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In humans, gamma-band oscillations in the primary somatosensory cortex (S1) correlate with subjective pain perception. However, functional contributions to pain and the nature of underlying circuits are unclear. Here we report that gamma oscillations, but not other rhythms, are specifically strengthened independently of any motor component in the S1 cortex of mice during nociception. Moreover, mice with inflammatory pain show elevated resting gamma and alpha activity and increased gamma power in response to sub-threshold stimuli, in association with behavioral nociceptive hypersensitivity. Inducing gamma oscillations via optogenetic activation of parvalbumin-expressing inhibitory interneurons in the S1 cortex enhances nociceptive sensitivity and induces aversive avoidance behavior. Activity mapping identified a network of prefrontal cortical and subcortical centers whilst morphological tracing and pharmacological studies demonstrate the requirement of descending serotonergic facilitatory pathways in these pain-related behaviors. This study thus describes a mechanistic framework for modulation of pain by specific activity patterns in the S1 cortex.
Learn More >Prior studies have found a substantial risk of persistent opioid use among adolescents and young adults undergoing surgical and dental procedures. It is unknown whether family-level factors, such as long-term opioid use in family members, is associated with persistent opioid use.
Learn More >Loss-of-function mutations in Na1.7 cause congenital insensitivity to pain (CIP); this voltage-gated sodium channel is therefore a key target for analgesic drug development. Utilizing a multi-modal approach, we investigated how Na1.7 mutations lead to human pain insensitivity. Skin biopsy and microneurography revealed an absence of C-fiber nociceptors in CIP patients, reflected in a reduced cortical response to capsaicin on fMRI. Epitope tagging of endogenous Na1.7 revealed the channel to be localized at the soma membrane, axon, axon terminals, and the nodes of Ranvier of induced pluripotent stem cell (iPSC) nociceptors. CIP patient-derived iPSC nociceptors exhibited an inability to properly respond to depolarizing stimuli, demonstrating that Na1.7 is a key regulator of excitability. Using this iPSC nociceptor platform, we found that some Na1.7 blockers undergoing clinical trials lack specificity. CIP, therefore, arises due to a profound loss of functional nociceptors, which is more pronounced than that reported in rodent models, or likely achievable following acute pharmacological blockade.
Learn More >Pain is a characteristic feature of sickle cell disease (SCD), one of the most common inherited diseases. Patients may experience acute painful crises as well as chronic pain. In the Berkley transgenic murine model of SCD, HbSS-BERK mice express only human hemoglobin S. These mice share many features of SCD patients, including persistent inflammation and hyperalgesia. Cyclooxygenase-2 (COX-2) is elevated in skin, dorsal root ganglia (DRGs) and spinal cord in HbSS-BERK mice. In addition to arachidonic acid, COX-2 oxidizes the endocannabinoid 2-arachidonoylglycerol (2-AG) to produce prostaglandin E-glycerol (PGE-G); PGE-G is known to produce hyperalgesia. We tested the hypothesis that PGE-G is increased in DRGs of HbSS-BERK mice and sensitizes nociceptors, sensory neurons that respond to noxious stimuli, and that blocking its synthesis would decrease hyperalgesia in HbSS-BERK mice. Systemic administration of -flurbiprofen preferentially reduced production of PGE-G over that of PGE in DRGs, decreased mechanical and thermal hyperalgesia as well as decreased sensitization of nociceptors in HbSS-BERK mice. The same dose of -flurbiprofen had no behavioral effect in HbAA-BERK mice, the transgenic control, but local injection of PGE-G into the hind paw of HbAA-BERK mice produced sensitization of nociceptors and hyperalgesia. Co-administration of a P2Y6 receptor antagonist blocked the effect of PGE-G indicating this receptor is a mediator of pain in SCD. The ability of -flurbiprofen to block the synthesis of PGE-G and to normalize levels of 2-AG suggests that -flurbiprofen may be beneficial to treat pain in SCD, thereby reducing the use of opioids to relieve pain.
Learn More >Multimodal neuroimaging studies provide support for a role of alterations in sensory processing circuits and endogenous pain modulatory systems in provoked vestibulodynia (PVD). In this study we tested the hypotheses that PVD compared to healthy controls (HCs) would demonstrate gray matter volume (GMV) alterations in regions associated with sensorimotor, corticothalamic, and basal ganglia circuits. We also tested the replicability of previously reported gray matter increases in basal ganglia and hippocampal volumes in PVD versus HCs. Additionally, disease-specificity of GMV alterations were examined by comparing PVD to another chronic pain disorder. Finally we examine whether GMV alterations are correlated with symptom measures. Structural magnetic resonance imaging was obtained in 119 premenopausal women (45 PVD, 45 HCs, 29 irritable bowel syndrome (IBS)). A voxel-based morphometry analysis was applied to determine group differences in the hypothesized regions of interest. Compared to HCs, PVD women exhibited greater GMV in the basal ganglia, hippocampus, and sensorimotor cortices. Compared to IBS patients, women with PVD had greater GMV in the hippocampus, and sensorimotor network, but lower GMV in the thalamus and precentral gyrus. Regional gray matter volume alterations were associated with patient reports of pain during intercourse and muscles tenderness. The current findings provide further evidence that GMV is increased in PVD compared to HCs in several regions of the sensorimotor network and the hippocampus in PVD patients. In addition, GMV distinct alterations in the sensorimotor network were identified between two pelvic pain disorders, PVD compared to irritable bowel syndrome.
