerts synergistic anti-inflammation with metformin with no potential CNS adverse effects.
Learn More >The majority of people who have nonspecific chronic spinal pain (nCSP) report comorbid insomnia. However, in current treatment strategies for nCSP, insomnia is usually not addressed. Considering the bidirectional interaction between pain and sleep and its underlying psychophysiological mechanisms, insomnia may increase the risk of developing adverse physical and psychological health outcomes and should thus no longer be left untreated. As suggested by previous pilot studies, adding cognitive behavioral therapy for insomnia (CBT-I) to the contemporary evidence-based biopsychosocial physical therapy approach may also improve pain outcomes in nCSP. This manuscript aims to provide practical guidelines on hybrid physical therapy, including the combination of following components: (1) pain neuroscience education (eg, to reconceptualize pain) and cognition-targeted exercise therapy (eg, graded exposure to functional daily life movements), and (2) CBT-I (sleep psychoeducation, behavioral and cognitive therapy, correction of sleep hygiene, and relaxation therapy) can be deployed for the management of patients who have chronic spinal pain.
Learn More >In vitro models of the peripheral nervous system would benefit from further refinements to better support studies on neuropathies. In particular, the assessment of pain-related signals is still difficult in human cell cultures. Here, we harnessed induced pluripotent stem cells (iPSCs) to generate peripheral sensory neurons enriched in nociceptors. The objective was to generate a culture system with signaling endpoints suitable for pharmacological and toxicological studies. Neurons generated by conventional differentiation protocols expressed moderate levels of P2X3 purinergic receptors and only low levels of TRPV1 capsaicin receptors, when maturation time was kept to the upper practically useful limit of 6 weeks. As alternative approach, we generated cells with an inducible NGN1 transgene. Ectopic expression of this transcription factor during a defined time window of differentiation resulted in highly enriched nociceptor cultures, as determined by functional (P2X3 and TRPV1 receptors) and immunocytochemical phenotyping, complemented by extensive transcriptome profiling. Single cell recordings of Ca2+-indicator fluorescence from >9000 cells were used to establish the "fraction of reactive cells" in a stimulated population as experimental endpoint, that appeared robust, transparent and quantifiable. To provide an example of application to biomedical studies, functional consequences of prolonged exposure to the chemotherapeutic drug oxaliplatin were examined at non-cytotoxic concentrations. We found (i) neuronal (allodynia-like) hypersensitivity to otherwise non-activating mechanical stimulation that could be blocked by modulators of voltage-gated sodium channels; (ii) hyper-responsiveness to TRPV1 receptor stimulation. These findings and several other measured functional alterations indicate that the model is suitable for pharmacological and toxicological studies related to peripheral neuropathies.
Learn More >Monoclonal antibodies directed against the neuropeptide calcitonin gene-related peptide (CGRP) belong to a new generation of therapeutics that are effective in the prevention of migraine. CGRP, a potent vasodilator, is strongly implicated in the pathophysiology of migraine, but its role remains to be fully elucidated. The hemisected rat head preparation and laser Doppler flowmetry were used to examine the effects on CGRP release from the dura mater and meningeal blood flow of the subcutaneously injected anti-CGRP monoclonal antibody fremanezumab at 30 mg/kg, when compared to an isotype control antibody. Some rats were administered glycerol trinitrate (GTN) intraperitoneally to produce a migraine-like sensitized state. When compared to the control antibody, the fremanezumab injection was followed by reduced basal and capsaicin-evoked CGRP release from day 3 up to 30 days. The difference was enhanced after 4 h of GTN application. The samples from the female rats showed a higher CGRP release compared to that of the males. The increases in meningeal blood flow induced by acrolein (100 µM) and capsaicin (100 nM) were reduced 13-20 days after the fremanezumab injection, and the direct vasoconstrictor effect of high capsaicin (10 µM) was intensified. In conclusion, fremanezumab lowers the CGRP release and lasts up to four weeks, thereby lowering the CGRP-dependent meningeal blood flow. The antibody may not only prevent the released CGRP from binding but may also influence the CGRP release stimulated by noxious agents relevant for the generation of migraine pain.
Learn More >Sigma receptors modulate nociception, offering a potential therapeutic target to treat pain, but relatively little is known regarding the role of sigma-2 receptors (S2R) in nociception. The purpose of this study was to investigate the in vivo analgesic and anti-allodynic activity and liabilities of a novel S2R selective ligand, 1-[4-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)butyl]-3-methyl-1,3-dihydro-1,3-benzimidazol-2-one (CM-398). The inhibition of thermal, induced chemical, or inflammatory pain as well as the allodynia resulting from chronic nerve constriction injury (CCI) model of neuropathic pain were assessed in male mice. CM-398 dose-dependently (10-45 mg/kg i.p.) reduced mechanical allodynia in the CCI neuropathic pain model, equivalent at the higher dose to the effect of the control analgesic gabapentin (50 mg/kg i.p.). Likewise, pretreatment (i.p.) with CM-398 dose-dependently produced antinociception in the acetic acid writhing test (ED (and 95% C.I.) = 14.7 (10.6-20) mg/kg, i.p.) and the formalin assay (ED (and 95% C.I.) = 0.86 (0.44-1.81) mg/kg, i.p.) but was without effect in the 55 °C warm-water tail-withdrawal assay. A high dose of CM-398 (45 mg/kg, i.p.) exhibited modest locomotor impairment in a rotarod assay and conditioned place aversion, potentially complicating the interpretation of nociceptive testing. However, in an operant pain model resistant to these confounds, mice experiencing CCI and treated with CM-398 demonstrated robust conditioned place preference. Overall, these results demonstrate the S2R selective antagonist CM-398 produces antinociception and anti-allodynia with fewer liabilities than established therapeutics, adding to emerging data suggesting possible mediation of nociception by S2R, and the development of S2R ligands as potential treatments for chronic pain.
Learn More >The aim was to examine the responsiveness, presence of floor or ceiling effects, and minimal clinically important differences (MCIDs) for 2 new measures of pain-related catastrophizing and self-efficacy in individuals with chronic low back pain.
Learn More >COVID-19 abruptly halted in-person clinical care and research requiring a shift to virtual assessment and treatment. This unexpected transition of a 2-arm randomized controlled trial (RCT) examining interdisciplinary graded exposure treatment (GET Living) compared with multidisciplinary pain management for youth with chronic pain provided an opportunity to implement the first remotely delivered exposure treatment and remotely delivered biomechanical assessment for pediatric chronic pain. Here we describe these new approaches and provide lessons learned to inform future efforts in digital health care.
Learn More >The paucity of objective and reliable measurements of pain-like behaviors has impeded the translatability of mouse models of postsurgical pain. The advanced dynamic weight-bearing (DWB) system enables evaluation of spontaneous pain-like behaviors in pain models. This study investigated the suitability and efficiency of the DWB system for assessing spontaneous pain-like behaviors and analgesic therapies in murine models of postsurgical pain.
Learn More >Cyclooxygenase (COX) enzymes comprise COX-1 and COX-2 isoforms and are responsible for prostaglandin production. Prostaglandins have critical roles in the inflammation pathway and must be controlled by administration of selective nonsteroidal anti-inflammatory drugs (NSAIDs). Selective COX-2 inhibitors have been among the most used NSAIDs during the ongoing coronavirus 2019 pandemic because they reduce pain and protect against inflammation-related diseases. In this framework, the mechanism of action of both COX isoforms (particularly COX-2) as inflammation mediators must be reviewed. Moreover, proinflammatory cytokines such as tumor necrosis factor-α and interleukin (IL)-6, IL-1β, and IL-8 must be highlighted due to their major participation in upregulation of the inflammatory reaction. Structural and functional analyses of selective COX-2 inhibitors within the active-site cavity of COXs could enable introduction of lead structures with higher selectivity and potency against inflammation with fewer adverse effects. This review focuses on the biological activity of recently discovered synthetic COX-2, dual COX-2/lipoxygenase, and COX-2/soluble epoxide hydrolase hybrid inhibitors based primarily on the active motifs of related US Food and Drug Administration-approved drugs. These new agents could provide several advantages with regard to anti-inflammatory activity, gastrointestinal protection, and a safer profile compared with those of the NSAIDs celecoxib, valdecoxib, and rofecoxib.
Learn More >In 2016, the Centers for Disease Control and Prevention (CDC) released the evidence-based Guideline for Prescribing Opioids for Chronic Pain. How the release of this guideline coincided with changes in nonopioid pain medication prescribing rates remains unknown.
