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Nerve injury leads to chronic pain and exaggerated sensitivity to gentle touch (allodynia) as well as a loss of sensation in the areas in which injured and non-injured nerves come together. The mechanisms that disambiguate these mixed and paradoxical symptoms are unknown. Here we longitudinally and non-invasively imaged genetically labelled populations of fibres that sense noxious stimuli (nociceptors) and gentle touch (low-threshold afferents) peripherally in the skin for longer than 10 months after nerve injury, while simultaneously tracking pain-related behaviour in the same mice. Fully denervated areas of skin initially lost sensation, gradually recovered normal sensitivity and developed marked allodynia and aversion to gentle touch several months after injury. This reinnervation-induced neuropathic pain involved nociceptors that sprouted into denervated territories precisely reproducing the initial pattern of innervation, were guided by blood vessels and showed irregular terminal connectivity in the skin and lowered activation thresholds mimicking low-threshold afferents. By contrast, low-threshold afferents-which normally mediate touch sensation as well as allodynia in intact nerve territories after injury-did not reinnervate, leading to an aberrant innervation of tactile end organs such as Meissner corpuscles with nociceptors alone. Genetic ablation of nociceptors fully abrogated reinnervation allodynia. Our results thus reveal the emergence of a form of chronic neuropathic pain that is driven by structural plasticity, abnormal terminal connectivity and malfunction of nociceptors during reinnervation, and provide a mechanistic framework for the paradoxical sensory manifestations that are observed clinically and can impose a heavy burden on patients.
Learn More >In perilous and stressful situations, the ability to suppress pain can be critical for survival. The rostral ventromedial medulla (RVM) contains neurons that robustly inhibit nociception at the level of the spinal cord through a top-down modulatory pathway. Although much is known about the role of the RVM in the inhibition of pain, the precise ability to directly manipulate pain-inhibitory neurons in the RVM has never been achieved. We now expose a cellular circuit that inhibits nociception and itch in mice. Through a combination of molecular, tracing, and behavioral approaches, we found that RVM neurons containing the kappa-opioid receptor (KOR) inhibit itch and nociception. With chemogenetic inhibition, we uncovered that these neurons are required for stress-induced analgesia. Using intersectional chemogenetic and pharmacological approaches, we determined that RVMKOR neurons inhibit nociception and itch through a descending circuit. Lastly, we identified a dynorphinergic pathway arising from the periaqueductal gray (PAG) that modulates nociception within the RVM. These discoveries highlight a distinct population of RVM neurons capable of broadly and robustly inhibiting itch and nociception.
Learn More >The anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase known for its oncogenic potential and involved in the development of the peripheral and central nervous system. ALK receptor ligands, ALKAL1 and ALKAL2 were recently found to promote neuronal differentiation and survival. Here we show that inflammation or injury enhanced ALKAL2 expression in a subset of TRPV1+ sensory neurons. Notably, ALKAL2 was particularly enriched in both mice and human peptidergic nociceptors, yet weakly expressed in non peptidergic, large diameter myelinated neurons or in the brain. Using a co-culture expression system, we found that nociceptors exposed to ALKAL2 exhibited heightened excitability and neurite outgrowth. Intraplantar Complete Freund's adjuvant (CFA) or intrathecal infusion of recombinant ALKAL2 led to ALK phosphorylation in the lumbar dorsal horn of the spinal cord. Finally, depletion of ALKAL2 in dorsal root ganglia or blocking ALK with clinically available compounds Crizotinib or Lorlatinib, reversed thermal hyperalgesia and mechanical allodynia induced by inflammation or nerve injury, respectively. Overall, our work uncovers the ALKAL2-ALK signaling axis as a central regulator of nociceptor-induced sensitization. We propose that clinically approved ALK inhibitors used for Non-Small Cell Lung Cancer and neuroblastomas, could be repurposed to treat persistent pain conditions.
Learn More >Olfactory exposure to late-pregnant and lactating mice causes stress-induced analgesia in male mice.
In an attempt to improve reproducibility, more attention is being paid to potential sources of stress in the laboratory environment. Here, we report that the mere proximity of pregnant or lactating female mice causes olfactory-mediated stress-induced analgesia, to a variety of noxious stimuli, in gonadally intact male mice. We show that exposure to volatile compounds released in the urine of pregnant and lactating female mice can themselves produce stress and associated pain inhibition. This phenomenon, a novel form of female-to-male chemosignaling, is mediated by female scent marking of urinary volatiles, such as -pentyl-acetate, and likely signals potential maternal aggression aimed at defending against infanticide by stranger males.
Learn More >Skin diseases are common human illnesses that occur in all cultures, at all ages, and affect between 30% and 70% of individuals globally. TRPV3 is a cation-permeable TRP channel predominantly expressed in skin keratinocytes, implicated in cutaneous sensation and associated with numerous skin diseases. TRPV3 is inhibited by the local anesthetic dyclonine, traditionally used for topical applications to relieve pain and itch. However, the structural basis of TRPV3 inhibition by dyclonine has remained elusive. Here we present a cryo-EM structure of a TRPV3-dyclonine complex that reveals binding of the inhibitor in the portals which connect the membrane environment surrounding the channel to the central cavity of the channel pore. We propose a mechanism of TRPV3 inhibition in which dyclonine molecules stick out into the channel pore, creating a barrier for ion conductance. The allosteric binding site of dyclonine can serve as a template for the design of new TRPV3-targeting drugs.
Learn More >Chemotherapy-induced peripheral neuropathy (CIPN) and hypersensitivity reactions (HSRs) are among the most frequent and impairing side effects of the antineoplastic agent paclitaxel. Here, we demonstrated that paclitaxel can bind and activate complement component 5a receptor 1 (C5aR1) and that this binding is crucial in the etiology of paclitaxel-induced CIPN and anaphylaxis. Starting from our previous data demonstrating the role of interleukin (IL)-8 in paclitaxel-induced neuronal toxicity, we searched for proteins that activate IL-8 expression and, by using the Exscalate platform for molecular docking simulations, we predicted the high affinity of C5aR1 with paclitaxel. By in vitro studies, we confirmed the specific and competitive nature of the C5aR1-paclitaxel binding and found that it triggers intracellularly the NFkB/P38 pathway and c-Fos. In F11 neuronal cells and rat dorsal root ganglia, C5aR1 inhibition protected from paclitaxel-induced neuropathological effects, while in paclitaxel-treated mice, the absence (knock-out mice) or the inhibition of C5aR1 significantly ameliorated CIPN symptoms-in terms of cold and mechanical allodynia-and reduced the chronic pathological state in the paw. Finally, we found that C5aR1 inhibition can counteract paclitaxel-induced anaphylactic cytokine release in macrophages in vitro, as well as the onset of HSRs in mice. Altogether these data identified C5aR1 as a key mediator and a new potential pharmacological target for the prevention and treatment of CIPN and HSRs induced by paclitaxel.
Learn More >Neuropathic pain is a major, inadequately treated challenge for people with spinal cord injury (SCI). While SCI pain mechanisms are often assumed to be in the central nervous system, rodent studies have revealed mechanistic contributions from primary nociceptors. These neurons become chronically hyperexcitable after SCI, generating ongoing electrical activity (OA) that promotes ongoing pain. A major question is whether extrinsic chemical signals help to drive OA after SCI. People living with SCI exhibit acute and chronic elevation of circulating levels of macrophage migration inhibitory factor (MIF), a cytokine implicated in preclinical pain models. Probable nociceptors isolated from male rats and exposed to a MIF concentration reported in human plasma (1 ng/ml) showed hyperactivity similar to that induced by SCI, although, surprisingly, a ten-fold higher concentration failed to increase excitability. Conditioned behavioral aversion to a chamber associated with peripheral MIF injection suggested that MIF stimulates affective pain. A MIF inhibitor, Iso-1, reversed SCI-induced hyperexcitability. Unlike after SCI, acute MIF-induced hyperexcitability was only partially abrogated by inhibiting ERK signaling. Unexpectedly, MIF concentrations that induced hyperactivity in nociceptors from Naïve animals, after SCI induced a long-lasting conversion from a highly excitable nonaccommodating type to a rapidly accommodating, hypoexcitable type, possibly as a homeostatic response to prolonged depolarization. Treatment with conditioned medium from cultures of dorsal root ganglion (DRG) cells obtained after SCI was sufficient to induce MIF-dependent hyperactivity in neurons from Naïve rats. Thus, changes in systemic and DRG levels of MIF may help to maintain SCI-induced nociceptor hyperactivity that persistently promotes pain.Chronic neuropathic pain is a major challenge for people with spinal cord injury (SCI). Pain can drastically impair quality of life, and produces substantial economic and social burdens. Available treatments, including opioids, remain inadequate. This study shows that the cytokine macrophage migration inhibitory factor (MIF) can induce pain-like behavior and plays an important role in driving persistent ongoing electrical activity in injury-detecting sensory neurons (nociceptors) in a rat SCI model. The results indicate that SCI produces an increase in MIF release within sensory ganglia. Low MIF levels potently excite nociceptors, but higher levels trigger a long-lasting hypoexcitable state. These findings suggest that therapeutic targeting of MIF in neuropathic pain states may reduce pain and sensory dysfunction by curbing nociceptor hyperactivity.