Learn More >Previous studies have shown a robust correlation between variability of clinical pain scores and responsiveness to placebo (but not active drug) in pain studies, but explanations for these relationships are lacking. We investigated this further by assessing relationship between the Focused Analgesia Selection Test (FAST); a psychophysical method that quantifies pain reporting variability in response to experimental stimuli, variability of daily clinical pain scores as captured via diary, and response to treatment in the context of a randomized controlled crossover trial of naproxen vs. placebo in knee osteoarthritis. Evoked pain using the Staircase-Evoked Pain Procedure (StEPP®) served as the primary efficacy endpoint. Variability of daily pain scores and the FAST were assessed at baseline. Fifty-five subjects completed the study and were included in the analyses. Our results indicated a statistically significant, moderate linear relationship between variability of clinical and experimental pain reports (r= -0.416, P=0.004); and both also correlated with the placebo response (r= 0.393, P=0.004; r=-0.371, P=0.009 respectively), but only the FAST predicted the treatment difference between naproxen and placebo, as demonstrated both in a regression model (P=0.002, Beta=0.456, t=3.342) and in a Receiver Operator Curve analysis (ROC=0.721). Our results extend previous findings to include a correlation between experimental pain variability and the placebo response, and suggest that experimental pain variability is a better predictor of patients who respond preferentially to drug over placebo. A theoretical model unifying these observations is proposed and practical implications are discussed.
Learn More >Painful diabetic neuropathy (PDN) is a devastating neurological complication of diabetes. Methylglyoxal (MG) is a reactive metabolite whose elevation in the plasma corresponds to PDN in patients and pain-like behavior in rodent models of type 1 and type 2 diabetes. Here, we addressed the MG-related spinal mechanisms of PDN in type 2 diabetes using db/db mice, an established model of type 2 diabetes, and intrathecal injection of MG in conventional C57BL/6J mice. Administration of either a MG scavenger (GERP10) or a vector overexpressing glyoxalase 1, the catabolic enzyme for MG, attenuated heat hypersensitivity in db/db mice. In C57BL/6J mice, intrathecal administration of MG produced signs of both evoked (heat and mechanical hypersensitivity) and affective (conditioned place avoidance) pain. MG-induced Ca mobilization in lamina II dorsal horn neurons of C57BL/6J mice was exacerbated in db/db, suggestive of MG-evoked central sensitization. Pharmacological and/or genetic inhibition of transient receptor potential ankyrin subtype 1 (TRPA1), adenylyl cyclase type 1 (AC1), protein kinase A (PKA), or exchange protein directly activated by cyclic adenosine monophosphate (Epac) blocked MG-evoked hypersensitivity in C57BL/6J mice. Similarly, intrathecal administration of GERP10, or inhibitors of TRPA1 (HC030031), AC1 (NB001), or Epac (HJC-0197) attenuated hypersensitivity in db/db mice. We conclude that MG and sensitization of a spinal TRPA1-AC1-Epac signaling cascade facilitate PDN in db/db mice. Our results warrant clinical investigation of MG scavengers, glyoxalase inducers, and spinally-directed pharmacological inhibitors of a MG-TRPA1-AC1-Epac pathway for the treatment of PDN in type 2 diabetes.
Learn More >The voltage-gated sodium channel Nav1.8 is preferentially expressed in peripheral nociceptive neurons and contributes to inflammatory and neuropathic pain. Therefore, Nav1.8 has emerged as one of the most promising analgesic targets for pain relief. Using large-scale screening of various animal-derived toxins and venoms for Nav1.8 inhibitors, here we identified μ-EPTX-Na1a, a 62-residue three-finger peptide from the venom of the Chinese cobra (), as a potent inhibitor of Nav1.8, exhibiting high selectivity over other voltage-gated sodium channel subtypes. Using whole-cell voltage-clamp recordings, we observed that purified μ-EPTX-Na1a blocked the Nav1.8 current. This blockade was associated with a depolarizing shift of activation and repolarizing shift of inactivation, a mechanism distinct from that of any other gating modifier toxin identified to date. In rodent models of inflammatory and neuropathic pain, μ-EPTX-Na1a alleviated nociceptive behaviors more potently than did morphine, indicating that μ-EPTX-Na1a has a potent analgesic effect. μ-EPTX-Na1a displayed no evident cytotoxicity and cardiotoxicity, and produced no obvious adverse responses in mice even at a dose 30-fold higher than that producing a significant analgesic effect. Our study establishes μ-EPTX-Na1a as a promising lead for the development of Nav1.8-targeting analgesics to manage pain.
Learn More >Sensory neurons perceive environmental cues and are important of organismal survival. Peripheral sensory neurons interact intimately with glial cells. While the function of axonal ensheathment by glia is well studied, less is known about the functional significance of glial interaction with the somatodendritic compartment of neurons. Herein, we show that three distinct glia cell types differentially wrap around the axonal and somatodendritic surface of the polymodal dendritic arborization (da) neuron of the peripheral nervous system for detection of thermal, mechanical, and light stimuli. We find that glial cell-specific loss of the chromatin modifier gene dATRX in the subperineurial glial layer leads to selective elimination of somatodendritic glial ensheathment, thus allowing us to investigate the function of such ensheathment. We find that somatodendritic glial ensheathment regulates the morphology of the dendritic arbor, as well as the activity of the sensory neuron, in response to sensory stimuli. Additionally, glial ensheathment of the neuronal soma influences dendritic regeneration after injury.
Learn More >The transient receptor potential vanilloid-1 (TRPV1) ion channel is essential for sensation of thermal and chemical pain. TRPV1 activation is accompanied by Ca-dependent desensitization; acute desensitization reflects rapid reduction in channel activity during stimulation, whereas tachyphylaxis denotes the diminution in TRPV1 responses to repetitive stimulation. Acute desensitization has been attributed to conformational changes of the TRPV1 channel; however, the mechanisms underlying the establishment of tachyphylaxis remain to be defined. Here, we report that the degree of whole-cell TRPV1 tachyphylaxis is regulated by the strength of inducing stimulation. Using light-sheet microscopy and pH-sensitive sensor pHluorin to follow TRPV1 endocytosis and exocytosis trafficking, we provide real-time information that tachyphylaxis of different degrees concurs with TRPV1 recycling to the plasma membrane in a proportional manner. This process controls TRPV1 surface expression level thereby the whole-cell nociceptive response. We further show that activity-gated TRPV1 trafficking associates with intracellular Ca signals of distinct kinetics, and recruits recycling routes mediated by synaptotagmin 1 and 7, respectively. These results suggest that activity-dependent TRPV1 recycling contributes to the establishment of tachyphylaxis.