Learn More >Harris (1999) proposed that pain can arise in the absence of tissue damage because changes in the cortical representation of the painful body part lead to incongruences between motor intention and sensory feedback. This idea, subsequently termed the sensorimotor theory of pain, has formed the basis for novel treatments for pathological pain. Here we review the evidence that people with pathological pain have changes to processes contributing to sensorimotor function: motor function, sensory feedback, cognitive representations of the body and its surrounding space, multisensory processing, and sensorimotor integration. Changes to sensorimotor processing are most evident in the form of motor deficits, sensory changes, and body representations distortions, and for Complex Regional Pain Syndrome (CRPS), fibromyalgia, and low back pain. Many sensorimotor changes are related to cortical processing, pain, and other clinical characteristics. However, there is very limited evidence that changes in sensorimotor processing actually lead to pain. We therefore propose that the theory is more appropriate for understanding why pain persists rather than how it arises.
Learn More >To describe, through a literature review, the results and benefits of oral and topical probiotics for adult patients with atopic dermatitis.
Learn More >OnabotulinumtoxinA has been widely used for control of chronic migraine. The aim of the current study was to evaluate the efficacy of different doses of the onabotulinumtoxinA therapy in patients with chronic migraine.
Learn More >Pruritus is prevalent in psoriasis but still many features of pruritus, its response to therapy and its burden in psoriasis remain to be better characterized.
Learn More >Although insomnia and migraine are often comorbid, the genetic association between insomnia and migraine remains unclear. This study aimed to identify susceptibility loci associated with insomnia and migraine comorbidity.
Learn More >The International Headache Society has been offering multiple award opportunities for young researchers and clinicians for many years, with the aim of supporting the development of careers in headache science and medicine.
Learn More >Neuropathic pain is a debilitating symptom reported by patients presenting with postherpetic neuralgia (PHN). Efforts to alleviate this pain have been projected to lie in individualization of pharmacological treatment through pain phenotyping and subsequent investigations into the genetic basis of postherpetic neuralgia therapy. Understanding the various mechanisms related to these phenotypes can aid in improvement of available treatment options and discovery of new ones. Knowledge and application of genetic variations in postherpetic neuralgia – structural proteins and genes can aid in ascertaining risk, susceptibility to, severity of and protection from postherpetic neuralgia. This review summarizes the most recent information that has been published on phenotypes and genotypes with possible clinical applications and directions for future research.
Learn More >Cannabis policy liberalization has increased cannabis availability for medical or recreational purposes. Up-to-date trends in medical cannabis licensure can inform clinical policy and care.
Learn More >Atopic dermatitis is a prevalent, inflammatory skin disease that presents with an eczematous, itchy rash. As of late, there have been many emerging monoclonal antibody inhibitor and small molecule therapies that have changed the course of eczema treatment. One of the treatments in the pipeline for atopic dermatitis is interleukin 13 monoclonal antibody inhibitor, lebrikizumab. As interleukin 13 has been identified as a pro-inflammatory cytokine in the immunological cascade of eczema, it is thought that lebrikizumab can be a great treatment choice for patients with atopic dermatitis. Lebrikizumab is currently being investigated in several studies. Thus far, lebrikizumab for the treatment of eczema has been found to be efficacious; in particular, a rapid response of pruritus improvement has been demonstrated in as early as 2 days. Additionally, it is well tolerated and has an acceptable safety profile, with reports suggesting that are decreased risks of infection when compared to dupilumab. In this review, we aim to summarize the current understanding of lebrikizumab in terms of the mechanism of action, preclinical pharmacology, pharmacokinetics and metabolism, efficacy and safety, and drug indications.
Learn More >Urinary tract infections (UTIs) can evoke a rapid host immune response leading to bladder inflammation and epithelial damage. Neuroimmune interactions are critical for regulating immune function in mucosal tissues. Yet the role of nociceptor neurons in bladder host defense has not been well defined. This study aimed to explore the interaction between nociceptor neurons and bladder immune system during UTIs.
Learn More >To investigate the long-term effects of motor cortex stimulation (MCS) on central poststroke pain (CPSP) in patients with thalamic and extrathalamic stroke.
Learn More >Current German and European guidelines suggest migraine patients undertake a treatment break after 9 to 12 months of treatment with CGRP (pathway) monoclonal antibodies.
Learn More >Spontaneous intracranial hypotension (SIH), which is often caused by a spinal cerebrospinal fluid leak, is an important cause of disabling headaches. Many patients report devastating changes in their quality of life because of their symptoms. This study aimed to evaluate the impact of SIH on patients' social/ working life and health-related quality of life (HRQoL).
Learn More >An increasing number of studies have suggested that the important role of vasoactive peptides, such as pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38) and calcitonin gene-related peptide (CGRP), in the pathophysiology of migraine seems undeniable in adults, but studies in pediatric migraine patients remain scarce. We prospectively investigated CGRP and PACAP-38 plasma levels in children with migraine during ictal and interictal periods and compared the results between migraine patients with aura and without aura. We were the first to explore the diagnostic value of a combination of CGRP and PACAP-38.
Learn More >Determine the impact of 24-week risankizumab (RZB) versus placebo (PBO) on patient-reported outcomes (PROs) in patients with psoriatic arthritis (PsA) and inadequate response to one or two biologics (Bio-IR) and/or ≥1 conventional synthetic disease-modifying antirheumatic drug (csDMARD-IR).
Learn More >The human gut microbiome can be altered with probiotics, prebiotics, synbiotics, and anti-inflammatory foods and spices as part of an evidence-based strategy that targets inflammation and pain in common orthopedic conditions. Implementing these strategies avoids adverse effects associated with nonsteroidal anti-inflammatory drugs and minimizes the potential for opioid use. This review focuses exclusively on human trials studying the effects of gut microbiome alterations to address pain and inflammatory markers in common orthopedic conditions: osteoarthritis, rheumatoid arthritis, fractures/osteoporosis, and bone pain associated with chemotherapy. Individualized supplementation strategies can be further explored with the information in this review. [. 20XX;XX(X):xx-xx.].
Learn More >Microglia, the dynamic innate immune cells of the central nervous system, become activated in epilepsy. The process of microglial activation in epilepsy results in the creation of an inflammatory environment around the site of seizure onset, which contributes to the epileptogenic process and epilepsy progression. Cannabidiol (CBD) has been effective for use as an adjunctive treatment for two severe pediatric seizure disorders. Newly recognized as an Food and Drug Administration (FDA)-approved drug treatment in epilepsy, it has gained in popularity primarily for pain management. Although CBD is readily available in stores and online retailers, its mechanism of action and specifically its effects on microglia and their functions are yet fully understood. In this study, we examine the effects of commercially available CBD on microglia inflammatory activation and neurogenic response, in the presence and absence of seizures. We use systemic administration of kainate to elicit seizures in mice, which are assessed behaviorally. Artisanal CBD is given in different modes of administration and timing to dissect its effect on seizure intensity, microglial activation and aberrant seizure-related neurogenesis. CBD significantly dampens microglial migration and accumulation to the hippocampus. While long term artisanal CBD use does not prevent or lessen seizure severity, CBD is a promising adjunctive partner for its ability to depress epileptogenic processes. These studies indicate that artisanal CBD is beneficial as it both decreases inflammation in the CNS and reduces the number of ectopic neurons deposited in the hippocampal area post seizure.
Learn More >The P2X4 receptor (P2X4R) can be upregulated after nerve injury, and its mediated spinal microglial activation makes a critical contribution to pathologically enhanced pain processing in the dorsal horn. Although some studies have partly clarified the mechanism underlying altered P2X4R expression, the specific mechanism is not well understood. MicroRNAs (miRNAs) are small noncoding RNAs which control gene expression by binding with their target mRNAs. Thus, in the present study, we investigated whether miRNA is involved in the pathogenesis of neuropathic pain by regulating P2X4R. Our results showed that P2X4R was upregulated in the spinal dorsal horn of mice following spared nerve injury (SNI), and 69 miRNAs (46 upregulated and 23 downregulated miRNAs) were differentially expressed (fold change > 2.0, P < 0.05). P2X4R was found to be a major target of miR-106b-5p (one of the downregulated miRNAs) using bioinformatics technology; quantitative real-time PCR analysis confirmed the change in expression of miR-106b-5p, and dual-luciferase reporter assays confirmed the correlation between them. Fluorescence in situ hybridization was used to show cell co-localization of P2X4R and miR-106b-5p in the spinal dorsal horn. Transfection with miR-106b-5p mimic into BV2 cells reversed the upregulation of P2X4R induced by lipopolysaccharide (LPS). Moreover, miR-106b-5p overexpression significantly attenuated neuropathic pain induced by SNI, with decreased expression of P2X4R mRNA and protein in the spinal dorsal horn; intrathecal miR-106b-5p antagomir induced pain behaviors, and increased expression of P2X4R in the spinal dorsal horn of naïve mice. These data suggest that miR-106b-5p can serve as an important regulator of neuropathic pain development by targeting P2X4R.