Learn More >Monoclonal antibodies (mAbs) against calcitonin gene-related peptides (CGRP) are novel treatments for migraine prevention. Based on a previous functional imaging study which investigated the CGRP receptor mAb (erenumab), we hypothesized that (i) the CGRP ligand mAb galcanezumab would alter central trigeminal pain processing; (ii) responders to galcanezumab treatment would show specific hypothalamic modulation in contrast to non-responders; and (iii) the ligand and the receptor antibody differ in brain responses.
Learn More >Recently a new classification system for chronic pain was included in the 11 edition of the International Classification of Diseases (ICD-11). This study aims to investigate how expectancies of coping, i.e. pain catastrophizing and general self-efficacy, are associated with ICD-11 chronic pain categories in a large pain clinic population. Further, we investigate how coping expectancies are associated with pain-related disability, cross-sectionally and longitudinally across the novel pain classifications.
Learn More >SignificanceCartilage mineralization is imperative in various processes such as skeletal growth and fracture repair. However, this process may also be pathological, as in the case of the degenerative joint disease, osteoarthritis (OA). Using a posttraumatic OA model (PTOA), we find that cartilage-specific genetic nulls caused severe synovitis and mineralization of the lateral joint compartment, due to augmented gene expression. Conversely, cartilage-specific nulls exhibited impaired synovitis and mineralization of the lateral joint, accompanied by a reduction of local pain. Consistently, transcriptomic profiles of -ablated chondrocytes exhibited enhanced anabolism, yet impaired pathways related to calcification and inflammation. Accordingly, cartilage mineralization of the lateral joint compartment relies on amplified inflammatory pathways, contributing to articular damage following PTOA.
Learn More >SignificanceTransmembrane signaling through G protein-coupled receptors (GPCRs), originally described as requiring coupling to intracellular G proteins, also uses G protein-independent pathways through β-arrestin recruitment. Biased ligands, by favoring one of the multiple bioactive conformations of GPCRs, allow selective signaling through either of these pathways. Here, we identified Serodolin as the first β-arrestin-biased agonist of the serotonin 5-HT receptor. This new ligand, while acting as an inverse agonist on G signaling, selectively induces ERK activation in a β-arrestin-dependent way. Importantly, we report that Serodolin decreases pain intensity caused by thermal, mechanical, or inflammatory stimuli. Our findings suggest that targeting the 5-HTR with β-arrestin-biased ligand could be a valid alternative strategy to the use of opioids for the relief of pain.
Learn More >There is conflicting evidence on the association between intrapartum epidural analgesia and risk of autism spectrum disorder (ASD) in offspring.
Learn More >Converging evidence suggests that anatomical and functional mesocorticolimbic abnormalities support the chronicization of pain disorders.
Learn More >Hysteroscopy is increasingly performed in an outpatient setting. Pain is the primary reason for abandonment of procedure or incomplete assessment. There is no consensus upon routine use of analgesia during hysteroscopy.
Learn More >Sickle cell disease (SCD) is the most common inherited disease. Pain is a key morbidity of SCD and opioids are the main treatment but their side effects emphasize the need for new analgesic approaches. Humanized transgenic mouse models have been instructive in understanding the pathobiology of SCD and mechanisms of pain. Homozygous (HbSS) Berkley mice express >99% human sickle hemoglobin and several features of clinical SCD including hyperalgesia. Previously, we reported that the endocannabinoid 2-arachidonoylglycerol (2-AG) is a precursor of the pro-nociceptive mediator prostaglandin E2-glyceryl ester (PGE2-G) which contributes to hyperalgesia in SCD. We now demonstrate the causal role of 2-AG in hyperalgesia in sickle mice. Hyperalgesia in HbSS mice correlated with elevated levels of 2-AG in plasma, its synthesizing enzyme diacylglycerol lipase β (DAGLβ) in blood cells, and with elevated levels of PGE2 and PGE2-G, pro-nociceptive derivatives of 2-AG. A single intravenous injection of 2-AG produced hyperalgesia in non-hyperalgesic HbSS mice, but not in control (HbAA) mice expressing normal human HbA. JZL184, an inhibitor of 2-AG hydrolysis also produced hyperalgesia in non-hyperalgesic HbSS or hemizygous (HbAS) mice, but did not influence hyperalgesia in hyperalgesic HbSS mice. Systemic and intraplantar administration of KT109, an inhibitor of DAGLβ, decreased mechanical and heat hyperalgesia in HbSS mice. The decrease in hyperalgesia was accompanied by reductions in 2-AG, PGE2 and PGE2-G in the blood. These results indicate that maintaining the physiological level of 2-AG in the blood by targeting DAGLβ may be a novel and effective approach to treat pain in SCD.
Learn More >A system of lymphatic vessels has been recently characterized in the meninges, with a postulated role in 'cleaning' the brain via cerebral fluid drainage. As meninges are the origin site of migraine pain, we hypothesized that malfunctioning of the lymphatic system should affect the local trigeminal nociception. To test this hypothesis, we studied nociceptive and inflammatory mechanisms in the hemiskull preparations (containing the meninges) of K14-VEGFR3-Ig (K14) mice lacking the meningeal lymphatic system. We recorded the spiking activity of meningeal afferents and estimated the local mast cells population, calcitonin gene-related peptide (CGRP) and cytokine levels as well as the dural trigeminal innervation in freshly-isolated hemiskull preparations from K14-VEGFR3-Ig (K14) or wild type C57BL/6 mice (WT). Spiking activity data have been confirmed in an acquired model of meningeal lymphatic dysfunction (AAV-mVEGFR3(1-4)Ig induced lymphatic ablation). We found that levels of the pro-inflammatory cytokine IL12-p70 and CGRP, implicated in migraine, were reduced in the meninges of K14 mice, while the levels of the mast cell activator MCP-1 were increased. The other migraine-related pro-inflammatory cytokines (basal and stimulated), did not differ between the two genotypes. The patterns of trigeminal innervation in meninges remained unchanged and we did not observe alterations in basal or ATP-induced nociceptive firing in the meningeal afferents associated with meningeal lymphatic dysfunction. In summary, the lack of meningeal lymphatic system is associated with a new balance between pro- and anti-migraine mediators but does not directly trigger meningeal nociceptive state.
Learn More >We previously reported the efficacy of an 8-week home-based therapeutic immersive virtual reality (VR) program in a double-blind randomized placebo-controlled study. Community-based adults with self-reported chronic low back pain were randomized 1:1 to receive either (1) a 56-day immersive therapeutic pain relief skills VR program (EaseVRx) or (2) a 56-day sham VR program. Immediate posttreatment results revealed the superiority of therapeutic VR over sham VR for reducing pain intensity; pain-related interference with activity, mood, and stress (but not sleep); physical function; and sleep disturbance. At 3 months posttreatment, therapeutic VR maintained superiority for reducing pain intensity and pain-related interference with activity, stress, and sleep (new finding).
Learn More >The endogenous opioid system plays a crucial role in stress-induced analgesia. Mu-opioid receptors (MORs), one of major opioid receptors, are expressed widely in sub-populations of cells throughout the central nervous system. However, the potential roles of MORs expressed in glutamatergic (MOR) and γ-aminobutyric acidergic (MOR) neurons in stress-induced analgesia remains unclear. By examining tail-flick latencies to noxious radiant heat of male mice, here we investigated the contributions of MOR and MOR to behavioral analgesia and activities of neurons projecting from periaqueductal gray (PAG) to rostral ventromedial medulla (RVM) induced by a range of time courses of forced swim exposure. The moderate but not transitory or prolonged swim exposure induced a MOR-dependent analgesia, although all of these three stresses enhanced β-endorphin (β-EP) release. Selective deletion of MOR but not MOR clearly attenuated analgesia and blocked the enhancement of activities of PAG-RVM neurons induced by moderate swim exposure. Under transitory swim exposure, in contrast, selective deletion of MOR elicited an analgesia behavior via strengthening the activities of PAG-RVM neurons. These results indicate that MOR-dependent endogenous opioid signaling participates in nociceptive modulation in a wide-range, not limited to moderate, of stress intensities. Endogenous activation of MOR exerts analgesia whereas MOR produces anti-analgesia. More importantly, with increasement of stress intensities, the efficiencies of MORs on nociception shifts from balance between MOR and MOR to biasing towards MOR mediated processes. Thus, our results point to cellular dynamic characters of MORs expressed in excitatory and inhibitory neurons in pain modulation under various stress intensities.Mu-opioid receptors (MORs) are one of major opioid receptors playing a critical role in stress-induced analgesia, they are widely expressed on different types of neurons, but the potential roles of them expressed in glutamatergic (MOR) and γ-aminobutyric acidergic (MOR) neurons are poorly understood. This work clarifies the divergent roles of MOR and MOR in analgesia under various swim stress intensities. We demonstrate that MOR are essential for stress-induced analgesia, whereas MOR elicit an anti-analgesic like response. The contributions of MOR and MOR to analgesia depends on stress intensity, their opposite effects neutralizing each other under transitory stress and then biasing towards MOR under moderate stress. This report appraises different roles for these neuronal populations' MORs in modulating opioid-dependent stress-induced analgesia.
Learn More >Chemotherapy-induced peripheral neuropathy (CIPN) is the most common side-effect of anti-cancer therapy. To date, there are no clinically effective analgesics that could prevent and treat CIPN. However, the exact pathogenesis of CIPN is still unclear.