Learn More >Neonatal hindpaw incision primes developing spinal nociceptive circuitry, resulting in enhanced hyperalgesia following re-injury in adulthood. Spinal microglia contribute to this persistent effect and microglial inhibition at the time of adult re-incision blocks the enhanced hyperalgesia. Here, we pharmacologically inhibited microglial function with systemic minocycline or intrathecal SB203580 at the time of neonatal incision and evaluated sex-dependent differences following adult re-incision. Incision in adult male and female rats induced equivalent hyperalgesia and spinal dorsal horn expression of genes associated with microglial proliferation () and transformation to a reactive phenotype (). In control adults with prior neonatal incision, the enhanced degree and duration of incision-induced hyperalgesia and spinal microglial responses to re-incision were equivalent in males and females. However, microglial inhibition at the time of the neonatal incision revealed sex-dependent effects: the persistent mechanical and thermal hyperalgesia following re-incision in adulthood was prevented in males but unaffected in females. Similarly, re-incision induced and gene expression was downregulated in males, but not in females following neonatal incision with minocycline. To evaluate the distribution of re-incision hyperalgesia, prior neonatal incision was performed at different body sites. Hyperalgesia was maximal when the same paw was re-incised, and was increased following prior incision at ipsilateral, but not contralateral sites; supporting a segmentally restricted spinal mechanism. These data highlight the contribution of spinal microglial mechanisms to persistent effects of early-life injury in males, and sex-dependent differences in the ability of microglial inhibition to prevent the transition to a persistent pain state spans developmental stages. Following the same surgery, some patients develop persistent pain. Contributory mechanisms are not fully understood, but early-life experience and sex/gender may influence the transition to chronic pain. Surgery and painful procedural interventions in vulnerable preterm neonates are associated with long-term alterations in somatosensory function and pain that differ in males and females. Surgical injury in neonatal rodents primes the developing nociceptive system and enhances re-injury response in adulthood. Neuroimmune interactions are critical mediators of persistent pain, but sex-dependent differences in spinal neuroglial signaling influence the efficacy of microglial inhibitors following adult injury. Neonatal microglial inhibition has beneficial long-term effects on re-injury response in adult males only, emphasizing the importance of evaluating sex-dependent differences at all ages in pre-clinical studies.
Learn More >The opioid crisis constitutes a public health challenge at the intersection of two interrelated medical problems – opioid addiction and chronic pain. Overlap of the reward and pain circuits in the brain underlies the frequent comorbidity of chronic pain and opioid addiction, whereas inadequate support, treatment and health-care reimbursement for both of these conditions are major contributors underlying the magnitude of the problem. Neurologists are uniquely positioned to help address the opioid crisis, not only through their involvement in the management of chronic pain conditions but also because they can screen for and manage opioid use disorders. The new NIH Helping to End Addiction Long-term (HEAL) Initiative will support research into pain and opioid use disorders to help address the opioid crisis. Neurologists' involvement in basic, translational and clinical research is needed for the development of new pain therapeutics and biomarkers and interventions to prevent chronic pain and to prevent and treat opioid addiction.
Learn More >As the opioid epidemic evolves, it is vital to identify changes in the geographical distribution of opioid-related deaths, and the specific opioids to which those deaths are attributed, to ensure that federal and state public health interventions remain appropriately targeted.
Learn More >Metformin, an adenosine monophosphate (AMP)-activated protein kinase activator, as well as a common drug for type 2 diabetes, has previously been shown to decrease mechanical allodynia in mice with neuropathic pain. The objective of this study is to determine if treatment with metformin during the first 3 weeks after fracture would produce a long-term decrease in mechanical allodynia and improve a complex behavioral task (burrowing) in a mouse tibia fracture model with signs of complex regional pain syndrome.
Learn More >Sphingosine-1-phosphate (S1P) receptor 1 subtype (S1PR1) activation by its ligand S1P in the dorsal horn of the spinal cord (DH-SC) causes mechano-hypersensitivity. The cellular and molecular pathways remain poorly understood. We now report that activation of S1PR1 with intrathecal injection of the highly selective S1PR1 agonist SEW2871 led to the development of mechano-allodynia by activating the nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome (increased expression of NLRP3, cleaved caspase 1 and mature interleukin (IL)-1β) in the DH-SC. The functional S1PR1 antagonist FTY720 blocked NLRP3 activation and IL-1β production. Moreover, inhibiting IL-10 signaling with an intrathecal injection of an anti-IL-10 antibody attenuated the beneficial effects exerted by FTY720. This suggests that disrupting S1PR1 signaling engages beneficial IL-10-dependent pathways. Noteworthy, we found that mice with astrocyte-specific deletions of S1pr1 did not develop mechano-allodynia following intrathecal injection of SEW2871 and exhibited reduced levels of cleaved caspase 1; identifying astrocytes as a key cellular locus for S1PR1 activity. Our findings provide novel mechanistic insights on how S1PR1 activation in the spinal cord contributes to the development of nociception while identifying the cellular substrate for these activities. PERSPECTIVE: This is the first study to link the activation of NLRP3 and IL-1β signaling in the spinal cord and S1PR1 signaling in astrocytes to the development of S1PR1-evoked mechano-allodynia. These findings provide critical basic science insights to support the development of therapies targeted toward S1PR1.
Learn More >The glutamate type 1 transporter (GLT1) plays a major role in glutamate homeostasis in the brain. Although alterations of GLT1 activity have been linked to persistent pain, the significance of these changes is poorly understood. Focusing on the rostral ventromedial medulla, a key site in pain modulation, we examined the expression and function of GLT1 and related transcription factor kappa B-motif binding phosphoprotein (KBBP) in rats after adjuvant-induced hind paw inflammation.