Learn More >Photobiomodulation (PBM) is reported in many studies to produce dental analgesia without producing thermal damage to tissues. This systematic review aims to assess in vivo studies to support the statement that PBM can produce dental analgesia.
Learn More >Although there has been increasing interest in the role of systemic cytokines in chronic spinal pain (CSP), the evidence on their potential contribution is still unclear. Therefore, the current study systematically reviewed the evidence on systemic cytokine level differences between people with CSP compared to healthy controls (HCs) and the potential associations with pain severity.
Learn More >Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is more than merely a respiratory disease, as it also presents with various neurological symptoms. SARS-CoV-2 may infect the central nervous system (CNS) and thus is neurotropic. However, the pathophysiological mechanism of coronavirus disease 2019 (COVID-19)-associated neuropathy remains unclear. Many studies have reported that SARS-CoV-2 enters the CNS through the hematogenous and neuronal routes, as well as through the main host neurological immune responses and cells involved in these responses. The neurological immune responses to COVID-19 and potential mechanisms of the extensive neuroinflammation induced by SARS-CoV-2 have been investigated. Although CNS infection with SARS-CoV-2 was shown to lead to neuronal impairment, certain aspects of this mechanism remain controversial and require further analysis. In this review, we discussed the pathway and mechanisms of SARS-CoV-2 invasion in the CNS, and associated clinical manifestations, such as anosmia, headache, and hyposmia. Moreover, the mechanism of neurological damage caused by SARS-CoV-2 may provide potential treatment methods for patients presenting with SARS-CoV-2-associated neuropathy.
Learn More >Refractory migraine is associated with low quality of life and great socioeconomic burden. Despite high need for effective, tolerable preventive therapies, there has been little research on potential therapeutic options. Monoclonal antibodies (mAbs) against Calcitonin Gene-Related Peptide (CGRP) are the first preventive therapeutic approach for migraine based on the underlying pathophysiology.
Learn More >Patients use medical cannabis for a wide array of illnesses and symptoms, and many substitute cannabis for pharmaceuticals. This substitution often occurs without physician oversight, raising patient safety concerns. We aimed to characterize substitution and doctor-patient communication patterns in Canada, where there is a mature market and national regulatory system for medical cannabis.
Learn More >Prostaglandin E (PGE) is an important inflammatory mediator for the initiation and maintenance of inflammatory and neuropathic pain. The acute effect of PGE on sodium currents has been widely characterized in sensory neurons; however, the prolonged effect of PGE remains to be determined. Here, we performed patch clamp recordings to evaluate the acute and prolonged effects of PGE on sodium currents in trigeminal ganglionic (TG) neurons from male Sprague-Dawley rats. We found that 24-h treatment with PGE (10 μM) increased the peak sodium current density by approximately 31% in a voltage-dependent manner and shifted the activation curve in a hyperpolarized direction but did not affect steady-state inactivation. Furthermore, treatment with PGE for 24 h increased the current density of tetrodotoxin-sensitive (TTX-S) but not TTX-resistant (TTX-R) channels significantly. Interestingly, TTX-S current was increased mostly in medium-sized, but not in small-sized, neurons after 24 h of treatment with PGE. Moreover, the mRNA level of TTX-S Nav1.1 but not TTX-R Nav1.8 or Nav1.9 was significantly increased after 24 h of treatment with PGE In contrast, 5-min treatment with PGE (10 μM) increased the peak sodium current density by approximately 29% and increased TTX-R sodium currents, but not TTX-S currents, in both small- and medium-sized TG neurons. Our results presented a differential regulation of subtypes of sodium channels by acute and prolonged treatments of PGE, which may help to better understand the mechanism of PGE-mediated orofacial pain development.
Learn More >Transient receptor potential canonical 5 (TRPC5) is a polymodal, calcium-permeable, nonselective ion channel that is expressed in the brain and 75 % of human sensory neurons. Its pharmacological or genetic inhibition leads to the relief of neuropathic and inflammatory pain. The clinically approved drug duloxetine is superior to other serotonin and norepinephrine reuptake inhibitors at managing painful neuropathies, but it is not known why. Here we ask whether the TRPC5 receptor is modulated by duloxetine and may contribute to its analgesic effect. Electrophysiological measurements of heterologously expressed human TRPC5 in HEK293T cells were performed to evaluate the effect of duloxetine. The interaction site was identified by molecular docking and molecular dynamics simulations in combination with point mutagenesis. We found that duloxetine inhibits TRPC5 in a concentration-dependent manner with a high potency (IC = 0.54 ± 0.03 µM). Our data suggest that duloxetine binds into a voltage sensor-like domain. For the interaction, Glu exhibited particular importance due to putative hydrogen bond formation. Duloxetine effectively inhibits TRPC5 currents induced by cooling, voltage, direct agonists and by the stimulation of the PLC pathway. The finding that this TRPC5 inhibitor is widely used and well tolerated provides a scaffold for new pain treatment strategies.
Learn More >Maximal exercise testing is considered the gold standard to assess V̇Omax. However, maximal exercise testing was previously deemed unfeasible and unsafe in chronic low back pain (CLBP) patients. Consequently, most previous studies on aerobic capacity and functioning in patients with CLBP were performed with submaximal testing protocols. A recent study demonstrated the safety, feasibility and tolerance of maximal exercise testing in patients with CLBP. Therefore, the relation between aerobic capacity and functioning should be reevaluated. This cross-sectional study aims to determine the relationship between maximal aerobic capacity and four measures of functioning: lifting capacity, work ability, pain-related disability and physical functioning in patients with CLBP.
Learn More >Our psychological state greatly influences our perception of sensations and pain, both external and visceral, and is expected to contribute to individual pain sensitivity as well as chronic pain conditions. This investigation sought to examine the integration of cognitive and emotional communication across brainstem regions involved in pain modulation by comparing data from previous functional MRI studies of affective modulation of pain. Data were included from previous studies of music analgesia (Music), mood modulation of pain (Mood), and individual differences in pain (ID), totaling 43 healthy women and 8 healthy men. The Music and Mood studies were combined into an affective modulation group consisting of runs with music and positive-valenced emotional images plus concurrent presentation of pain, and a control group of runs with no-music, and neutral-valenced images with concurrent presentation of pain. The ID group was used as an independent control. Ratings of pain intensity were collected for each run and were analyzed in relation to the functional data. Differences in functional connectivity were identified across conditions in relation to emotional, autonomic, and pain processing in periods before, during and after periods of noxious stimulation. These differences may help to explain healthy pain processes and the cognitive and emotional appraisal of predictable noxious stimuli, in support of the Fields' Decision Hypothesis. This study provides a baseline for current and future investigation of expanded neural networks, particularly within higher limbic and cortical structures. The results obtained by combining data across studies with different methods of pain modulation provide further evidence of the neural signaling underlying the complex nature of pain.
Learn More >Scrambler therapy (ST) is a noninvasive method of transcutaneous neuromodulation that has 510(K) clearance from the United States Food and Drug Administration for treating acute pain, postoperative pain, and intractable chronic pain. Since its inception, ST has been used to treat many chronic pain syndromes in a variety of patient populations. We synthesized the available literature for ST to delineate its overall evidence basis.
Learn More >Opioids administered into the spinal space by intrathecal or epidural routes can provide potent and prolonged selective analgesia. Compared to the systemic administration of opioids, spinal administration can bring about analgesia with fewer central and systemic adverse effects. For the past 40 years, spinal opioid analgesia has achieved great popularity in various fields of pain treatment. The aim of this work is to identify clinical studies that initiated the use of spinal opioids for the treatment of pain. To determine the historical role of each of the review's studies we used the combination of two factors: the study priority in terms of the time of its publication and the degree of its acknowl-edgement in the form of citation impact. The date of publication was regarded as the primary factor, but only if the count of citations indicated a sufficient acknowledgement by the other authors. The citation impact was assessed as the initial citation count – for period of five years after the year of article publication – and the total count. The selection of studies most important for the introduction of spinal opioids to clinical practice was based on two factors – the study priority in terms of the time of its publication and the degree of acknowledgement in the form of citation impact. The date of publication was regarded as the primary factor, but only if the citation count was indicative of sufficient acknowledgement by other authors. Analysis of the related data shows that the clinical studies initiating the use of spinal opioids for the treatment of pain belong to two groups of authors – Wang et al. and Behar et al. Both studies were published in 1979 and described delivery of morphine into the spinal space, although the techniques of administration were different: Wang et al. injected morphine intrathecally, Behar et al. administered morphine epidurally. The response to these studies was overwhelming — close to a dozen reports on this topic were published in 1979 and more than a hundred – in 1980-1981. The total citation response to the Wang et al. article reached 699, and that to Behar et al. – 518. Two earlier records (1900-1901) of the use of intrathecal morphine, by Nicolae Racoviceanu-Pitesti and Otojiro Kitagawa, found no following in medical literature for more than three quarters of a century.