Learn More >5-hydroxytryptamine receptor 5A (5-HT) belongs to the 5-HT receptor family and signals through the G protein. It is involved in nervous system regulation and an attractive target for the treatment of psychosis, depression, schizophrenia, and neuropathic pain. 5-HT is the only G-coupled 5-HT receptor subtype lacking a high-resolution structure, which hampers the mechanistic understanding of ligand binding and G coupling for 5-HT. Here we report a cryo-electron microscopy structure of the 5-HT-G complex bound to 5-Carboxamidotryptamine (5-CT). Combined with functional analysis, this structure reveals the 5-CT recognition mechanism and identifies the receptor residue at 6.55 as a determinant of the 5-CT selectivity for G-coupled 5-HT receptors. In addition, 5-HT shows an overall conserved G protein coupling mode compared with other G-coupled 5-HT receptors. These findings provide comprehensive insights into the ligand binding and G protein coupling of G-coupled 5-HT receptors and offer a template for the design of 5-HT-selective drugs.
Learn More >Pain alters motor function. This is supported by studies showing reduced corticomotor excitability in response to experimental pain lasting <90 minutes. Whether similar reductions in corticomotor excitability are present with pain of longer durations or whether alterations in corticomotor excitability are associated with pain severity is unknown. Here we evaluated the evidence for altered corticomotor excitability in response to experimental pain of differing durations in healthy individuals. Databases were systematically searched for eligible studies. Measures of corticomotor excitability and pain were extracted. Meta-analyses were performed to examine i) group-level effect of pain on corticomotor excitability and ii) individual-level associations between corticomotor excitability and pain severity. 49 studies were included. Corticomotor excitability was reduced when pain lasted milliseconds-seconds (hedges g's = -1.26 to -1.55) and minutes-hours (g's = -0.55 to -0.9). When pain lasted minutes-hours, a greater reduction in corticomotor excitability was associated with lower pain severity (g = -0.24). For pain lasting days-weeks, there were no group level effects (g = -0.03 to 0.27). However, a greater reduction in corticomotor excitability was associated with higher pain severity (g = 0.26). In otherwise healthy individuals, suppression of corticomotor excitability may be a beneficial short-term strategy with long-term consequences.
Learn More >To develop and assess new dosage forms for the alternative to existing oral medication for peripheral neuropathy, a hydrogel film in the skin patch formation containing tramadol hydrochloride (TRA), a water-soluble drug used as an analgesic, was prepared and evaluated. A hydrogel film composed of 20%(w/w) hydroxypropyl methylcellulose (HPMC) irradiated with electron beams had high transparency and elasticity similar to commercially available wound dressings and soft tissues, suggesting that it is a suitable substrate for TRA. The inclusion of TRA was enabled by immersing the HPMC hydrogel film in TRA aqueous solution. The release and skin permeation of TRA from TRA-containing hydrogel films differed depending on the electron beam dose. Moreover, the analgesic effects in mice were confirmed in a dose-dependent manner. This study demonstrated the usefulness of a hydrogel film containing TRA as a new dosage form alternative to the existing oral medication for peripheral neuropathy.
Learn More >Prelimbic medial prefrontal cortex (PL-mPFC) and nucleus accumbens core region (NAcc) play an important role in supporting several executive cognitive mechanisms, such as spatial working-memory (WM). Recently, this circuit has been also associated with both sensory and affective components of pain. However, it is still unclear whether this circuit is endogenously engaged in neuropathic pain-related cognitive dysfunctions.
Learn More >The mechanisms that link maternal immune activation (MIA) with the onset of neurodevelopmental disorders remain largely unclear. Accelerated puberty is also associated with a heightened risk for psychopathology in later life, but there is a dearth of evidence on the impacts of maternal infection on pubertal timing. We examined the effects of MIA on reproductive development, mechanical allodynia, and sensorimotor gating in juvenile, adolescent, and adult male and female mice. Moreover, we investigated hypothalamic neural markers associated with the reproductive and stress axes. Finally, we tested the mitigating effects of environmental enrichment (EE), which has clinical relevancy in human rehabilitation settings. Our results show that administration of polyinosinic-polycytidylic acid (poly(I:C)) on gestational day 12.5 led to early preputial separation, vaginal openings, and age of first estrus in offspring. MIA exposure altered pain sensitivity across development and modestly altered prepulse inhibition. The downregulation of Nr3c1 and Oprk mRNA in the hypothalamus of juvenile mice suggests that MIA's effects may be mediated through disruption of hypothalamic-pituitary-adrenal axis activity. In contrast, life-long housing with EE rescued many of these MIA-induced consequences. Overall, our findings suggest that accelerated puberty may be associated with the deleterious effects of infection during pregnancy and the onset of psychopathology.
Learn More >Estimates suggest that 10-40% of lumbar spine surgery patients experience persistent post-surgical pain (PPSP). PPSP is associated with 50% greater healthcare costs, along with risks of emotional distress and impaired quality of life. In 2019, U.S. Health and Human Services identified brief and digital behavioral treatments as important for pain management after surgery. Indeed, brief behavioral pain treatments delivered in the perioperative period may offer patients a low burden opportunity to acquire essential pain coping strategies for enhanced surgical recovery. Additionally, the COVID-19 pandemic has diminished in-person pain treatment access during extended perioperative time frames, thus underscoring the need for on-line options and home based care. This report describes the integration of an online, live-instructor delivered single-session pain self-management intervention (Empowered Relief) into the standard of care for lumbar spine surgery. Here, we apply the RE-AIM framework; describe systems implementation of the Empowered Relief intervention in a large, academic medical center during the COVID-19 pandemic; describe operational challenges and financial considerations; and present patient engagement data. Finally, we discuss the scalable potential of Empowered Relief and other single-session interventions in surgical populations, their importance during extended perioperative periods, practical and scientific limitations, and new directions for future research on this topic.
Learn More >Osteoarthritis (OA) affects more than 500 million people worldwide and is among the five diseases in Germany causing the highest suffering of the patients and cost for the society. The quality of life of OA patients is severely compromised, and adequate therapy is lacking owing to a knowledge gap that acts as a major barrier to finding safe and effective solutions. Chronic, low-grade inflammation plays a central role in OA pathogenesis and is associated with both OA pain and disease progression. Innate immune pathways, such as the complement- and pattern-recognition receptor pathways, are pivotal to the inflammation in OA and key components of the innate immune system implicated in OA include DAMP-TLR signaling, the complement system, carboxypeptidase B (CPB), and mononuclear cells. Anaphylatoxins C3a and C5a are small polypeptides (77 and 74 amino acids, respectively) which are released by proteolytic cleavage of the complement components C3 and C5. The alternative complement pathway seems to play a crucial role in OA pathogenesis as these complement components, mostly C3 and its activation peptide C3a, were detected at high levels in osteoarthritic cartilage, synovial membrane, and cultured chondrocytes. Targeting the complement system by using anti-complement drugs as a therapeutic option bears the risk of major side effects such as increasing the risk of infection, interfering with cell regeneration and metabolism, and suppressing the clearance of immune complexes. Despite those adverse effects, several synthetic complement peptide antagonists show promising effects in ameliorating inflammatory cell responses also in joint tissues.
Learn More >Although the dentate gyrus (DG) as a component of the hippocampal formation has been well known for its role in memory, various studies showed a diverse population of unique cell types and various inputs and outputs in this region. Besides, brain dopamine is known for its roles in reward, motivation, pleasure, and being involved in the pain process. Further, previous studies demonstrated the participation of DG dopaminergic receptors in antinociception induced by lateral hypothalamus stimulation. This study aimed to investigate the role of DG dopaminergic receptors (D1- and D2-like dopamine receptors) in stress-induced analgesia (SIA) using the formalin test as a persistent inflammatory pain model. One hundred two male Wistar rats were unilaterally implanted with a cannula into the DG. Animals received an intra-DG infusion of SCH23390 (0.25, 1, and 4 μg/rat), or Sulpiride (0.25, 1, and 4 μg/rat) as D1- and D2-like dopamine receptor antagonists, respectively, five min before exposure to forced swim stress (FSS). Ten minutes after FSS termination, 2.5% formalin solution as an inflammatory agent was subcutaneously injected into the plantar surface of the hind paw, and the pain score was quantified for one hour. The findings revealed that exposure to FSS produced SIA, though this FSS-induced analgesia was attenuated in the early and late phase of the formalin test by intra-DG microinjection of SCH23390 or Sulpiride. These results suggested that both D1- and D2-like dopamine receptors in the DG have a considerable role in analgesia induced by FSS.
Learn More >Diagnosis of patients with occipital headache can be challenging, as both primary and secondary causes must be considered. Our study assessed how often migraine is screened for, diagnosed, and treated in patients receiving greater occipital nerve blocks (GONBs) in a pain clinic.
Learn More >Pain in children living with and beyond cancer is understudied and undertreated. Pain science education (PSE) is a conceptual change strategy facilitating patients' understanding of the biopsychosocial aspects of pain. Preliminary studies on the adaptation of PSE interventions to adults with and beyond cancer provide a foundation for pediatric research. PSE could help childhood cancer survivors experiencing persistent pain and pain-related worry after active treatment. PSE may also help children receiving cancer treatment, providing them with a foundation of adaptive pain beliefs and cognitions, and preparing them for procedural and treatment-related pain. We direct this paper toward pediatric oncology clinicians, policy makers, and researchers working with children living with and beyond cancer. We aim to (a) identify challenges in adapting PSE for children living with and beyond cancer, (b) offer possible solutions, and (c) propose research questions to guide the implementation of PSE for children living with and beyond cancer.