Learn More >Pain-related behavior secondary to masticatory function can be assessed with the rodent bite force model. A reduction of the bite force has been shown to be related to pain associated with the masseter muscle and jaw activity, while an increase in bite force suggests improvement of muscle function and less pain. To evaluate the usefulness of the bite force measure in studying long-lasting orofacial pain we analyzed biting parameters during prolonged myofascial pain induced by ligation injury of the masseter muscle tendon (TL) in mice.
Learn More >Pain is a debilitating symptom of rheumatoid arthritis (RA), caused by joint inflammation and cartilage and bone destruction. Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to treat pain and inflammation in RA, but are not disease-modifying and do not prevent joint destruction when administered alone. KBPs (Key Bioscience peptides) are synthetic peptides based on salmon calcitonin and are expected to inhibit bone resorption and to be chondroprotective. In this study, we investigated if combining a standard of care NSAID (naproxen) with a KBP resulted in improvement in pain scores, as well as disease activity and structural damage in a rat model of RA.
Learn More >Native Americans (NAs) have a higher prevalence of chronic pain than any other U.S. racial/ethnic group; however, little is known about the mechanisms for this pain disparity. This study used quantitative sensory testing (QST) to assess pain experience in healthy, pain-free adults (N=137 NAs [87 female], N=145 non-Hispanic whites [NHW; 68 female]) following painful electric, heat, cold, ischemic, and pressure stimuli. Following each stimulus, ratings of pain intensity, sensory pain, affective pain, pain-related anxiety, and situation-specific pain catastrophizing were assessed. Results suggested that NAs reported greater sensory pain in response to suprathreshold electric and heat stimuli, greater pain-related anxiety to heat and ischemic stimuli, and more catastrophic thoughts in response to electric and heat stimuli. Sex differences were also noted; however, with the exception of catastrophic thoughts to cold, these were not moderated by race/ethnicity. Together, findings suggest NAs experience heightened sensory, anxiety, and catastrophizing reactions to painful stimuli. This could place NAs at risk for future chronic pain and could ultimately lead to a vicious cycle that maintains pain (e.g., pain→anxiety/catastrophizing→pain). PERSPECTIVE: Native Americans experienced heightened sensory, anxiety, and catastrophizing reactions in response to multiple pain stimuli. Given the potential for anxiety and catastrophic thoughts to amplify pain, this may place them at risk for pain disorders and could lead to a vicious cycle that maintains pain.
Learn More >Opioid therapy is the cornerstone of treatment for acute procedural and postoperative pain and is regularly prescribed for severe and debilitating chronic pain conditions. Although beneficial for many patients, opioid therapy may have side effects, limited efficacy, and potential negative outcomes. Multidisciplinary pain management treatments incorporating pharmacological and integrative non-pharmacological therapies have been shown to be effective in acute and chronic pain management for pediatric populations. A multidisciplinary approach can also benefit psychological functioning and quality of life, and may have the potential to reduce reliance on opioids. The aims of this paper are to: (1) provide a brief overview of a multidisciplinary pain management approach for pediatric patients with acute and chronic pain, (2) highlight the mechanisms of action and evidence base of commonly utilized integrative non-pharmacological therapies in pediatric multidisciplinary pain management, and (3) explore the opioid sparing effects of multidisciplinary treatment for pediatric pain.
Learn More >The aetiological role of work-related psychological stress in the development of musculoskeletal pain disorders (MDs) has been systematically investigated. Less clear however, is the role of perceived stress and life stressors. This review aimed to assess the evidence for an aetiological role of perceived stress and life stressors in the development of chronic MDs. Database searches were conducted to identify prospective longitudinal studies that assessed perceived stress and life stressors in individuals without, or in the first 6 weeks of musculoskeletal pain. The primary outcome was the development of a chronic MD. Methodological quality was investigated using an adapted version of the Quality Assessment Tool for Observational Cohort studies and Cross-Sectional studies, and the strength of evidence using the GRADE approach. Seven studies were included representing data from six independent cohorts. There was some evidence to support the aetiological role of perceived stress and life stressors in the development of arthritis (low quality) and chronic spinal pain (low quality). The limited number of studies, the poor quality of the evidence and heterogeneity of stress measures used across studies suggest that further high quality prospective studies are required to clarify the role of perceived stress and life stressors in the development of chronic MDs. PROSPERO: CRD42017059949 Perspective: This review summarizes and critically appraises the evidence for the aetiological role of perceived stress and life stressors in the development of chronic MDs. The limited number of studies, the low quality of the evidence and heterogeneity across studies suggest that further research is needed on perceived stress and life stressors in MDs.
Learn More >Introduction Neuromodulation techniques play an increasing role in the treatment of primary headaches. While initially reserved for refractory cases they are now increasingly taken into consideration in earlier treatment phases and in non-refractory situations. One of the main reasons of this paradigm shift is that most neuromodulation techniques are better tolerated as compared to the majority of pharmacological approaches. However, these techniques have their limitations that should be considered. Areas covered The review provides an overview of the available techniques and their therapeutic rationale as well as on the evidence for their efficacy and their limitations. The review covers these aspects for non-invasive vagal nerve stimulation, sphenopalatine ganglion stimulation, external trigeminal nerve stimulation, occipital nerve stimulation as well as single-pulse and repetitive-pulse transcranial magnetic stimulation. Expert commentary Most of the evidence is based on open-label studies. Sham devices used in controlled studies remain problematic as they either do not produce the paresthesias perceived during stimulation or induce some degree of stimulation. Invasive techniques require a surgical intervention with all the potential complications that may arise. In summary some of the techniques provide an effective expansion of available treatment options but their indication should be thoroughly evaluated before treatment is considered.