Learn More >Fibromyalgia syndrome (FMS) is a chronic pain condition associated with a significant reduction in health-related quality of life (HRQoL). This study compared the different components of HRQoL between FMS and rheumatoid arthritis (RA) patients, and evaluated the relationships between HRQoL and clinical and emotional factors in FMS and RA patients.
Learn More >As a technique that can guide brain plasticity, non-invasive brain stimulation (NIBS) has the potential to improve the treatment of chronic pain (CP) because it can interfere with ongoing brain neural activity to regulate specific neural networks related to pain management. Treatments of CP with various forms of NIBS, such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), using new parameters of stimulation have achieved encouraging results. Evidence of moderate quality indicates that high-frequency rTMS of the primary motor cortex has a clear effect on neuropathic pain (NP) and fibromyalgia. However, evidence on its effectiveness regarding pain relief in other CP conditions is conflicting. Concerning tDCS, evidence of low quality supports its benefit for CP treatment. However, evidence suggesting that it exerts a small treatment effect on NP and headaches is also conflicting. In this paper, we describe the underlying principles behind these commonly used stimulation techniques; and summarize the results of randomized controlled trials, systematic reviews, and meta-analyses. Future research should focus on a better evaluation of the short-term and long-term effectiveness of all NIBS techniques and whether they decrease healthcare use, as well as on the refinement of selection criteria.
Learn More >Interactions between female patients with chronic pain and their medical providers in which providers question or contest the "realness" or nature of their illness experience (e.g. "It's all in your head") have been reported extensively in the extant qualitative literature, particularly for poorly understood ("contested") chronic pain syndromes. Many terms have been offered to describe this talk (e.g. invalidating, dismissive), resulting in conceptual fragmentation and isolated silos of research which together report about one communicative phenomenon. To rectify this fragmentation, the present study offers a meta-synthesis which explores, analyzes, and integrates the findings of 82 qualitative interview studies representing the patient-provider communication experiences of 2,434 female patients living with one or more of 10 chronic overlapping pain conditions (COPCs). COPCs are costly, gendered, and poorly understood. From the meta-synthesis, three key concepts are identified: (1) Functions of disenfranchising talk: Discrediting, silencing, and stereotyping; (2) Effects of disenfranchising talk: Harmed agency, credibility; access to care, support, and resources; and perception of patient-provider relationship; and (3) Responses to disenfranchising talk: Submission, critique, and resistance. Findings confirm the centrality of gender in the experience of disenfranchising talk, underscore the need to adopt an intersectional approach to the study of this talk along additional axes of race and class, and offer heuristic value toward conceptually unifying research about female COPC patients' experiences of disenfranchising talk from providers.
Learn More >Experimental studies on the pathogenetic process of paclitaxel-induced neuropathic pain (PINP) have been initially carried out, but PINP still has no effective therapy. Recently reported studies have highlighted the involvement of glutamate receptors and neuroinflammation in peripheral and central nociceptive transmission in PINP. Artesunate is a first-line antimalarial drug with established efficacy in alleviating pain in a variety of pathologies. The current work assessed whether artesunate inhibits PINP by modulating metabotropic glutamate receptor 5 (mGluR5) and neuroinflammation in mice. The anti-hyperalgesic effect of artesunate was verified by assessing mechanical frequency and thermal latency in the paw withdrawal test as well as spontaneous pain. The expression levels of mGluR5, pain-related receptors and neuroinflammatory markers in dorsal root ganglion (DRG) were examined. In addition, treatment with CHPG and 2-methyl-6-(phenyl ethynyl) pyridine (MPEP) (mGluR5 agonist and antagonist, respectively) was performed to determine mGluR5's role in the anti-hyperalgesic properties of artesunate. We demonstrated artesunate prevented PINP in a dose-dependent manner, while exerting a clear anti-hyperalgesic effect on already existing PINP. Artesunate normalized paclitaxel-related expression changes in DRG mGluR5, NR1, and GluA2, as well as six paclitaxel related neuroinflammation markers. Intrathecal application of MPEP treated PINP by reversing NR1 and GluA2 expression changes but had no effects on chemokines and inflammatory factors. Furthermore, artesunate treatment reversed acute pain following CHPG application. In conclusion, this study revealed that artesunate alleviates paclitaxel-induced hyperalgesia and spontaneous pain by decreasing DRG mGluR5 expression and neuroinflammation in the mouse model of PINP.
Learn More >The addition of morphine to neuraxial anaesthesia leads to improved postoperative analgesia and lower opioid consumption, but is often accompanied by pruritus. Studies on preventing or treating pruritus show contradictory results. Our objective was to identify effective drugs for the prevention or treatment of pruritus by a scoping review of clinical trials. A systematic literature search was conducted in PubMed, Embase and Web of Science. We identified clinical trials investigating the prevention or treatment of neuraxial morphine-induced pruritus in adults. Systematic reviews and meta-analyses were screened for eligible studies. One-hundred-and-four articles were included covering 13 pharmacological groups. We conclude that dopamine antagonists, µ-opioid agonist/antagonists and neuraxial or orally administered µ-opioid antagonists prevent pruritus caused by neuraxial morphine regardless of the timing of administration. In the reviewed literature, 5HT3-antagonists prevent neuraxial morphine-induced pruritus when administered before morphine administration. For the treatment of neuraxial morphine-induced pruritus, only nalbuphine appears to be consistently effective. More research is needed to find the most effective doses and the optimal timing of the effective medication.
Learn More >Functional pain syndromes (FPS) occur in the absence of identifiable tissue injury or noxious events and include conditions such as migraine, fibromyalgia, and others. Stressors are very common triggers of pain attacks in various FPS conditions. It has been recently demonstrated that kappa opioid receptors (KOR) in the central nucleus of amygdala (CeA) contribute to FPS conditions, but underlying mechanisms remain unclear. The CeA is rich in KOR and encompasses major output pathways involving extra-amygdalar projections of corticotropin releasing factor (CRF) expressing neurons. Here we tested the hypothesis that KOR blockade in the CeA in a rat model of FPS reduces pain-like and nocifensive behaviors by restoring inhibition of CeA-CRF neurons. Intra-CeA administration of a KOR antagonist (nor-BNI) decreased mechanical hypersensitivity and affective and anxiety-like behaviors in a stress-induced FPS model. In systems electrophysiology experiments in anesthetized rats, intra-CeA application of nor-BNI reduced spontaneous firing and responsiveness of CeA neurons to peripheral stimulation. In brain slice whole-cell patch-clamp recordings, nor-BNI increased feedforward inhibitory transmission evoked by optogenetic and electrical stimulation of parabrachial afferents, but had no effect on monosynaptic excitatory transmission. Nor-BNI decreased frequency, but not amplitude, of spontaneous inhibitory synaptic currents, suggesting a presynaptic action. Blocking KOR receptors in stress-induced FPS conditions may therefore represent a novel therapeutic strategy.
Learn More >eHealth refers to health services and health information delivered or enhanced through the internet and related technologies. The number of eHealth interventions for chronic pain self-management is increasing. However, little evidence has been found for the overall efficacy of these interventions for older adults. The aim of the current study was to use a Collective Intelligence approach to identify the barriers and specific user needs of middle-aged and older adults using eHealth for chronic pain self-management.
Learn More >Cervicogenic headache (CEH) is a secondary headache caused by lesions of the cervical spine and surrounding soft tissues. Cervical muscle dysfunction may be related to the onset of CEH. However, whether cervical muscle stiffness changes in patients with CEH has not been well studied. The purpose of this study was to explore changes in superficial cervical extensor muscle stiffness in patients with CEH using shear wave elastography (SWE).