Learn More >The search for safe and efficient chronic pain treatments is dampened by the lack of reliable models that faithfully reproduce current pharmacological treatments for chronic spontaneous pain in humans. Preclinical models often assess the antinociceptive efficacy of non-contingent pharmacological treatments evaluated in the short-term. Here, we provide a protocol of contingent operant self-medication in mice, which allows the estimation of spontaneous pain relief and drug abuse liability in models of persistent pain. This paradigm requires preliminary habituation and animal handling, followed by training of mice in operant conditioning boxes, to allow subsequent analgesic drug self-administration. After the initial acquisition of food-maintained operant behavior, a chronic pain sensitization is induced. Posterior intravenous jugular catheterization and coupling of operant conditioning boxes to perfusion pumps allow quantification of operant responding for intravenous drug self-administration. All mice show an initial operant drug self-administration behavior associated with the previous food-maintained operant training. This initial operant responding is extinguished after administration of ineffective treatments, but continues when the compounds have analgesic efficacy or intrinsic reinforcing properties. The identification of a significant drug self-administration selectively expressed in mice exposed to the chronic pain condition is indicative of analgesic drug effects, whereas persistent self-administration in control mice is indicative of abuse liability. The present protocol provides the behavioral and surgical procedures needed to assess spontaneous pain relief and potential for abuse of pharmacological treatments, through contingent analgesic self-medication in mice. Graphic abstract: Animals are subjected to a 5-day food self-administration protocol with a fixed ratio of reinforcement of 1 (FR1, 1 interaction with the active nose-poke causes the release of 1 reinforcer/infusion), to acquire the operant behavior. After this training, mice are subjected to the chronic pain or sham procedure, and four days later an intravenous (i.v.) catheterization is performed, to allow self-administration with the selected compound or its vehicle. Three days after the catheterization, animals start the drug/vehicle self-administration protocol at FR1. The patency of the catheter is evaluated with the thiopental test after the last self-administration session. Adapted from Bura (2018).
Learn More >The real-world use of triptans in the treatment of migraine is disappointing. Only 12% of the Danish migraine population purchased a triptan between 2014 and 2019, and only 43% repurchased a triptan after first prescription. The aim of the present study was to assess whether physicians and patients adhere to the therapeutic guideline on acute migraine treatment. We interviewed 299 triptan experienced participants with migraine and 101 triptan naïve participants with migraine from the Danish Migraine Population Cohort, using a semi-structured questionnaire. Descriptive statistical analyses were used to study the association with triptan use and the assessed factors. Among triptan naïve participants with migraine, 64% had consulted their general practitioner about their migraine, of whom only 23% received information about the possibility of triptan treatment. Among triptan experienced participants, 77% had only tried one type of triptan. Only 12% could recall they had been informed by their general practitioner to try each triptan three times before giving up. Twenty percent were informed to try three different triptans in total, if the first did not work. In disagreement with the guideline, participants who reported a low pain reduction by a triptan had only tried one type of triptan. Our study shows a low adherence to therapeutic guideline for the attack treatment of migraine. There is a need for better education of general practitioners regarding treatment of migraine. Future campaigns should aim to inform both the public and the general practitioner about antimigraine treatments.
Learn More >Diabetes is by far, the most common cause of neuropathy, inducing neurodegeneration of terminal sensory nerve fibers associated with loss of sensation, paresthesia, and persistent pain. Foretinib prevents die-back degeneration in cultured sensory and sympathetic neurons by rescuing mitochondrial activity and has been proven safe in prospective clinical trials. Here we aimed at investigating a potential neuroprotective effect of Foretinib in experimental diabetic neuropathy. A mouse model of streptozotocin induced diabetes was used that expresses yellow fluorescent protein (YFP) in peripheral nerve fibers under the thy-1 promoter. Streptozotocin-injected mice developed a stable diabetic state (blood glucose > 270 mg/dl), with a significant reduction of intraepidermal nerve fiber density by 25% at 5 weeks compared to the non-diabetic controls. When diabetic mice were treated with Foretinib, a significantly greater volume of the cutaneous nerve fibers (67.3%) in the plantar skin was preserved compared to vehicle treated (37.8%) and non-treated (44.9%) diabetic mice while proximal nerve fiber morphology was not affected. Our results indicate a neuroprotective effect of Foretinib on cutaneous nerve fibers in experimental diabetic neuropathy. As Foretinib treated mice showed greater weight loss compared to vehicle treated controls, future studies may define more sustainable treatment regimen and thereby may allow patients to take advantage of this neuroprotective drug in chronic neurodegenerative diseases like diabetic neuropathy.
Learn More >Chronic hemolytic anemia and intermittent acute pain episodes are the 2 hallmark characteristics of sickle cell disease (SCD). Anemia in SCD not only signals a reduction of red cell mass and oxygen delivery, but also ongoing red cell breakdown and release of cell-free hemoglobin, which together contribute to a number of pathophysiological responses and play a key role in the pathogenesis of cumulative multiorgan damage. However, although anemia is clearly associated with many detrimental outcomes, it may also have an advantage in SCD in lowering risks of potential viscosity-related complications. Until recently, clinical drug development for SCD has predominantly targeted a reduction in the frequency of vaso-occlusive crises as an endpoint, but increasingly, more attention is being directed toward addressing the contribution of chronic anemia to poor outcomes in SCD. This article aims to explore the complex pathophysiology and mechanisms of anemia in SCD, as well as the need to balance the benefits of raising hemoglobin levels with the potential risks of increasing blood viscosity, in the context of the current therapeutic landscape for anemia in SCD.
Learn More >Chronic itch is a socioeconomic burden with limited management options. Non-histaminergic itch, involved in problematic pathological itch conditions, is transmitted by a subgroup of polymodal C-fibers. Cowhage is traditionally used for studying experimentally induced non-histaminergic itch in humans, but encounter some limitations. The present study therefore aims to design a new human, experimental model of non-histaminergic itch based on the application of bovine adrenal medulla (BAM)8-22, an endogenous peptide that activates MrgprX1 receptor. 22 healthy subjects were recruited. Different concentrations (0.5, 1, and 2 mg/ml) of BAM8-22 solution and vehicle, applied by a single skin prick test (SPT), were tested in the first session. In the second session, the BAM8-22 solution (1 mg/ml) was applied by different number of SPTs (1, 5, and 25) and by heat-inactivated cowhage spicules coated with BAM8-22. Provoked itch and pain intensities were monitored for 9 minutes followed by the measurement of superficial blood perfusion (SBP), mechanical and thermal sensitivity. BAM8-22 induced itch at the concentration of 1 mg/ml, 2 mg/ml (p<0.05), and with the significantly highest intensity when applied through BAM8-22 spicules (p<0.001). No concomitant pain sensation nor increased SBP were observed. SBP increased only in the 25 SPTs area probably due to micro-trauma from the multiple skin penetrations. Mechanical and thermal sensitivities were not affected by any of the applications. BAM8-22 applied through heat-inactivated spicules was the most efficient method to induce itch (without pain nor changes in SBP, mechanical and thermal sensitivity) suggesting BAM8-22 as a novel non-histaminergic, human, experimental itch model.
Learn More >Considering the widespread use of rabbits in research that potentially causes pain and discomfort and the limited number of pain assessment validated tools in this species, we aimed to develop and validate a scale of acute postoperative pain in rabbits (RPBS). Footage of 58 rabbits from previous studies were used, recorded at 'baseline' (before orthopaedic and soft tissue surgeries), 'pain' (after surgery), 'analgesia' (after analgesic), and '24h post' (24 hours after surgery). The videos were randomised and assessed twice by four evaluators, within one-month interval between evaluations. After content validation, RBPS was further refined using the criteria from the validation. According to the principal component analysis, RPBS was considered unidimensional. The intra- and inter-observer reliability was excellent (ICC>0.80) for all evaluators. There was a high Spearman's correlation of the RPBS with unidimensional scales (>0.80) and a moderate correlation with the Rabbit Grimace Scale (0.68), confirming criterion validity. According to the mixed linear model, the scale was responsive, shown by the increase in pain scores after surgery. Construct validity was confirmed by known-group approach and internal relationships among items. Adequate item-total correlation (>0.3) was observed for all items, except for the attention to the affected area (0.04). The internal consistency was very good (Cronbach's α coefficient = 0.78; Mcdonald's ω coefficient = 0.83). The cut-off score for rescue analgesia was ≥3, with an area under the curve >0.95, demonstrating a high discriminatory capacity of the instrument. Scores 3 and 4 were within the uncertainty diagnostic zone. Specificity was 87% and sensitivity was 90%. It was concluded that the RPBS presented content, criterion, and construct validities, responsiveness, and reliability to assess acute pain in rabbits submitted to orthopaedic and soft tissue surgeries. The cut-off for rescue analgesia serves as a basis for the administration of analgesics to rabbits submitted to painful procedures.
Learn More >The purpose of this study was to investigate pain and radiological features of different types of first-episode demyelinating optic neuritis (ON).