Learn More >Fibromyalgia (FM) is a highly prevalent and disabling syndrome characterized by chronic widespread musculoskeletal pain and a broad range of cognitive and affective symptoms. Up to now, the pathogenesis of FM is unknown although a peripheral and central sensitization involving an imbalance on immune biomarkers appears to have a relevant role in its aetiology. The aim of this study was to extend previous clinical findings of Mindfulness-Based Stress Reduction (MBSR) to both its impact on clinical symptomatology and immune biomarkers (IL-6, CXCL8, IL-10 and hs-CRP), and also to explore the role of biomarkers as predictors of efficacy.
Learn More >The antineoplastic agent oxaliplatin is a first-line treatment for colorectal cancer. However, neuropathic pain, characterized by hypersensitivity to cold, emerges soon after treatment. In severe instances, dose reduction or curtailing treatment may be necessary. While a number of potential treatments for oxaliplatin-induced neuropathic pain have been proposed based on preclinical findings, few have demonstrated efficacy in randomized, placebo-controlled clinical studies. This failure could be related, in part, to the use of rodents as the primary preclinical species, as there are a number of distinctions in pain-related mechanisms between rodents and humans. Also, an indicator of preclinical pharmacological efficacy less subjective than behavioral endpoints that is translatable to clinical usage is lacking. Three days after oxaliplatin treatment in Macaca fascicularis, a significantly reduced response latency to cold (10C) water was observed, indicating cold hypersensitivity. Cold-evoked bilateral activation of the secondary somatosensory (SII) and insular (Ins) cortex was observed with functional magnetic resonance imaging. Duloxetine alleviated cold hypersensitivity and significantly attenuated activation in both SII and Ins. By contrast, neither clinically used analgesics pregabalin nor tramadol affected cold hypersensitivity and cold-evoked activation of SII and Ins. The current findings suggest that suppressing SII and Ins activation leads to antinociception, and, therefore, could be used as a non-behavioral indicator of analgesic efficacy in patients with oxaliplatin-induced neuropathic pain.
Learn More >Cancer survivors may be at increased risk for opioid-related harms. Trends in opioid use over time since diagnosis are unknown.
Learn More >Understanding how painful hypersensitive states develop and persist beyond the initial hours to days is critically important in the effort to devise strategies to prevent and/or reverse chronic painful states. Changes in nociceptor transcription can alter the abundance of nociceptive signaling elements, resulting in longer-term change in nociceptor phenotype. As a result, sensitized nociceptive signaling can be further amplified and nocifensive behaviors sustained for weeks to months. Building on our previous finding that transcription factor Sp4 positively regulates the expression of the pain transducing channel TRPV1 in Dorsal Root Ganglion (DRG) neurons, we sought to determine if Sp4 serves a broader role in the development and persistence of hypersensitive states in mice. We observed that more than 90% of Sp4 staining DRG neurons were small to medium sized, primarily unmyelinated (NF200 neg) and the majority co-expressed nociceptor markers TRPV1 and/or isolectin B4 (IB4). Genetically modified mice (Sp4+/-) with a 50% reduction of Sp4 showed a reduction in DRG TRPV1 mRNA and neuronal responses to the TRPV1 agonist-capsaicin. Importantly, Sp4+/- mice failed to develop persistent inflammatory thermal hyperalgesia, showing a reversal to control values after 6 hours. Despite a reversal of inflammatory thermal hyperalgesia, there was no difference in CFA-induced hindpaw swelling between CFA Sp4+/- and CFA wild type mice. Similarly, Sp4+/- mice failed to develop persistent mechanical hypersensitivity to hind-paw injection of NGF. Although Sp4+/- mice developed hypersensitivity to traumatic nerve injury, Sp4+/- mice failed to develop persistent cold or mechanical hypersensitivity to the platinum-based chemotherapeutic agent oxaliplatin, a non-traumatic model of neuropathic pain. Overall, Sp4+/- mice displayed a remarkable ability to reverse the development of multiple models of persistent inflammatory and neuropathic hypersensitivity. This suggests that Sp4 functions as a critical control point for a network of genes that conspire in the persistence of painful hypersensitive states.
Learn More >Estrogen status is a significant risk factor in the development of temporomandibular joint disorders (TMD). Classically, estrogen status is thought to derive mainly from ovarian sources; however, it is well known that estradiol (E2) also is synthesized by neurons in the brain. This study tested the hypothesis that E2 is produced by neurons in trigeminal subnucleus caudalis (Vc), the principal site of termination for sensory afferents that supply the temporomandibular joint (TMJ), to modify evoked responses in a model of TMJ nociception in male and female rats. Intra-TMJ injection of the small fiber excitant, allyl isothiocyanate (AIC), increased the levels of E2 collected from microdialysis probes sites at Vc of ovariectomized (OvX) female rats, ipsilateral to the stimulus, whereas males displayed no change. Dialysate levels of E2 collected from probe sites in the contralateral Vc or cerebellum in OvX rats were not affected by TMJ stimulation. Reverse dialysis of anastrozole, an aromatase (ARO) inhibitor, via the probe reduced perfusate levels of E2 in Vc. Systemic administration of letrozole, a non-steroid ARO inhibitor, for 4 days prevented TMJ-evoked increases in masseter muscle electromyography (MMemg) activity. ARO-positive neurons were distributed mainly in superficial laminae (I-III) at Vc and cell counts revealed no significant difference between OvX and male rats. Intra-TMJ injection of AIC revealed similar numbers of ARO/Fos dual-labeled neurons in OvX and male rats. By contrast, the percentage of ARO neurons co-labeled for glutamic acid decarboxylase (GAD), the biosynthetic enzyme for GABA, was greater in OvX (35%) than male rats (14%). Few ARO-positive neurons were co-labeled for estrogen receptor alpha. These data indicate that E2 is secreted continuously by Vc neurons and that acute stimulation of TMJ nociceptors evokes further secretion in a sex-dependent manner. Reduced TMJ-evoked MMemg activity after ARO inhibition suggests that locally produced E2 by Vc neurons acts via paracrine mechanisms to modify TMJ nociception in female rats.