Learn More >The high incidence of treatment-resistant pain calls for the urgent preclinical translation of new analgesics. Understanding the behavioral readout of pain in animals is crucial for efficacy evaluation when developing novel analgesics. Mas-related G protein-coupled receptor D-positive (Mrgprd) and transient receptor potential vanilloid 1-positive (TRPV1) sensory neurons are two major non-overlapping subpopulations of C-fiber nociceptors. Their activation has been reported to provoke diverse nocifensive behaviors. However, what kind of behavior reliably represents subjectively conscious pain perception needs to be revisited. Here, we generated transgenic mice in which Mrgprd or TRPV1 sensory neurons specifically express channelrhodopsin-2 (ChR2). Under physiological conditions, optogenetic activation of hindpaw Mrgprd afferents evoked reflexive behaviors (lifting, etc.), but failed to produce aversion. In contrast, TRPV1 afferents activation evoked marked reflexive behaviors and affective responses (licking, etc.), as well as robust aversion. Under neuropathic pain conditions induced by spared nerve injury (SNI), affective behaviors and avoidance can be elicited by Mrgprd afferents excitation. Mechanistically, spinal cord-lateral parabrachial nucleus (lPBN) projecting neurons in superficial layers (lamina I-II ) were activated by TRPV1 nociceptors in naïve conditions or by Mrgprd nociceptors after SNI, whereas only deep spinal cord neurons were activated by Mrgprd nociceptors in naïve conditions. Moreover, the excitatory inputs from Mrgprd afferents to neurons within inner lamina II (II ) are partially gated under normal conditions. Altogether, we conclude that optogenetic activation of the adult Mrgprd nociceptors drives non-pain-like reflexive behaviors the deep spinal cord pathway under physiological conditions and drives pain-like affective behaviors superficial spinal cord pathway under pathological conditions. The distinct spinal pathway transmitting different forms of nocifensive behaviors provides different therapeutic targets. Moreover, this study appeals to the rational evaluation of preclinical analgesic efficacy by using comprehensive and suitable behavioral assays, as well as by assessing neural activity in the two distinct pathways.
Learn More >Psoriasis is an immune-mediated protracted ailment that perturbs about 100 million people globally. Anti-interleukin (IL)-23 agents have a distinctive status of safety and clinical efficacy. Anti-IL-23 operatives have demonstrated therapeutic prominences in cases of psoriasis in preceding global research. However, arrays of adverse events have been associated with the anti-IL-23 agents in the remedies of psoriasis. This systematic review aimed to assess the adverse developments of anti-IL-23 operatives for patients with psoriasis determined in phase III trials.
Learn More >Dupilumab ameliorates the signs and symptoms of atopic dermatitis (AD) and improves the patient's quality of life. Multiple-dose regimens of dupilumab have been applied by clinicians, but the efficacy of some regimens remains unclear.
Learn More >The adaption of brain region is fundamental to the development and maintenance of nervous system disorders. The prelimbic cortex (PrL) participates in the affective components of the pain sensation. However, whether and how the adaptation of PrL contributes to the comorbidity of neuropathic pain and depression are unknown.
Learn More >In the spinal cord stimulation (SCS) and dorsal root ganglion stimulation (DRG-S) literature, the typical primary outcome measure includes pain relief, whether numeric rating scale changes or percentage pain relief, and functional outcomes and patient satisfaction are included as secondary outcomes. This systematic review and meta-analysis aims to determine the rate of patient satisfaction with the use of SCS and DRG-S in the treatment of chronic intractable pain.
Learn More >Neuropathic pruritus conditions arise from structural and/or functional damage of the peripheral or central nervous system. Novel findings of pruritus specific mediators and pathways strengthen the specificity theory of pruritus transmission, however electrophysiological studies suggest that focal activation of nociceptors and distinct discharge patterns of primary afferents also contribute to the development of the sensation of pruritus. A complex interplay between excitatory and inhibitory interneurons at spinal level, non-neuronal cells and descending modulation from upper centers contributes to neuronal sensitization and clinically to the chronicity of pruritus, as well as accompanying phenomena such as alloknesis and hyperknesis. Several topical, systemic and non-pharmacological therapeutic approaches directed at distinct targets are currently available.
Learn More >Bone is the preferential site of metastasis for breast cancer. Invasion of cancer cells induces the destruction of bone tissue and damnification of peripheral nerves and consequently induced central sensitization which contributes to severe pain. Herein, cancer induced bone pain (CIBP) rats exhibited destruction of tibia, mechanical allodynia and spinal inflammation. Inflammatory response mainly mediated by astrocyte and microglia in central nervous system. Our immunofluorescence analysis revealed activation of spinal astrocytes and microglia in CIBP rats. Transmission electron microscopy (TEM) observations of mitochondrial outer membrane disruption and cristae damage in spinal mitochondria of CIBP rats. Proteomics analysis identified abnormal expression of proteins related to mitochondrial organization and function. Intrathecally, injection of GSK-3β activity inhibitor TDZD-8 significantly attenuated Drp1-mediated mitochondrial fission and recovered mitochondrial function. Inhibition of GSK-3β activity also suppressed NLRP3 inflammasome cascade and consequently decreased mechanical pain sensitivity of CIBP rats. For cell research, TDZD-8 treatment significantly reversed TNF-α induced mitochondrial membrane potential (MMP) deficiency and high mitochondrial reactive oxygen species level. Taken together, GSK-3β inhibition by TDZD-8 decreases spinal inflammation and relieves cancer induced bone pain via reducing Drp1-mediated mitochondrial damage.
Learn More >Fibromyalgia is a clinical condition that affects 1% to 5% of the population. No proper therapy has been currently found. It has been described that inflammation plays a central role in the nerve sensitizations that characterize the pathology.
Learn More >Chronic pain is a major public health problem and an economic burden worldwide. However, its underlying pathological mechanisms remain unclear. MicroRNAs (miRNAs) are a class of small noncoding RNAs that post-transcriptionally regulate gene expression and serve key roles in physiological and pathological processes. This review aims to synthesize the human studies examining miRNA expression in the pathogenesis of chronic primary pain and chronic secondary pain. Additionally, to understand the potential pathophysiological impact of miRNAs in these conditions, an in silico analysis was performed to reveal the target genes and pathways involved in primary and secondary pain and their differential regulation in the different types of chronic pain. The findings, methodological issues and challenges of miRNA research in the pathophysiology of chronic pain are discussed. The available evidence suggests the potential role of miRNA in disease pathogenesis and possibly the pain process, eventually enabling this role to be exploited for pain monitoring and management.
Learn More >Chronic migraine (CM) is a great challenge for physicians dealing with headaches. Despite the introduction of the monoclonal antibodies (mAbs) acting against the calcitonin gene-related peptide (CGRP) that has revolutionized the treatment of CM, some patients still experience an incomplete relief. So, the association of two preventive treatments may be a reliable option for these patients. So, onabotulinumtoxinA (BT-A) and anti-CGRP mAbs may be used together, and some pre-clinical and clinical evidence of an additive action of the 2 drugs is emerging. In particular, since BT-A acts mainly on C-fibers and anti-CGRP mAbs on Aδ ones, their association may prevent the wearing-off phenomenon of BT-A, thus giving an additional benefit in those patients experiencing an incomplete response to BT-A alone. Despite this, the clinical studies available in the literature have a small sample size, often a retrospective design, and are heterogeneous in terms of the outcomes chosen. Considering this, the evidence of a favorable effect of the association between BT-A and anti-CGRP mAbs is still scarce. Furthermore, this association is explicitly forbidden by many National regulatory agencies, due to the high costs of both treatments. Anyway, their association could help in reducing the burden associated with the most severe cases of CM, thus relieving the direct and indirect costs of this condition. More well-designed studies with big samples are needed to unveil the real therapeutic gain of this association. Moreover, pharmacoeconomics studies should be performed, to assess the economic suitability of this association.
Learn More >Chronic neuropathic pain emerges from either central or peripheral lesions inducing spontaneous or amplified responses to non-noxious stimuli. Despite different pharmacological approaches to treat such a chronic disease, neuropathic pain still represents an unmet clinical need, due to long-term therapeutic regimens and severe side effects that limit application of currently available drugs. A critical phenomenon involved in central sensitization is the exchange of signalling molecules and cytokines, between glia and neurons, driving the chronicization process. Herein, using a chronic constriction injury (CCI) model of neuropathic pain, we evaluated the efficacy of the mu (M-) and delta (D-) opioid receptor (-OR) targeting agent LP2 in modulating connexin-based heterocellular coupling and cytokine levels. We found that long-term efficacy of LP2 is consequent to MOR-DOR targeting resulting in the reduction of CCI-induced astrocyte-to-microglia heterocellular coupling mediated by connexin 43. We also found that single targeting of DOR reduces TNF and IL-6 levels in the chronic phase of the disease, but the peripheral and central discharge as the primary source of excitotoxic stimulation in the spinal cord requires a simultaneous MOR-DOR targeting to reduce CCI-induced neuropathic pain.