Learn More >Opioids are widely used in chronic pain management, despite major concerns about their risk of adverse events, particularly abuse, misuse, and respiratory depression from overdose. Multi-mechanistic opioids, such as tapentadol and buprenorphine, have been widely studied as a valid alternative to traditional opioids for their safer profile. Special interest was focused on the role of the nociceptin opioid peptide (NOP) receptor in terms of analgesia and improved tolerability. Nociceptin opioid peptide receptor agonists were shown to reinforce the antinociceptive effect of mu opioid receptor (MOR) agonists and modulate some of their adverse effects. Therefore, multi-mechanistic opioids involving both MOR and NOP receptor activation became a major field of pharmaceutical and clinical investigations. Buprenorphine was re-discovered in a new perspective, as an atypical analgesic and as a substitution therapy for opioid use disorders; and buprenorphine derivatives have been tested in animal models of nociceptive and neuropathic pain. Similarly, cebranopadol, a full MOR/NOP receptor agonist, has been clinically evaluated for its potent analgesic efficacy and better tolerability profile, compared with traditional opioids. This review overviews pharmacological mechanisms of the NOP receptor system, including its role in pain management and in the development of opioid tolerance. Clinical data on buprenorphine suggest its role as a safer alternative to traditional opioids, particularly in patients with non-cancer pain; while data on cebranopadol still require phase III study results to approve its introduction on the market. Other bifunctional MOR/NOP receptor ligands, such as BU08028, BU10038, and AT-121, are currently under pharmacological investigations and could represent promising analgesic agents for the future.
Learn More >Medical cannabis is often used to alleviate common symptoms in patients with chronic conditions. With cannabis legalisation in Canada and easier access, it is important that rheumatologists understand its potential impact on their practice. Among patients attending rheumatology clinics in Ontario we assessed: the prevalence of medical cannabis use; symptoms treated; rheumatologists' perceptions.
Learn More >This study aims to determine domains of pain interference in daily routines assessed using the Brief Pain Inventory, in relation to multisite musculoskeletal pain among older adults living in the community.
Learn More >The clinical use of calcitonin gene-related peptide receptor (CGRP-R) antagonists and monoclonal antibodies against CGRP and CGRP-R has offered new treatment possibilities for migraine patients. CGRP activates both the CGRP-R and structurally related amylin 1 receptor (AMY-R). The relative effect of erenumab and the small-molecule CGRP-R antagonist, rimegepant, towards the CGRP-R and AMY-R needs to be further characterized.
Learn More >There is limited information on immune checkpoint inhibitor-induced bullous pemphigoid (ICI-BP) in patients with cancer, with most existing studies being case reports or small case series from a single institution. Prior review attempts have not approached the literature in a systematic manner and have focused only on ICI-BP secondary to anti-programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) therapy. The current knowledge base of all aspects of ICI-BP is limited.
Learn More >To explore the effect of moxibustion instrument combined with ultrashort wave on pain and oxidative stress in elderly patients with knee osteoarthritis (KOA).
Learn More >Polymyalgia rheumatica (PMR) is the most common inflammatory rheumatic disease affecting people older than 50 years and is 2-3 times more common in women. The most common symptoms are pain and morning stiffness in the shoulder and pelvic girdle and the onset may be acute or develop over a few days to weeks. General symptoms such as fatigue, fever and weight loss may occur, likely driven by systemic IL-6 signalling. The pathology includes synovial and periarticular inflammation and muscular vasculopathy. A new observation is that PMR may appear as a side effect of cancer treatment with checkpoint inhibitors. The diagnosis of PMR relies mainly on symptoms and signs combined with laboratory markers of inflammation. Imaging modalities including ultrasound, magnetic resonance imaging and PET-CT are promising new tools in the investigation of suspected PMR. However, they are still limited by availability, high cost and unclear performance in the diagnostic workup. Glucocorticoid (GC) therapy is effective in PMR, with most patients responding promptly to 15-25 mg prednisolone per day. There are challenges in the management of patients with PMR as relapses do occur and patients with PMR may need to stay on GC for extended periods. This is associated with high rates of GC related comorbidities, such as diabetes and osteoporosis, and there is limited data on the use of disease-modifying antirheumatic drugs and biologics as GC sparing agents. Finally, PMR is associated with giant cell arteritis that may complicate the disease course and require more intense and prolonged treatment. This article is protected by copyright. All rights reserved.
Learn More >External low-frequency peripheral nerve stimulation (LFS) has been proposed as a novel method for neuropathic pain relief. Previous studies have reported that LFS elicits long-term depression-like effects on human pain perception when delivered at noxious intensities, while lower intensities are ineffective. To shed light on cortical regions mediating the effects of LFS, we investigated changes in somatosensory-evoked potentials (SEPs) during four LFS intensities. LFS was applied to the radial nerve (600 pulses, 1 Hz) of twenty-four healthy participants at perception (1×), low (5×), medium (10×) and high intensities (15× detection threshold). SEPs were recorded during LFS, and averaged SEPs in 10 consecutive one-minute epochs of LFS were analysed using source dipole modelling. Changes in resting electroencephalography (EEG) were investigated after each LFS block. Source activity in the midcingulate cortex (MCC) decreased linearly during LFS, with greater attenuation at stronger LFS intensities, and in the ipsilateral operculo-insular cortex during the two lowest LFS stimulus intensities. Increased LFS intensities resulted in greater augmentation of contralateral primary sensorimotor cortex (SI/MI) activity. Stronger LFS intensities were followed by increased alpha (9-11 Hz) band power in SI/MI and decreased theta (3-5 Hz) band power in MCC. Intensity-dependent attenuation of MCC activity with LFS is consistent with a state of long-term depression. Sustained increases in contralateral SI/MI activity suggests that effects of LFS on somatosensory processing may also be dependent on satiation of SI/MI. Further research could clarify if the activation of SI/MI during LFS competes with nociceptive processing in neuropathic pain.
Learn More >Effective symptom control in painful knee osteoarthritis (OA) may improve patient quality of life. In a randomised crossover trial (NCT03381248), COOLIEF* cooled radiofrequency ablation (CRFA) reduced pain and stiffness and improved physical function and quality of life compared with intra-articular hyaluronan (HA) injections. The present study aimed to establish the cost effectiveness of CRFA versus intra-articular HA injections for treating moderate-to-severe OA knee pain from a US Medicare perspective.
Learn More >Around 20% of the Dutch population is living with chronic musculoskeletal pain (CMP), which is a complex and multifactorial problem. This complexity makes it hard to define a classification system, which results in non-satisfactory referring from the general practitioner (GP). CMP is often explained using the biopsychosocial model in which biological, psychological and social factors cause and maintain the pain. The presented study investigated the factors related to the GPs' referral for patients with CMP to further treatment.Using convenience sampling, semi-structured interviews and a focus group were conducted among 14 GPs. The interviews were iteratively analyzed using inductive conventional content analysis.Analysis of the interviews demonstrated that there were 28 referral factors that were mentioned by more than 50% of the interviewed GPs. The results showed that the GPs were mostly focussing on the physical (e.g. pain location) and psychological (e.g. acceptation of pain) factors, indicating that they lack focus on the social factors. Furthermore, unfamiliarity of GPs with treatment options was a noteworthy finding.The referral of patients with CMP by GPs is complex and based on multiple factors. To improve referral, it is recommended to include social factors in the decision-making process and to increase the familiarity of the GPs with available treatments.
Learn More >Characterised by chronic widespread musculoskeletal pain, generalised hyperalgesia, and psychological distress, fibromyalgia (FM) is a significant unmet clinical need. The endogenous cannabinoid system plays an important role in modulating both pain and the stress response. Here, we appraise the evidence, from preclinical and clinical studies, for a role of the endocannabinoid system in FM and the therapeutic potential of targeting the endocannabinoid system. While many animal models have been used to study FM, the reserpine-induced myalgia model has emerged as the most translatable to the clinical phenotype. Inhibition of fatty acid amide hydrolase (FAAH) has shown promise in preclinical studies, ameliorating pain- and anxiety-related behaviour, and not associated with the development of tolerance. Clinically, there is evidence for alterations in the endocannabinoid system in patients with FM, including single nucleotide polymorphisms and increased levels of circulating endocannabinoids and related N-acylethanolamines. Single entity cannabinoids, cannabis, and cannabis-based medicines in patients with FM show promise therapeutically but limitations in methodology and lack of longitudinal studies to assess efficacy and tolerability preclude the current recommendation for their use in patients with FM. Gaps in the literature that warrant further investigation are discussed, particularly the need for further development of animal models with high validity for the multifaceted nature of FM, balanced studies to eliminate sex-bias in preclinical research, and ultimately, better translation between preclinical and clinical research.
Learn More >Trigeminal neuralgia (TN) is a neuropathic pain that occurs in branches of the trigeminal nerve. MicroRNAs (miRNAs) have been considered key mediators of neuropathic pain. This study was aimed to elucidate the pathophysiological function and mechanisms of miR-223-3p in mouse models of TN.