Learn More >The quality of clinical trials is an essential part of the evidence base for the treatment of headache disorders. In 1991, the International Headache Society Clinical Trials Standing Committee developed and published the first edition of the Guidelines for controlled trials of drugs in migraine. Scientific and clinical developments in headache medicine led to second and third editions in 2000 and 2012, respectively. The current, fourth edition of the Guidelines retains the structure and much content from previous editions. However, it also incorporates evidence from clinical trials published after the third edition as well as feedback from meetings with regulators, pharmaceutical and device manufacturers, and patient associations. Its final form reflects the collective expertise and judgement of the Committee. These updated recommendations and commentary are intended to meet the Society's continuing objective of providing a contemporary, standardized, and evidence-based approach to the conduct and reporting of randomised controlled trials for the acute treatment of migraine attacks.
Learn More >Opioid-mediated modulation of acid-sensing ion channel (ASIC) currents in adult rat sensory neurons.
Muscle ischemia, associated with peripheral artery disease (PAD), leads to the release of pro-inflammatory mediators that decrease extracellular pH and trigger the activation of proton-activated acid-sensing ion channels (ASIC). Claudication pain, linked with low blood flow, can be partially relieved by endogenous opioid peptide release. However, we previously reported that sustained ASIC currents in dorsal root ganglion (DRG) neurons were enhanced by naturally occurring endomorphin-1 and -2 opioid peptides, indicating a role of opioid involvement in hyperalgesia. The aim of the present study was to examine whether clinically employed synthetic (fentanyl, remifentanil) and the semi-synthetic opioid (oxycodone) would also potentiate sustained ASIC currents, which arise from ASIC3 channel isoforms. Here, we show that exposure of each opioid to DRG neurons resulted in potentiation of the sustained ASIC currents. On the other hand, the potentiation was not observed in DRG neurons from ASIC3 knockout rats. Further, the enhancement of the ASIC currents was resistant to pertussis toxin treatment, suggesting that Gα/Gα G-proteins are not involved. Additionally, the potentiation of sustained ASIC currents was greater in DRG neurons isolated from rats with ligated femoral arteries-a model of PAD. The effect of all three opioids on the transient ASIC peak current was mixed (increase, decrease, no effect). The inhibitory action appears to be mediated by the presence of ASIC1 isoform, while the potentiating effect is primarily due to ASIC3 isoform expression. These findings reveal that, under certain conditions, these three opioids can increase ASIC channel activity and give rise to opioid-induced hyperalgesia.
Learn More >Chronic itch is notoriously difficult to treat. Counter-stimuli are able to inhibit itch, but this principle is difficult to apply in clinical practice, and the mechanisms behind counter-stimulation-induced itch suppression in humans are unclear.
Learn More >To conduct a systematic review on pain self-efficacy measures in children and adolescents. The review aims: (a) to summarize all self-report measures of pain self-efficacy that have been used with children and adolescents; (b) to rate the quality of these measures; (c) to summarize associations between pain self-efficacy and other constructs.
Learn More >Opioids are administered peri-operatively for postoperative analgesia, and intra-operatively to control the sympathetic response to surgical stimuli, frequently as a surrogate for presumed pain. However, opioid use during surgery is a matter of dispute in contemporary practice and carries the risk of side-effects such as postoperative nausea and vomiting. This meta-analysis investigated whether opioid-inclusive, compared with opioid-free anaesthesia, would reduce postoperative pain, without increasing the rate of postoperative nausea and vomiting. The electronic databases Medline and PubMed were searched until June 2018. We included trials investigating pain outcomes and comparing any type of intra-operative opioid administration with placebo injection or no intra-operative opioid. Most meta-analyses were performed using a random effects model. We rated the quality of evidence for each outcome. The primary outcome was pain score at rest (analogue scale, 0-10) at two postoperative hours. Our secondary outcomes included the rate of postoperative nausea and vomiting within the first 24 postoperative hours and length of stay in the recovery area. Twenty-three randomised controlled trials, including 1304 patients, were identified. Pain scores at rest at two postoperative hours were equivalent in the opioid-inclusive and opioid-free groups with a mean difference (95%CI) of 0.2 (-0.2 to 0.5), I = 83%, p = 0.38 and a high quality of evidence. Similarly, there was high-quality evidence that the rate of postoperative nausea and vomiting was reduced in the opioid-free group, with a risk ratio (95%CI) of 0.77 (0.61-0.97), I = 16%, p = 0.03 and high-quality evidence for a similar length of stay in the recovery area, the mean difference (95%CI) being 0.6 (-8.2 to 9.3), min, I = 60%, p = 0.90. As there is strong evidence that opioid-inclusive anaesthesia does not reduce postoperative pain, but is associated with more postoperative nausea and vomiting, when compared with opioid-free anaesthesia, we suggest that anaesthetists should reconsider their intra-operative opioid choices on a case-by-case basis.
Learn More >Abnormal neuronal activity in sensory ganglia contributes to chronic pain. There is evidence that signals can spread between cells in these ganglia, which may contribute to this activity. Satellite glial cells (SGCs) in sensory ganglia undergo activation following peripheral injury and participate in cellular communication via gap junctions and chemical signaling. Nitric oxide (NO) is released from neurons in dorsal root ganglia (DRG) and induces cyclic GMP (cGMP) production in SCGs, but its role in SGC activation and neuronal excitability has not been explored. It was previously reported that induction of intestinal inflammation with dinitrobenzoate sulfonate (DNBS) increased gap junctional communications among SGCs, which contributed to neuronal excitability and pain. Here we show that DNBS induced SGC activation in mouse DRG, as assayed by glial fibrillary acidic protein upregulation. DNBS also upregulated cGMP level in SGCs, consistent with NO production. In vitro studies on intact ganglia from DNBS-treated mice showed that blocking NO synthesis inhibited both SGCs activation and cGMP upregulation, indicating an ongoing NO production. Application of NO donor in vitro induced SGC activation, augmented gap junctional communications, and raised neuronal excitability, as assessed by electrical recordings. The cGMP analog 8-Br-cGMP mimicked these actions, confirming the role of the NO-cGMP pathway in intraganglionic communications. NO also augmented Ca waves propagation in DRG cultures. It is proposed that NO synthesis in DRG neurons increases after peripheral inflammation and that NO induces SGC activation, which in turn contributes to neuronal hyperexcitability. Thus, NO plays a major role in neuron-SGC communication.