Learn More >Specialized cutaneous Schwann cells (SCs), termed nociceptive SCs, were recently discovered. Their function is not fully understood, but they are believed not only to support peripheral axons in mouse skin by forming a mesh-like neural-glio networking structure in subepidermal area, but also contributing to transduction of mechanical sensation and neuropathic pain. Diabetic neuropathy (DPN) is one of the most common complication of diabetes, however, the mechanisms behind painful and painless DPN remain unclear. Using a mouse model of DPN, we want to investigate if there are quantitative differences in nociceptive SC density between the condition of hyperglycemia-induced sensory abnormalities and control condition and at which stage in the disease the damage occurs. Here, we developed a set of counting rules for nociceptive SCs based on immunofluorescent staining, and applied the method to quantify the density of nociceptive SCs in control mice (n=10), mice with nociceptive hypersensitivity at early diabetic stage (n=5), and mice with sensory hyposensitivity at late diabetic stage (n=5) in the Streptozotocin (STZ) model of type 1 diabetes. Nociceptive SCs were identified as S100/Sox10/DAPI cells abutting to peripheral nerves, with the somas located within 25µm depth in the subepidermal area and outside glands and large fiber bundles. Hypersensitive diabetic mice had decreased nociceptive SC density, despite having normal epidermal nerve fiber density, compared with age-matched control mice (P=0.023). In contrast, there was a reduction in intraepidermal nerve fiber density but no difference in nociceptive SC density between hyposensitive diabetic mice and the age-matched control mice. This study provides a detailed description of how to identify and quantify nociceptive SC and demonstrates that nociceptive SC density declines before nerve fiber deterioration, which supports previous observations that nociceptive SCs are critical for maintenance of cutaneous sensory nerves.
Learn More >The aim of this study was to analyze the impact of circadian variation of blood pressure (BP) in patients with chronic musculoskeletal pain (CPM). A further purpose was to study differences in circadian variation of BP between genders and the correlation between BP circadian variation and pain. We performed a cross-sectional, observational study in which seventy-five participants with CMP participated. Circadian variation in BP was calculated using the diurnal/nocturnal BP ratio, and all participants used validated self-measurement BP devices. The Numeric Pain Rating Scale was used to assess pain perception. All circadian BP values from participants who suffered from CPM followed pathologic cardiovascular parameters (BP ratio < 10%). When comparing BP ratios between genders, statistically significant differences were found ( = 0.011). BP itself did not correlate with pain in any subgroup. Circadian variations of BP in those suffering from CMP are shown and new possibilities of research and treatment are proposed.
Learn More >This systematic review examined studies that used mediation analysis to investigate the mechanisms of action of cognitive-behavioral, mind-body, and exercise-based interventions for pain and disability in people with chronic primary musculoskeletal pain.
Learn More >Neuropathic pain affects more than one million people across the globe. The quality of life of people suffering from neuropathic pain has been considerably declining due to the unavailability of appropriate therapeutics. Currently, available treatment options can only treat patients symptomatically, but they are associated with severe adverse side effects and the development of tolerance over prolonged use. In the past decade, researchers were able to gain a better understanding of the mechanisms involved in neuropathic pain; thus, continuous efforts are evident, aiming to develop novel interventions with better efficacy instead of symptomatic treatment. The current review discusses the latest interventional strategies used in the treatment and management of neuropathic pain. This review also provides insights into the present scenario of pain research, particularly various interventional techniques such as spinal cord stimulation, steroid injection, neural blockade, transcranial/epidural stimulation, deep brain stimulation, percutaneous electrical nerve stimulation, neuroablative procedures, opto/chemogenetics, gene therapy, etc. In a nutshell, most of the above techniques are at preclinical stage and facing difficulty in translation to clinical studies due to the non-availability of appropriate methodologies. Therefore, continuing research on these interventional strategies may help in the development of promising novel therapies that can improve the quality of life of patients suffering from neuropathic pain.
Learn More >Neuropathy development is a major dose-limiting side effect of anticancer treatments that significantly reduces patient's quality of life. The inadequate pharmacological approaches for neuropathic pain management warrant the identification of novel therapeutic targets. Mitochondrial dysfunctions that lead to reactive oxygen species (ROS) increase, cytosolic Ca imbalance, and lactate acidosis are implicated in neuropathic pain pathogenesis. It has been observed that in these deregulations, a pivotal role is played by the mitochondrial carbonic anhydrases (CA) VA and VB isoforms. Hence, preclinical studies should be conducted to assess the efficacy of two novel selenides bearing benzenesulfonamide moieties, named and , and able to inhibit CA VA and VB against paclitaxel-induced neurotoxicity in mice. Acute treatment with and (30-100 mg/kg, per os – p.o.) determined a dose-dependent and long-lasting anti-hyperalgesic effect in the Cold plate test. Further, repeated daily treatment for 15 days with 100 mg/kg of both compounds (starting the first day of paclitaxel injection) significantly prevented neuropathic pain development without the onset of tolerance to the anti-hyperalgesic effect. In both experiments, acetazolamide (AAZ, 100 mg/kg, p.o.) used as the reference drug was partially active. Moreover, ex vivo analysis demonstrated the efficacy of and repeated treatments in reducing the maladaptive plasticity that occurs to glia cells in the lumbar portion of the spinal cord and in improving mitochondrial functions in the brain and spinal cord that were strongly impaired by paclitaxel-repeated treatment. In this regard, and ameliorated the metabolic activity, as observed by the increase in citrate synthase activity, and preserved an optimal mitochondrial membrane potential (ΔΨ) value, which appeared depolarized in brains from paclitaxel-treated animals. In conclusion, and have therapeutic and protective effects against paclitaxel-induced neuropathy without tolerance development. Moreover, and reduced glial cell activation and mitochondrial dysfunction in the central nervous system, being a promising candidate for the management of neuropathic pain and neurotoxicity evoked by chemotherapeutic drugs.
Learn More >The calcitonin gene-related peptide (CGRP) is implicated in the pathogenesis of several pain-related syndromes, including migraine. Targeting CGRP and its receptor by their antagonists and antibodies was a breakthrough in migraine therapy, but the need to improve efficacy and limit the side effects of these drugs justify further studies on the regulation of CGRP in migraine. The expression of the CGRP encoding gene, , is modulated by epigenetic modifications, including the DNA methylation, histone modification, and effects of micro RNAs (miRNAs), circular RNAs, and long-coding RNAs (lncRNAs). On the other hand, CGRP can change the epigenetic profile of neuronal and glial cells. The promoter of the gene has two CpG islands that may be specifically methylated in migraine patients. DNA methylation and lncRNAs were shown to play a role in the cell-specific alternative splicing of the primary transcript. CGRP may be involved in changes in neural cytoarchitecture that are controlled by histone deacetylase 6 (HDAC6) and can be related to migraine. Inhibition of HDAC6 results in reduced cortical-spreading depression and a blockade of the CGRP receptor. CGRP levels are associated with the expression of several miRNAs in plasma, making them useful peripheral markers of migraine. The fundamental role of CGRP in inflammatory pain transmission may be epigenetically regulated. In conclusion, epigenetic connections of CGRP should be further explored for efficient and safe antimigraine therapy.
Learn More >To investigate the prevalence of neuropathic pain symptoms and to analyze the correlation between neuropathic symptoms with pain-related, psychological, and cognitive variables in COVID-19 survivors exhibiting "de novo" post-COVID pain.
Learn More >Relative to men, women present with pain conditions more commonly. Although consistent differences exist between men and women in terms of physiological pain sensitivity, the underlying mechanisms are incompletely understood and yet could inform the development of effective sex specific treatments for pain. The gut microbiota can modulate nervous system functioning, including pain signaling pathways. We hypothesized that the gut microbiota and critical components of the gut-brain axis might influence electrical pain thresholds. Further, we hypothesized that sex, menstrual cycle, and hormonal contraceptive use might account for inter-sex differences in pain perception.
Learn More >Atopic dermatitis (AD) is a chronic inflammatory skin disease that greatly impacts patient quality of life. Type 2 cytokine interleukin (IL)-13 is integral to the pathogenesis of AD. Tralokinumab is a fully human IgG4 monoclonal antibody that specifically targets IL-13, preventing downstream signaling of inflammatory pathways that may contribute to AD. Tralokinumab was US Food and Drug administration (FDA) recently approved for the treatment of moderate to severe AD on December 28, 2021. In our review, we will explore the efficacy and adverse effects (AEs) of tralokinumab for the treatment of patients with moderate to severe AD. A PubMed search for key articles on the emerging clinical data of tralokinumab was performed. Six randomized controlled trials of tralokinumab identified improvements in disease severity measures, including Investigator's Global Assessment (IGA) scores and Eczema Area Severity Index 75 (EASI75) scores. Four of these studies demonstrated improvements in quality of life measures with tralokinumab, including pruritus scores, sleep interference scores, Dermatology Life Quality Index, SCORing Atopic Dermatitis (SCORAD), Patient Oriented Eczema Measure, and The Short Form 36 Health Survey (SF-36v2) scores. One study identified a similar immune response in patients taking tralokinumab to those taking the Tdap and meningococcal vaccines. Upper respiratory infection, conjunctivitis, and headaches were the most common adverse events. The varying criteria to assess changes in AD disease severity across different studies is a limitation of this review. Tralokinumab is another promising biologic option for the treatment of moderate to severe AD, which may reduce disease burden and improve patient quality of life.