Learn More >Lumbar epidural is the gold standard for labour analgesia. Low concentrations of local anaesthetic are recommended. This network meta-analysis investigated whether further reducing the concentration of local anaesthetic can improve maternal and neonatal outcomes without compromising analgesia. We conducted a systematic search of relevant databases for randomised controlled trials comparing high (>0.1%), low (>0.08% to ≤0.1%) or ultra-low (≤0.08%) concentration local anaesthetic (bupivacaine or equivalent) for labour epidural. Outcomes included mode of delivery, duration of labour and maternal/neonatal outcomes. Bayesian network meta-analysis with random-effects modelling was used to calculate odds ratios or weighted mean differences and 95% credible intervals. A total of 32 studies met inclusion criteria (3665 women). The total dose of local anaesthetic received increased as the concentration increased; ultra-low compared with low (weighted mean difference -14.96 mg, 95% credible interval [-28.38 to -1.00]) and low compared with high groups (weighted mean difference -14.99 [-28.79 to -2.04]), though there was no difference in the number of rescue top-ups administered between the groups. Compared with high concentration, ultra-low concentration local anaesthetic was associated with increased likelihood of spontaneous vaginal delivery (OR 1.46 [1.18 to 1.86]), reduced motor block (Bromage score >0; OR 0.32 [0.18 to 0.54]) and reduced duration of second stage of labour (weighted mean difference -13.02 min [-21.54 to -4.77]). Compared with low, ultra-low concentration local anaesthetic had similar estimates for duration of second stage of labour (weighted mean difference -1.92 min [-14.35 to 10.20]); spontaneous vaginal delivery (OR 1.07 [0.75 to 1.56]; assisted vaginal delivery (OR 1.35 [0.75 to 2.26]); caesarean section (OR 0.76 [0.49 to 1.22]); pain (scale 1-100, weighted mean difference -5.44 [-16.75 to 5.93]); and maternal satisfaction. Although a lower risk of an Apgar score < 7 at 1 min (OR 0.43 [0.15 to 0.79]) was reported for ultra-low compared with low concentration, this was not sustained at 5 min (OR 0.12 [0.00 to 2.10]). Ultra-low concentration local anaesthetic for labour epidural achieves similar or better maternal and neonatal outcomes as low and high concentration, but with reduced local anaesthetic consumption.
Learn More >This study explores the biomechanics underlying the sit-to-stand (STS) functional maneuver in chronic LBP patients to understand how different spinal disorders and levels of pain severity relate to unique compensatory biomechanical behaviors. This work stands to further our understanding of the relationship between spinal loading and symptoms in LBP patients.
Learn More >Current treatments of osteoarthritis, such as oral medication and intra-articular injections, only provided temporary relief from pain and achieved limited advance in inhibiting progression. The development of new treatments is hindered by the complicated and unclear pathological mechanisms. Oxidative stress and immune inflammation are believed to be the important factors in the induction and progression of osteoarthritis. Herein, this work presents a bioactive material strategy to treat osteoarthritis, based on the FPSOH matrixgel with robust anti-inflammatory activity through inhibiting the oxidative stress and nuclear factor kappa B signaling, preventing the metalloproteinase, as well as inducing M2 polarization of macrophage, thereby providing immune regulation of synovial macrophages and suppressing the progression of synovitis and osteoarthritis. experiments demonstrated that FPSOH hydrogel can prevent papain-induced osteoarthritis and its progression, and provide dual protection for cartilage and synovium, as compared with commercial sodium hyaluronate.
Learn More >Refractory chronic pain in the orofacial region involves central sensitization (CS). However, not all chronic pain patients exhibit CS. An objective assessment of CS may be useful for pain management. Changes in the balance of excitatory and inhibitory neural activity or excessive activity of nerves and glial cells may cause CS and contribute to pain chronification.
Learn More >Opioids are often the mainstay of postoperative pain management, despite strong evidence of their ill effects and potential for long-term addiction. The goal of this study was to quantify opioid use and contrast pain management strategies of multiple international institutions performing fibula free flap reconstruction. A retrospective multicenter cohort study was designed, including five international centers. For inclusion, the patients had to have undergone a primary fibula free flap reconstruction of the mandible. A total of 185 patients were included. The median opioid use across all centers at 72 hours was 133 oral morphine equivalents. The highest utilization was in the USA (P < 0.001), which was approximately six times that of Italy, four times that of Argentina, and twice that of India, despite all centers performing a similar procedure. Based on this study there are clear differences in prescribing practices and ideologies among surgeons from different countries.
Learn More >Inflammatory Bowel Disease is characterised by abdominal pain, diarrhoea, rectal bleeding and weight loss. Sometimes it may lead to severe health complications resulting in death of an individual. Current research efforts to highlight the role of melatonin in regulating EZH2, a master epigenetic regulator and its beneficiary effect in case of IBD management.
Learn More >Type 2 immunity evolved to combat helminth infections by orchestrating a combined protective response of innate and adaptive immune cells and promotion of parasitic worm destruction or expulsion, wound repair, and barrier function. Aberrant type 2 immune responses are associated with allergic conditions characterized by chronic tissue inflammation, including atopic dermatitis (AD) and asthma. Signature cytokines of type 2 immunity include interleukin (IL)-4, IL-5, IL-9, IL-13, and IL-31, mainly secreted from immune cells, as well as IL-25, IL-33, and thymic stromal lymphopoietin, mainly secreted from tissue cells, particularly epithelial cells. IL-4 and IL-13 are key players mediating the prototypical type 2 response; IL-4 initiates and promotes differentiation and proliferation of naïve T-helper (Th) cells toward a Th2 cell phenotype, whereas IL-13 has a pleiotropic effect on type 2 inflammation, including, together with IL-4, decreased barrier function. Both cytokines are implicated in B-cell isotype class switching to generate immunoglobulin E, tissue fibrosis, and pruritus. IL-5, a key regulator of eosinophils, is responsible for eosinophil growth, differentiation, survival, and mobilization. In AD, IL-4, IL-13, and IL-31 are associated with sensory nerve sensitization and itch, leading to scratching that further exacerbates inflammation and barrier dysfunction. Various strategies have emerged to suppress type 2 inflammation, including biologics targeting cytokines or their receptors, and Janus kinase inhibitors that block intracellular cytokine signaling pathways. Here we review type 2 inflammation, its role in inflammatory diseases, and current and future therapies targeting type 2 pathways, with a focus on AD.
Learn More >The aim of this systematic review was to assess the reproducibility of exercise therapy used in clinical trials for chronic neck pain (CNP) based on reported items from the Template for Intervention Description and Replication (TIDieR) and the Consensus on Exercise Reporting Template (CERT) checklists.
Learn More >Pain, a complex subjective experience, is common in care home residents. Despite advances in pain management, optimal pain control remains a challenge. In this updated systematic review, we examined effectiveness of interventions for treating chronic pain in care home residents.
Learn More >This secondary analysis of a randomised controlled patient-blinded trial comparing effectiveness and side effect briefings in patients with chronic low back pain (CLBP) investigated the association between patients' pre-treatment expectations about minimal acupuncture treatment and pain intensity as outcome during and after the end of the treatment.
Learn More >To assess the long-term efficacy and safety of erenumab in the subgroup of patients with chronic migraine (CM) in whom prior preventive treatments had failed (TF) (≥1, ≥2, and ≥3 TF medication categories) and never failed (preventive naïve or prior preventive treatments had not failed), using the data from a 52-week, open-label treatment period (OLTP) of the parent study.
Learn More >To investigate the impact of having headaches prior to traumatic brain injury (TBI) on headache features and long-term patient health outcomes.
Learn More >Oxytocin (OT), a nonapeptide, has a variety of functions. Despite extensive studies on OT over past decades, our understanding of its neural functions and their regulation remains incomplete. OT is mainly produced in OT neurons in the supraoptic nucleus (SON), paraventricular nucleus (PVN) and accessory nuclei between the SON and PVN. OT exerts neuromodulatory effects in the brain and spinal cord. While magnocellular OT neurons in the SON and PVN mainly innervate the pituitary and forebrain regions, and parvocellular OT neurons in the PVN innervate brainstem and spinal cord, the two sets of OT neurons have close interactions histologically and functionally. OT expression occurs at early life to promote mental and physical development, while its subsequent decrease in expression in later life stage accompanies aging and diseases. Adaptive changes in this OT system, however, take place under different conditions and upon the maturation of OT release machinery. OT can modulate social recognition and behaviors, learning and memory, emotion, reward, and other higher brain functions. OT also regulates eating and drinking, sleep and wakefulness, nociception and analgesia, sexual behavior, parturition, lactation and other instinctive behaviors. OT regulates the autonomic nervous system, and somatic and specialized senses. Notably, OT can have different modulatory effects on the same function under different conditions. Such divergence may derive from different neural connections, OT receptor gene dimorphism and methylation, and complex interactions with other hormones. In this review, brain functions of OT and their underlying neural mechanisms as well as the perspectives of their clinical usage are presented.
Learn More >Behavioral symptoms, including mood disorders, substantially impact the quality of life of patients with inflammatory bowel disease (IBD), even when clinical remission is achieved. Here, we used multimodal magnetic resonance imaging (MRI) to determine if IBD is associated with changes in the structure and function of deep gray matter brain regions that regulate and integrate emotional, cognitive, and stress responses.
Learn More >The objectives of the study were: 1) Describe the thematic structure and evolution of the field of physical therapy; 2) identify the main research producers (i.e. countries and institutions); and 3) compare their research output and citation impact.
Learn More >The aim of this article is to examine the extent of structural and inflammatory lesions by ultrasound in elderly subjects with hand osteoarthritis (HOA) fulfilling the ACR classification criteria (Group A), in subjects with painless enlarged finger joints (Group B), and in individuals without clinical abnormalities at hands (Group C).
Learn More >The role of low-level laser therapy (LLLT) in the management of carpal tunnel syndrome (CTS) is controversial. While some trials have shown distinct advantages of LLLT over placebo and some other non-surgical treatments, other trials have not.
Learn More >Crosstalk between Sirtuins and Nrf2: SIRT1 activators as emerging treatment for diabetic neuropathy.