Learn More >The purpose of this randomized controlled trial is to determine whether the quantity of opioid pills prescribed at discharge is associated with the number of opioid pills consumed or unused by patients after primary hip and knee arthroplasty within 30 days after discharge.
Learn More >Previously we reported that a group of inflammatory mediators significantly enhanced resurgent currents in dorsal root ganglion (DRG) neurons. To understand the underlying intracellular signaling mechanism, we investigated the effects of inhibition of extracellular signal-regulated kinases (ERK) and protein kinase C (PKC) on the enhancing effects of inflammatory mediators on resurgent currents in rat DRG neurons. We found that the ERK inhibitor U0126 completely prevented the enhancing effects of the inflammatory mediators on both Tetrodotoxin-sensitive (TTX-S) and Tetrodotoxin-resistant (TTX-R) resurgent currents in both small and medium DRG neurons. U0126 substantially reduced repetitive firing in small DRG neurons exposed to inflammatory mediators, consistent with prevention of resurgent current amplitude increases. The PKC inhibitor Bisindolylmaleimide I also showed attenuating effects on resurgent currents, although to a lesser extent compared to ERK inhibition. These results indicate a critical role of ERK signaling in modulating resurgent currents and membrane excitability in DRG neurons treated with inflammatory mediators. It is also suggested that targeting ERK-resurgent currents might be a useful strategy to reduce inflammatory pain.
Learn More >Cav3 channels play an important role in modulating chronic pain. However, less is known about the functional changes of Cav3 channels in superficial spinal dorsal horn (SDH) in neuropathic pain states. Here, we examined the effect of partial sciatic nerve ligation (PSNL) on either expression or electrophysiological properties of Cav3 channels in superficial SDH. Our in vivo studies showed that the blockers of Cav3 channels robustly alleviated PSNL-induced mechanical allodynia and thermal hyperalgesia, which lasted at least 14 days following PSNL. Meanwhile, PSNL triggered an increase in both mRNA and protein levels of Cav3.2, but not Cav3.1 or Cav3.3 in rats. However, in Cav3.2 knockout (KO) mice, PSNL predominantly attenuated mechanical allodynia but not thermal hyperalgesia. In addition, the results of whole-cell patch-clamp recordings showed that both the overall proportion of Cav3 current-expressing neurons and the Cav3 current density in individual neurons were elevated in spinal lamina II neurons from PSNL rats, which could not be recapitulated in Cav3.2 KO mice. Altogether, our findings reveal that the elevated functional Cav3.2 channels in superficial SDH may contribute to the mechanical allodynia in PSNL-induced neuropathic pain model.
Learn More >Patients suffering from neuropathic pain have a higher incidence of depression and cognitive decline. Although environment enrichment (EE) may be effective in the treatment of neuropathic pain, the precise mechanisms underlying its actions remain determined. The aim of the study was to examine the molecular mechanisms underlying the EE's beneficial effects in mice with neuropathic pain. EE attenuated the pain threshold reduction, depression-like phenotype, and memory deficit in mice after chronic constriction injury (CCI). Furthermore, EE attenuated decreased neurogenesis and increased inflammation in the hippocampus of mice with neuropathic pain after CCI. Moreover, the suppression of adult hippocampal neurogenesis by temozolomide antagonized the beneficial effects of EE on depression-like phenotype and cognitive deficit in the mice with neuropathic pain. In addition, lipopolysaccharide-induced increase in tumor necrosis factor-α (TNF-α) in the hippocampus antagonized the beneficial effects of EE for these behavioral abnormalities in mice with neuropathic pain. Knock-down of NPAS4 (neuronal PAS domain protein 4) in the hippocampus by lentivirus targeting NPAS4 blocked these beneficial effects of EE in the mice with neuropathic pain. These all findings suggest that hippocampal NPAS4 plays a key role in the beneficial effects of EE on the pain sensitivity, depression-like phenotype, and memory deficit in mice with neuropathic pain. Therefore, it is likely that NPAS4 would be a new therapeutic target for perceptional, affective, and cognitive dimensions in patients with chronic pain.
Learn More >Most studies fail to show an association between higher levels of pain-related fear and protective movement behavior in patients with chronic low back pain (CLBP). This may be explained by the fact that only general measures of pain-related fear have been used to examine the association with movement patterns. This study explored whether task-specific, instead of general measures of pain-related fear can predict movement behavior.
Learn More >Preoperative stress could delay the recovery of postoperative pain and has been reported to be a risk factor for chronic postsurgical pain. As stress could facilitate the proinflammatory activation of microglia, we hypothesized that these cells may play a vital role in the development of preoperative stress-induced pain chronification after surgery. Our experiments were conducted in a rat model that consists of a single prolonged stress (SPS) procedure and plantar incision. A previous SPS exposure induced anxiety-like behaviors, prolonged incision-induced mechanical allodynia, and potentiated the activation of spinal microglia. Based on the results from ex vivo experiments, spinal microglia isolated from SPS-exposed rats secreted more proinflammatory cytokines upon challenge with LPS. Our results also demonstrated that microglia played a more important role than astrocytes in the initiation of SPS-induced prolongation of postsurgical pain. We further explored the therapeutic potential of agonism of α7 nAChR, an emerging anti-inflammatory target, for SPS-induced prolongation of postsurgical pain. Multiple intrathecal (i.t.) injections of PHA-543613 (an α7 nAChR agonist) or PNU-120596 (a type II positive allosteric modulator) during the perioperative period shortened the duration of postsurgical pain after SPS and suppressed SPS-potentiated microglia activation, but their effects were abolished by pretreatment with methyllycaconitine (an α7 nAChR antagonist; i.t.). Based on the results from ex vivo experiments, the anti-inflammatory effects of PHA-543613 and PNU-120596 may have been achieved by the direct modulation of microglia. In conclusion, stress-induced priming of spinal microglia played a key role in the initiation of preoperative stress-induced prolongation of postsurgical pain, and PHA-543613 and PNU-120596 may be potential candidates for preventing pain chronification after surgery.