Learn More >Lower extremity amputations are common and post-operative neuropathic pain (phantom limb pain or symptomatic neuroma) is frequently reported. The use of active treatment of the nerve end has shown to reduce pain but requires additional resources and should therefore be performed primarily in high-risk patients. The aim of this study is to identify the factors associated with the development of neuropathic pain following above the knee amputation (AKA), knee disarticulation (KD) or below the knee amputation (BKA).
Learn More >State regulations have decreased prescribed opioids with more than 25% of patients abstaining from opioids. Despite this, 2 distinct populations of patients exist who consume "high" or "low" amounts of opioids. The aim of this study was to identify factors associated with postoperative opioid use after common surgical procedures and develop an opioid risk score.
Learn More >Premature neonates require regular ophthalmological examination, generally indirect ophthalmoscopy, to screen for retinopathy of prematurity (ROP). Conventional analgesia is provided with topical anaesthetic eyedrops and oral sugar solution, but neonates still experience significant pain. Here, the literature base was examined to evaluate the usefulness of other pharmacological analgesics.
Learn More >Visceral hypersensitivity in irritable bowel syndrome (IBS) is widespread, but effective therapies for it remain elusive. As a canonical anti-inflammatory protein, suppressor of cytokine signaling 3 (SOCS3) reportedly relays exchange protein 1 directly activated by cAMP (Epac1) signaling and inhibits the intracellular response to inflammatory cytokines. Despite the inhibitory effect of SOCS3 on the pro-inflammatory response and neuroinflammation in PVN, the systematic investigation of Epac1-SOCS3 signaling involved in visceral hypersensitivity remains unknown. This study aimed to explore Epac1-SOCS3 signaling in the activity of hypothalamic paraventricular nucleus (PVN) corticotropin-releasing factor (CRF) neurons and visceral hypersensitivity in adult rats experiencing neonatal colorectal distension (CRD).
Learn More >Guidelines recommend a number of pharmacotherapeutic options used as monotherapy or in combination with others for treating the pain of trigeminal neuropathy.
Learn More >The diagnostic criteria for opioid use disorder, originally developed for heroin, did not anticipate the surge in prescription opioid use and the resulting complexities in diagnosing prescription opioid use disorder (POUD), including differentiation of pain relief (therapeutic intent) from more common drug use motives, such as to get high or to cope with negative affect. The authors examined the validity of the Psychiatric Research Interview for Substance and Mental Disorders, DSM-5 opioid version, an instrument designed to make this differentiation.
Learn More >Individuals with major limb amputation(s) frequently experience phantom limb sensations, which are described as vivid impressions of either parts or entire missing limb(s). Despite the high incidence and prevalence of phantom limb pain (PLP), the underlying pathophysiology of PLP remains poorly understood. The objective of this study was to evaluate a possible role of microRNAs (miRNAs) in the pathophysiology of PLP.
Learn More >Nociplastic pain (NP), as a mechanistic term, denotes pain arising from altered nociception without clear evidence of tissue or somatosensory damage. Fibromyalgia (FM), a prototypical NP condition, incorporates a broad continuum of phenotypes with a distinct neurobiological signature and shared NP attributes. The nociplastic concept may provide a new opportunity for early diagnosis of FM by identifying the characteristic NP features before a state of pain generalization and symptoms clustering. In this approach, even individual symptoms associated with NP features are worthy of attention to denote FM. It may provide a timely diagnosis of FM before clinical progression to a severe and hard-to-manage condition. Furthermore, collecting all various FM phenotypes under the nociplastic concept and not delimiting FM to the only typical presentation allows investigators to identify FM subgroups reflecting potentially distinct pathophysiologic mechanisms and biomarkers. This viewpoint can be served in future studies to develop individualized management. In this review, we postulate a novel approach to early FM diagnosis and management based on NP conceptualization and phenotype recognition. Key Points • FM as a NP condition represents overlapping clinical phenotypes and incomplete presentations especially in early stage of illness. • The mechanistic approach based on the NP features of FM can be implicated in the timely diagnosis and management of FM. • The NP-based approach to FM provides a broader viewpoint beyond FM delimitation to pain generalization and polysymptomatic complaints.
Learn More >The somatosensory system processes diverse types of information including mechanical, thermal, and chemical signals. It has an essential role in sensory perception and body movement and, thus, is crucial for organism survival. The neural network for processing somatosensory information comprises multiple key nodes. Spinal projection neurons represent the key node for transmitting somatosensory information from the periphery to the brain. Although the anatomy of spinal ascending pathways has been characterized, the mechanisms underlying somatosensory information processing by spinal ascending pathways are incompletely understood. Recent studies have begun to reveal the diversity of spinal ascending pathways and their functional roles in somatosensory information processing. Here, we review the anatomic, molecular, and functional characteristics of spinal ascending pathways.
Learn More >Rheumatoid arthritis (RA) is a prolonged inflammatory disease resulting from autoimmune reactions that leads to local and systemic bone erosion, joint defects and functional impairment. Although the inflammation is subsided through the prescription of anti-inflammatory therapeutics, the patients persistently complained of sleepless nights due to flare pain. This indicates the possible contribution of other pathways besides inflammation in leading to RA pain. This review aims to uncover the roles and involvement of several inflammatory-associated apoptotic markers in facilitating pain transmission and processing during the pathogenesis of RA.
Learn More >Clinical trials have demonstrated galcanezumab as safe and effective in migraine prevention. However, real-life data are still lacking and overlook the impact of galcanezumab on those different migraine facets strongly contributing to migraine burden. Herein we report the clinical experience from an Italian real-world setting using galcanezumab in patients with migraine experiencing previous unsuccessful preventive treatments.
Learn More >The effects of hypnosis on acute pain have been discussed recently, resulting in increased attention in the dental/maxillofacial field offering new perspectives, especially in emergency situations, trauma, or acute inflammatory situations where conventional pharmaceuticals are contraindicated due to allergies or intolerance reactions.
Learn More >Emerging information suggests a potential role of medicinal cannabis in pain medication in addition to enhancing immune functions. Endometriosis is a disease of women of reproductive age associated with infertility and reproductive failure as well as chronic pain of varying degrees depending on the stage of the disease. Currently, opioids are being preferred over nonsteroidal anti-inflammatory drugs (NSAID) due to the latter's side effects. However, as the opioids are becoming a source of addiction, additional pain medication is urgently needed. Cannabis offers an alternative therapy for treating the pain associated with endometriosis. Information on the use and effectiveness of cannabis against endometriotic pain is lacking. Moreover, expression of receptors for endocannabinoids by the ovarian endometriotic lesions is not known. The goal of this study was to examine whether cannabinoid receptors 1 and 2 (CB1 and CB2) are expressed by ovarian endometriotic lesions. Archived normal ovarian tissues, ovaries with endometriotic lesions, and normal endometrial tissues were examined for the presence of endometrial stromal cells using CD10 (a marker of endometrial stromal cells). Expression of CB1 and CB2 were determined by immunohistochemistry, immunoblotting, and gene expression studies. Intense expression for CB1 and CB2 was detected in the epithelial cells in ovarian endometriotic lesions. Compared with stroma in ovaries with endometriotic lesions, the expression of CB1 and CB2 was significantly higher in the epithelial cells in endometriotic lesions in the ovary ( < 0.0001 and < 0.05, respectively). Immunoblotting and gene expression assays showed similar patterns for CB1 and CB2 protein and (gene encoding CB1) and (gene encoding CB2) gene expression. These results suggest that ovarian endometriotic lesions express CB1 and CB2 receptors, and these lesions may respond to cannabinoids as pain medication. These results will form a foundation for a clinical study with larger cohorts.
Learn More >Assessment of pain responses and inflammation during animal surgery is difficult because traditional methods, such as visual analogue scores, are not applicable while under anaesthesia. Acute phase proteins (APPs), such as C-reactive protein and haptoglobin, that are typically monitored in veterinary research, do not show a significant change until at least 2 h post-surgery and therefore, immediate pathophysiological changes are uncertain. The current study used sequential window acquisition of all theoretical mass spectra (SWATH-MS) to investigate plasma proteome changes that occur immediately following surgery in dogs and also to assess the efficacy of a novel transdermal ketoprofen (TK) formulation. Castration was chosen as surgical model in this study. The procedure was performed on twelve dogs (n = 6 in two groups) and blood samples were collected at 0 h, 1 and 2 h after surgery for proteomic analysis. Following surgery, there was a general downregulation of proteins, including complement C- 3, complement factor B, complement factor D, transthyretin, and proteins associated with lipid, cholesterol, and glucose metabolisms, reflecting the systemic response to surgical trauma. Many of these changes were diminished in the transdermal group (TD) since ketoprofen, a non-steroidal anti-inflammatory drug (NSAID), inhibits prostanoids and the associated chemotactic neutrophil migration to site of tissue injury. SIGNIFICANCE: SWATH-MS Proteomic analysis revealed significant changes in plasma proteins, predominantly involved in early acute phase and inflammatory response at 1 & 2 h after surgery in castrated dogs. Pre-operative application of transdermal ketoprofen formulation had reduced systemic immune response, which was confirmed by negligible alteration of proteins in transdermal treated group. A key outcome of this experiment was studying the efficacy of a novel transdermal NSAID formulation in dogs.