About 50% of the diabetic patients worldwide suffer from Diabetic peripheral neuropathy (DPN) which is characterized by chronic pain and loss of sensation, frequent foot ulcerations, and risk for amputation. Numerous factors like hyperglycemia, oxidative stress (OS), impaired glucose signaling, inflammatory responses, neuronal cell death are known to be the various mechanisms underlying DACD and DPN. Development of tolerance, insufficient and inadequate relief and potential toxicity of classical antinociceptives still remains a challenge in the clinical setting. Therefore, there is an emerging need for novel treatments which are both without any potential side effects as well as which focus more on the pathophysiological mechanisms underlying the disease. Also, sirtuins are known to deacetylate Nrf2 and contribute to its action of reducing ROS by generation of anti-oxidant enzymes. Therefore, targeting sirtuins could be a favourable therapeutic strategy to treat diabetic neuropathy by reducing ROS and thereby alleviating OS in DPN. In the present review, we outline the potential use of SIRT1 activators as therapeutic alternatives in treating DPN. We have tried to highlight how sirtuins are interlinked with Nrf2 and NF-κB and put forth how SIRT activators could serve as potential therapy for DPN.
Learn More >To establish the role of inflammation in bortezomib induced peripheral neuropathy (BIPN).
Learn More >Cluster headache is a less-prevalent primary headache disorder but is overrepresented with regards to use of health care and social services. More insight into the socioeconomic impact is required.
Learn More >Patients with refractory chronic migraine have poor quality of life. Intravenous infusions are indicated to rapidly 'break the cycle' of pain. Lidocaine infusions may be effective but evidence is limited.
Learn More >To assess the variation in migraine management over time across U.S. children's hospitals and to identify factors associated with disparities in management.
Learn More >Disparities in access to pain management have been identified in several care settings, such as emergency departments and intensive care units, but with regard to labour analgesia, it remains poorly explored.
Learn More >Changes in gait characteristics have been reported in people with chronic neck pain (CNP).
Learn More >To evaluate the effectiveness of the cold intervention on relieving migraine symptoms among adult patients with migraine.
Learn More >To gather information about prescription of triptans and to evaluate whether vascular comorbidity differs in users and nonusers of triptans over the age of 50 years.
Learn More >Food-Specific IgG4 Antibody-Guided Exclusion Diet Improves Conditions of Patients with Chronic Pain.
Chronic pain is related to gastrointestinal (GI) functions because food components affect inflammation and pain through their action on the GI immune and/or neural system and because many analgesics interact with the gut to alter its structure and function. Immunoglobulin G4 (IgG4) are food-specific antibodies resulting from exposure of the gut immune system to nutrients. High IgG4 levels have been found to be associated with inflammation.
Learn More >The objective of this paper is to present a narrative review of the use of triptans in the treatment of trigeminal neuralgia (TN), as well as to outline possible therapeutic mechanisms of action.
Learn More >The brain mechanism of inflammatory pain is an understudied area of research, particularly concerning the descending pain modulatory system. The G protein-coupled receptor 55 (GPR55) is a lysophosphatidylinositol-sensitive receptor that has also been involved in cannabinoid signaling. It is widely expressed throughout the central nervous system, including the periaqueductal gray (PAG), a brainstem area and key element of the descending pain modulatory system. In this study, we used behavioral, stereotaxic injections, pharmacological tools, and two inflammatory pain models (formalin and carrageenan) to determine if GPR55 in the PAG plays a role in the pain associated with inflammation in rats. It was found that the blockade of GPR55 action in PAG can drive the descending pain modulatory system to mitigate inflammatory pain. These data show that GPR55 plays a role in the descending pain modulatory system in inflammatory pain.
Learn More >Retraction: "MicroRNA-217 relieved neuropathic pain through targeting toll-like receptor 5 expression", by Wanwei Jiang, Qinghui Wang, Xuemei Yu, Tong Lu, and Pengbo Zhang, J Cell Biochem. 2019; 3009-3017: The above article, published online on 11 December 2018 in Wiley Online Library (doi:10.1002/jcb.27269), has been retracted by agreement between the authors, the journal's Editor in Chief, Prof. Dr. Christian Behl, and Wiley Periodicals LLC. The retraction has been agreed after the authors asked to correct their article. The investigation additionally revealed several flaws and inconsistencies between results presented and experimental methods described. Thus, the editors consider the conclusions of this article to be invalid.
Learn More >Emotional profile is involved in the experience of chronic pain related to endometriosis. Following the Örebro Model of Behavioral Emotion Regulation of Pain, the aim of this study was to understand the processes involved in the psychological adaptation to pain experienced during menstruations in women either diagnosed or not diagnosed with endometriosis.
Learn More >Although migraine in adult and pediatric patients are overall very similar to each other, differences in prevalence, presentation, and treatment efficacy may reflect slight differences in the pathophysiological processes underlying migraine in these patient groups, perhaps because of ongoing development of the nervous system during childhood and adolescence. Although major gains have been made in understanding the pathophysiology of migraine in adults in recent years, equivalent research on migraine in pediatric patients continues to lag behind. In this review, we will describe the current state of migraine research in pediatric patients with regard to presentation and frequency of prodromal and postdromal symptoms, ictal and interictal calcitonin gene-related peptide elevation, and evidence for cortical spreading depression, thus covering all phases of migraine, and discuss how the findings seen here may relate to possible underlying pathophysiological mechanisms of migraine. We aim to elucidate possible differences between migraine in children and adults, and the need for further research specific to pediatric patients with migraine in order to improve treatment in this patient group.
Learn More >Mechanical stress plays a crucial role in the pathogenesis of intervertebral disc degeneration (IVDD). The mechanosensitive Piezo1 ion channel can sense the changes in mechanical stress and convert the mechanical signals into chemical signals. This study aims to investigate the effect of Piezo1 on the mechanical stress-induced IVDD and explore the possible mechanism.
Learn More >Opioids are the gold standard for chronic and acute pain management however its consequence on gastric function is relatively understudied. Opioid users have a higher incidence of gastric dysfunction, worse quality of life, increased hospitalizations, and increased use of antiemetic and pain modulator medications. In the current study, we show that morphine treatment in the murine model results in greater disruption of gastric epithelial cell morphology, increased gastric cell apoptosis, elevated inflammatory cytokines and MMP-9 secretion. Morphine treatment also increases gastric acid secretion and causes delays in gastric emptying. Moreover, morphine treatment causes an increase in systemic IL-6 level, which plays an important role in morphine-induced delayed gastric emptying and gastric damage. IL-6KO mice show a significant level of reduction in morphine-induced gastric delaying, acid retention and gastric damage. Thus, morphine-mediated gastric damage is a consequence of the accumulation of acid in the stomach due to increased gastric acid secretion and delayed gastric emptying. Treatment with a proton pump inhibitor resulted in a significant reduction in morphine-induced gastric inflammation, gastric delaying and improved morphine tolerance. Hence, these studies attribute morphine-mediated induction in gastric acidity and inflammatory cytokines as drivers for morphine-associated gastric pathology and show the therapeutic use of proton pump inhibitors as an inexpensive approach for clinical management of morphine-associated pathophysiology and analgesic tolerance.
Learn More >Buprenorphine has been widely used in opioid medication assisted treatment (MAT) in the past decade. However, due to misinterpretation of its intrinsic mu opioid receptor activity extrapolated from preclinical and animal data, buprenorphine's clinical application in pain management has been greatly limited. Buprenorphine acts as a full mu agonist with fewer side effects compared to traditional opioids and can be effectively used in the treatment of acute and chronic pain. A strong body of evidence demonstrates that buprenorphine is an effective analgesic agent in both adult and pediatric surgical patients. In addition, buprenorphine has been successfully used in treating chronic pain, particularly in cancer pain and neuropathic pain. In this Journal course, buprenorphine's receptor pharmacology and pharmacokinetics are reviewed. Specifically, misinterpretation of its intrinsic mu receptor activity, and both analgesic ceiling effect and efficacy are clarified. Differences between suboxone and buprenorphine, and specific applications are explained. Pain management options and guidelines for surgical patients on buprenorphine are discussed, as well.
Learn More >There is an ongoing debate on the use of long-term high-dose medically prescribed opioid analgesics for patients with chronic noncancer pain. Such use is elevated when there is comorbid pain and PTSD, which is quite prevalent. Therefore, it is relevant to investigate the psychological variables that may explain opioid misuse in this population. The purpose of this study was to examine the interaction effect of PTSD severity, distress intolerance, and pain catastrophizing on prescribed opioid misuse in chronic noncancer pain patients.
Learn More >Self-efficacy is a determinant of function and pain outcomes in patients with chronic low back pain receiving physiotherapy. The McKenzie approach is an effective intervention for patients with back pain that may affect self-efficacy. Study aims were to determine if, among patients with back pain being managed by McKenzie-credentialed physiotherapists: intake self-efficacy is correlated with intake function and pain; intake self-efficacy is associated with changes in function and pain during treatment; self-efficacy improves during treatment; and improvements in self-efficacy during treatment are associated with improvements in function and pain at discharge.
Learn More >The use of virtual reality (VR) in the mediation of acute pain in adults has shown real benefit to patients for the past 20 years. This review of the literature provides a descriptive synthesis of the types of VR technology, the mechanisms by which VR mediates pain, and a history of early research in the area. A review of the use of VR to mediate chronic pain in adults, and both acute and chronic pain in pediatric populations follows. The studies reviewed provide mixed results and it is noted that many studies have small sample sizes, are case studies, and do not control for extraneous variables such as the dosage and type of VR technology used. Although VR is an exciting area of inquiry that promises to yield multiple applications, there is a necessity to conduct larger random controlled trials to better understand the use cases for which VR is most effective.
Learn More >The effect of moderate neonatal stress induced by inflammatory pain in rat pups of both sexes on the hormonal response and cognitive processes in adult animals was studied in the Morris water maze. No significant differences in spatial learning and memory were found in experimental rats exposed to neonatal inflammatory pain vs. control animals. However, experimental rats exhibited sex differences in long-term spatial memory whose efficiency was higher in males vs. females. After long-term memory testing, stress responsiveness of the hypothalamic-pituitary-adrenocortical axis, as assessed by the plasma corticosterone level in the formalin test, was higher in experimental males vs. females. Only experimental females exhibited differences between short-term and long-term memory, with the efficiency being higher in the former. Thus, sexual dimorphism was found in the effect of neonatal nociceptive stress on long-term spatial memory in adult rats: experimental males vs. females demonstrated more effective long-term memory combined with a higher stress reactivity of the hormonal response.
Learn More >The pharmacological inhibition of soluble epoxide hydrolase (sEH) was shown to reduce inflammation and pain. Herein, we described a series of newly synthesized sEH inhibitors with the trident-shaped skeleton. Intensive structural modifications led to the identification of compound B15 as a potent sEH inhibitor with an IC value of 0.03±0.01 nM. Furthermore, compound B15 showed satisfactory metabolic stability in human liver microsomes with a half-time of 197 min. In carrageenan-induced inflammatory pain rat model, compound B15 exhibited a better therapeutic effect compared to t-AUCB and Celecoxib, which demonstrated the proof of potential as anti-inflammatory agents for pain relief.
Learn More >White matter lesions (WML) are more frequently observed in migraine patients than in the average population. Associations between Helicobacter pylori (H. pylori) infection and different extraintestinal pathologies have been identified. Here, we aimed to investigate the association between H. pylori infection and WML in patients diagnosed with episodic migraine.
Learn More >Chronic itch is a complex sensation of the skin frequently associated with skin diseases, such as atopic dermatitis (AD) and psoriasis. Although Serpin E1 is implicated in chronic itch, its receptor and signaling pathways involved in itch are not known. In this study, the clinical relevance of a putative Serpin E1 receptor PLAUR to chronic itch, and the neuro-cutaneous Serpin E1-PLAUR signaling are explored. We found that PLAUR is overexpressed in skin specimens of human lesional AD and lesional psoriasis, and sensory neurons innervating MC903-induced AD-like murine skin. Murine PLAUR sensory neurons responded to Serpin E1, resulting in enrichment of numerous itch- and inflammation-related genes and their protein release. PLAUR resides in TLR2 neurons and Serpin E1 stimulus led to transcriptional upregulation of TLR2 and its co-signaling proteins. Agonists of TLR2 propagated itch-related gene transcription including BNP, OSM, and PAR2. OSM induced acute itch in mice and promoted G-CSF and IL-8 release from human keratinocytes. Serpin E1 inhibitor reduced MC903-induced itch, epidermal hyperplasia, immunocyte infiltration, and resulted in lower transcription/expression levels of Serpin E1 and OSM. Taken together, the PLAUR-TLR2-OSM signaling promotes skin-nerve communication, cutaneous inflammation, and itch, all feeding into an aggravation of AD and exaggerated itch circuits.
Learn More >Chronic pain, a persistent or recurrent pain lasting more than 3 months, is a widespread problem among military women due to combat-related injuries and post-deployment stressors. Risk factors associated with chronic pain include gender, mental health, post-traumatic stress disorder, and prior physical or military sexual trauma. The most common prevalence of chronic pain is musculoskeletal (e.g., low back and neck), migraine, osteoarthritis, and fibromyalgia. Following deployment, 25% of military women are at risk for chronic pain. Military women are prescribed opioids for pain at a higher rate than men and are at risk for prescription opioid addiction. The unique medical needs of military women, including chronic pain, are poorly understood by health care providers and need to be addressed to achieve full integration into the military. The purpose of this study was to explore a typical day for military women living with chronic pain by examining the participants' daily life experiences.
Learn More >To assess the balance sensory organization among patients with migraine, considering the influence of migraine subdiagnosis, otoneurological function, falls, and psychosocial factors.
Learn More >Literature examining the relationship between elevated blood pressure and osteoarthritis (OA) has yielded conflicting results. This study aimed to systematically review the relationship between hypertension and OA in both load-bearing and non-load-bearing joints.
Learn More >Migraine is reportedly associated with several cardio-cerebrovascular diseases (CCDs), but some of these diseases have not received sufficient attention. We thus attempted to determine the associations of migraine with peripheral arterial disease (PAD), ischemic heart disease (IHD), atrial fibrillation/flutter (AF), ischemic stroke (IS), and hemorrhagic stroke (HS).
Learn More >Oxygen therapy (OT) can relieve head pain in certain primary headache disorders, including cluster headache (CH). The exact underlying mechanism is currently uncertain, but suggested mechanisms include inhibition of the trigeminoautonomic reflex, modulation of neurotransmitters, and cerebral vasoconstriction. OT is the standard for acute treatment of CH, but patients with CH often experience considerable difficulties accessing home OT due to problems with insurance coverage. Inhalation of 100% oxygen at 6-12 L/min for 15-30 min using a non-rebreather face mask is one of the most effective acute therapies for CH, but several trials have indicated the superiority of higher oxygen flow rates of up to 15 L/min and/or using a demand-valve oxygen mask that can produce very high flow rates. Two randomized controlled trials have demonstrated the efficacy of OT in migraine, but obtaining reliable evidence is considered difficult because of different inhalation protocols, varying outcome measures, and small samples. There are some reports on the efficacy of OT as an adjuvant therapy in hypnic headache, primary headache in the emergency department, and even postdural puncture headache. The goal of this review article is to expand the knowledge regarding the use of oxygen in the treatment of headache disorders.
Learn More >To evaluate the efficacy of chondroitin sulfate (CS) and glucosamine (GS), the most relevant drugs of "Symptomatic Slow Acting Drug for Osteoarthritis" (SYSADOA), in the functional and symptomatic improvement of temporomandibular dysfunction. Although, controversy exists regarding their benefit.
Learn More >The current quality of evidence supporting dry cupping for individuals with chronic low back pain (CLBP) is low and suggests that nonspecific factors impact experiences reported by patients. Therefore, this study assessed the impacts of social and professional support on the experience of individuals with CLBP treated with dry cupping or sham.
Learn More >Back and neck pain are widespread and can significantly reduce quality of life. A cross-sectional telephone survey (N=5,009) was carried out between October 2019 and March 2020 to gain a valid estimate of the prevalence of back and neck pain among adults in Germany. In addition to the frequency and intensity of back and neck pain, the study collected information about quality of life and comorbidity. The findings showed that 61.3% of respondents reported back pain in the last twelve months. Lower back pain was reported about twice as often as upper back pain, with 15.5% of respondents stating that they experienced chronic back pain. 45.7% reported neck pain, and 15.6% of respondents have experienced lower and upper back pain in addition to neck pain in the past year. Women are affected by all types of pain more often than men. About half of the respondents categorise their back or neck pain as moderate; older respondents report significantly more pain episodes per month than younger respondents. The results described here provide a comprehensive picture of the population-related limitations associated with back and neck pain and are used within the framework of the BURDEN 2020 study to quantify key indicators of burden of disease calculation.
Learn More >Irritable bowel syndrome (IBS) is characterized by visceral hypersensitivity (VH) associated with abnormal serotonin/5-hydroxytryptamine (5-HT) metabolism and neurotrophin-dependent mucosal neurite outgrowth. The underlying mechanisms of VH remain poorly understood. We investigated the role of 5-HT receptor in mucosal innervation and intestinal hyperalgesia. A high density of mucosal nerve fibres stained for 5-HT was observed in colonoscopic biopsy specimens from IBS patients compared with those from healthy controls. Staining of 5-HT and 5-HT receptors was observed mainly in colonic epithelia with comparable levels between IBS and controls. Visceromotor responses to colorectal distension were evaluated in two mouse models, one postinfectious with Giardia and subjected to water avoidance stress (GW) and the other postinflammatory with trinitrobenzene sulfonic acid-induced colitis (PT). Increased VH was associated with higher mucosal density of 5-HT-expressing nerve fibres and elevated neurotrophin and neurotrophin receptor levels in the GW and PT mice. The increased VH was inhibited by intraperitoneal injection of SB-269970 (a selective 5-HT antagonist). Peroral multiple doses of CYY1005 (a novel 5-HT ligand) decreased VH and reduced mucosal density of 5-HT-expressing nerve fibres in mouse colon. Human neuroblastoma SH-SY5Y cells incubated with bacteria-free mouse colonic supernatant, 5-HT, nerve growth factor, or brain-derived neurotrophic factor exhibited nerve fibre elongation, which was inhibited by 5-HT antagonists. Gene silencing of HTR7 also reduced the nerve fibre length. Activation of 5-HT upregulated NGF and BDNF gene expression, while stimulation with neurotrophins increased the levels of tryptophan hydroxylase 2 and 5-HT in neurons. A positive-feedback loop was observed between serotonin and neurotrophin pathways via 5-HT activation to aggravate fibre elongation, whereby 5-HT and 5-HT had no roles. In conclusion, 5-HT-dependent mucosal neurite outgrowth contributed to VH. A novel 5-HT antagonist could be used as peroral analgesics for IBS-related pain.
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