Learn More >Animal models of human pain conditions allow for detailed interrogation of known and hypothesized mechanisms of pain physiology in awake, behaving organisms. The importance of the glycinergic system for pain modulation is well known; however, manipulation of this system to treat and alleviate pain has not yet reached the sophistication required for the clinic. Here, we review the current literature on what animal behavioral studies have allowed us to elucidate about glycinergic pain modulation, and the progress toward clinical treatments so far. First, we outline the animal pain models that have been used, such as nerve injury models for neuropathic pain, chemogenic pain models for acute and inflammatory pain, and other models that mimic painful human pathologies such as diabetic neuropathy. We then discuss the genetic approaches to animal models that have identified the crucial glycinergic machinery involved in neuropathic and inflammatory pain. Specifically, two glycine receptor (GlyR) subtypes, GlyRα1(β) and GlyRα3(β), and the two glycine transporters (GlyT), GlyT1 and GlyT2. Finally, we review the different pharmacological approaches to manipulating the glycinergic system for pain management in animal models, such as partial . full agonism, reversibility, and multi-target approaches. We discuss the benefits and pitfalls of using animal models in drug development broadly, as well as the progress of glycinergic treatments from preclinical to clinical trials.
Learn More >The regeneration of the articular cartilage defects is characterized by the improvement in the quality of the repaired tissue and the reduction in the potential development of perifocal osteoarthritis (OA). Usually, the injection of dexamethasone (Dex) in the OA joints slows down the progression of inflammation and relieves pain. However, the anti-inflammatory Dex injected in the joint cavity is rapidly cleared, leading to a poor therapeutic effect. Multifunctional hydrogels with simultaneous chondrogenic differentiation, antioxidative, and anti-inflammatory capacities may represent a promising solution. Therefore, in this work, a novel injectable hydrogel based on double cross-linking of Schiff base bonds and coordination of catechol-Fe was developed. The obtained hydrogel (Gel-DA/DOHA/DMON@Dex@Fe) possessed molding performance in situ, excellent mechanical strength, controllable biodegradability, the on-demand release of the drug, and biocompatibility. The hydrogel system stimulated the HIF-1α signaling pathway and suppressed inflammation thanks to the introduction of DMON@Fe, consequently facilitating chondrogenic differentiation. The synergistic anti-inflammatory effect together with the induction of chondrogenesis by Dex-loaded Gel-DA/DOHA/DMON@Fe hydrogel allowed the promotion of cartilage repair, as demonstrated by experiments. Hence, the proposed multifunctional scaffold provides a promising advancement in articular cartilage tissue engineering and may have great prospects in the prevention of OA.
Learn More >Between 8 and 16 million people in Germany are affected by chronic pain, causing costs of up to 28.7 billion euros annually. Chronic pain is complex and has biopsychosocial aspects. Physiotherapeutic care requires special knowledge, skills and competencies. A publicly accessible description of these requirements does not currently exist in Germany.
Learn More >Myalgic encephalomyelitis is an illness characterized by profound malaise after mental or physical effort occurring in patients already suffering from constant fatigue. On the other hand, widespread pain and widespread allodynia are the core fibromyalgia clinical features. There is controversy on these two syndromes alikeness. Through the years, different diagnostic and/or classification criteria have been put forward to appraise both fibromyalgia and myalgic encephalomyelitis. The epidemiology of these two illnesses, and their overlap, may vary accordingly to the used definition. The most recent Wolfe et al. 2016 fibromyalgia diagnostic criteria incorporates three myalgic encephalomyelitis features including fatigue, waking unrefreshed and dyscognition. The objective of this meta-analysis was to define the clinical overlap between fibromyalgia and myalgic encephalomyelitis based on a systematic literature review.
Learn More >Real-World experience of interictal burden and treatment in migraine: a qualitative interview study.
The debilitating nature of migraine attacks is widely established; however, less is known about how the interictal burden (i.e., how patients are affected in-between migraine episodes) of migraine impacts on patients' health-related quality of life (HRQL). Acute and preventive treatments may lift the burden of the disease, but they often have unwanted side effects and limited effectiveness. The objective of this study was to understand the interictal burden of migraines, from the patient perspective, and to explore patient experience with migraine treatments.
Learn More >Bladder pain syndrome/interstitial cystitis (BPS/IC) is a persistent pain perceived in the urinary bladder region, accompanied by at least one symptom, such as pain worsening with bladder filling and daytime or nighttime urinary frequency without any proven infection or obvious pathology. The aim of this study is to evaluate the efficacy and safety of pentosan polysulfate (PPS) in patients with BPS/IC.
Learn More >Hot compress modalities are used to ameliorate pain despite prevalent confusion about which modality should be used and when. Most recommendations for hot compresses are based on empirical experience, with limited evidence to support its efficacy. To obtain insight into the nerve transmission mechanism of hot compresses and to identify the nerve injury marker proteins specifically associated with sciatic nerve pain, we established a rat model of chronic constriction injury (CCI) and performed mechanical allodynia, electrophysiology, and histopathological analysis. All CCI rats exhibited geometric representation of the affected hind paw, which indicated a hyper-impact on both mechanical gait and asymmetry of gait on day 28. The CCI model after 28 days of surgery significantly reduced compound muscle action potential (CMAP) amplitude, but also significantly reduced latency. Administration of hot compress for 3 weeks (heated at 40-42°C, cycle of 40 min, and rest for 20 min, three cycles each time, three times per week) significantly increased the paw withdrawal thresholds in response to stimulation by Von Frey fibers and reversed the CCI-induced reduced sciatic functional index (SFI) scores. Hot compress treatment in the CCI model improved CMAP amplitude and latency. The S100 protein expression level in the CCI+Hot compression group was 1.5-fold higher than in the CCI group; it dramatically reduced inflammation, such as tumor necrosis factor alpha and CD68 expression in nerve injury sites. Synaptophysin (Syn) expression in the CCI+Hot compression group was less than threefold in the CCI group at both nerve injury sites and brain (somatosensory cortex and hippocampus). This finding indicates that local nerve damage and inflammation cause significant alterations in the sensorimotor strip, and hot compress treatment could significantly ameliorate sciatic nerve pain by attenuating Syn and inflammatory factors from local pathological nerves to the brain. This study determines the potential efficacy and safety of hot compress, and may have important implications for its widespread use in sciatic nerve pain treatment.
Learn More >There has been a sparse exploration of the lived experience of men with urologic chronic pelvic pain syndrome (UCPPS), and none with the goal of Investigating the experience of "flares" as part of this chronic pain syndrome in men.
Learn More >Food strategies are currently used to improve inflammation and oxidative stress conditions in chronic pain which contributes to a better quality of life for patients. The main purpose of this systematic review is to analyze the effectiveness of different dietary strategies as part of the treatment plan for patients suffering from chronic pain and decreased health. PubMed, Web of Science, ProQuest, Scopus, Cumulative Index to Nursing & Allied Health Literature (CINAHL), Cambridge Core, and Oxford Academy databases were used to review and to appraise the literature. Randomized clinical trials (RCT), observational studies, and systematic reviews published within the last 6 years were included. The Physiotherapy Evidence Database (PEDro) scale, the PEDro Internal Validity (PVI), the Standard Quality Assessment Criteria for Evaluating Primary Research Papers from a variety of fields (QUALSYT), and the Quality Assessment Tool of Systematic Reviews scale were used to evaluate the risk of bias of the included studies. A total of 16 articles were included, of which 11 were RCTs and 5 were observational studies. Six of them showed an improvement in pain assessment, while two studies showed the opposite. Inflammation was shown to be decreased in four studies, while one did not show a decrease. The quality of life was shown to have improved in five studies. All of the selected studies obtained good methodological quality in their assessment scales. In the PVI, one RCT showed good internal validity, five RCTs showed moderate internal quality, while five of them were limited. Current research shows that consensus on the effects of an IF diet on pain improvement, in either the short or the long term, is lacking. A caloric restriction diet may be a good long term treatment option for people suffering from pain. Time restricted food and ketogenic diets may improve the quality of life in chronic conditions. However, more studies analyzing the effects of different nutritional strategies, not only in isolation but in combination with other therapies in the short and the long term, are needed.
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