Learn More >Neuropathic mechanisms are involved in burning mouth syndrome (BMS), and variation of the dopamine D2 receptor (DRD2) gene contributes to experimental pain perception. We investigated whether neurophysiologic findings differ in BMS patients compared to healthy controls, and whether 957C>T polymorphism of the DRD2 gene influences thermal sensitivity or pain experience in BMS.
Learn More >While evidence indicates that sigma-1 receptors (Sig-1Rs) play an important role in the induction of peripheral neuropathic pain, there is limited understanding of the role that the neurosteroidogenic enzymes, which produce Sig-1R endogenous ligands, play during the development of neuropathic pain. We examined whether sciatic nerve injury upregulates the neurosteroidogenic enzymes, cytochrome P450c17 and 3β-hydroxysteroid dehydrogenase (3β-HSD), which modulate the expression and/or activation of Sig-1Rs leading to the development of peripheral neuropathic pain. Chronic constriction injury (CCI) of the sciatic nerve induced a significant increase in the expression of P450c17, but not 3β-HSD, in the ipsilateral lumbar spinal cord dorsal horn at postoperative day 3. Intrathecal administration of the P450c17 inhibitor, ketoconazole during the induction phase of neuropathic pain (day 0 to day 3 post-surgery) significantly reduced the development of mechanical allodynia and thermal hyperalgesia in the ipsilateral hind paw. However, administration of the 3β-HSD inhibitor, trilostane had no effect on the development of neuropathic pain. Sciatic nerve injury increased astrocyte Sig-1R expression as well as dissociation of Sig-1Rs from BiP in the spinal cord. These increases were suppressed by administration of ketoconazole, but not by administration of trilostane. Co-administration of the Sig-1R agonist, PRE084 restored the development of mechanical allodynia originally suppressed by the ketoconazole administration. However, ketoconazole-induced inhibition of thermal hyperalgesia was not affected by co-administration of PRE084. Collectively these results demonstrate that early activation of P450c17 modulates the expression and activation of astrocyte Sig-1Rs, ultimately contributing to the development of mechanical allodynia induced by peripheral nerve injury.
Learn More >Patient-Reported Outcome (PRO) instruments have been developed to evaluate pain management in daily practice; the PGIC is particularly recommended by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT). The prospective non-interventional multicenter PRO-QURE study aimed at assessing correlations between PGIC and pain measurements and treatment effects in patients followed in French pain centers.
Learn More >Complete stop of acute medication and/or migraine medication for treatment of medication-overuse headache (MOH) has previously been reported more effective in reducing headache days and migraine days per month compared with restricted intake of acute medication. However, it is unknown whether complete stop or restricted intake is the most feasible treatment for patients.
Learn More >RBP-6000, referred to as BUP-XR (extended-release buprenorphine), is a subcutaneously injected, monthly buprenorphine treatment for opioid use disorder. BUP-XR provides sustained buprenorphine plasma concentrations to block drug-liking of abused opioids over the entire monthly dosing period, while controlling withdrawal and craving symptoms. Administration of BUP-XR in a health-care setting also mitigates abuse, misuse, diversion, and unintentional exposure. We aimed to investigate the efficacy of different BUP-XR dosing regimens in participants with opioid use disorder.
Learn More >Endometriosis, a systemic disease that is often painful and chronic, affects ∼10% of reproductive-age women. The disease can negatively impact a patient's physical and emotional well-being, quality of life, and productivity. Endometriosis also places significant economic and social burden on patients, their families, and society as a whole. Despite its high prevalence and cost, endometriosis remains underfunded and under-researched – greatly limiting our understanding of the disease and slowing much-needed innovation in diagnostic and treatment options. Due in part to the societal normalization of women's pain and stigma around menstrual issues, there is also a lack of disease awareness among patients, health care providers, and the public. The Society for Women's Health Research convened an interdisciplinary group of expert researchers, clinicians, and patients for a roundtable meeting to review the current state of the science on endometriosis and identify areas of need to improve a woman's diagnosis, treatment, and access to quality care. Comprehensive and interdisciplinary approaches to disease management and increased education and disease awareness for patients, health care providers, and the public are needed to remove stigma, increase timely and accurate diagnosis and treatment, and allow for new advancements.
Learn More >People with migraine disease face many challenges, and these challenges can be magnified when someone is part of an "underserved" population. We set out to examine various categories of "underserved" populations, consider the unique challenges faced by these groups, and discuss mechanisms to mitigate these challenges as much as possible.
Learn More >To systematically evaluate the safety and tolerability of calcitonin-gene-related peptide binding monoclonal antibodies from the results of randomized controlled trials.
Learn More >Kappa receptor activation by dynorphins contributes to the anxiogenic, dysphoric, and cognitive disrupting effects of repeated stress, suggesting that kappa receptor antagonists might have therapeutic utility in the treatment of stress disorders. Three classes of kappa antagonists have been distinguished: non-selective, selective-competitive (readily reversible), and non-competitive (receptor-inactivating); however, which would be the most effective medication has not been established. To assess the utility of receptor inactivating antagonists, we tested the effects of a range of doses in both male and female mice. As previously established, the antinociceptive effects of the kappa agonist U50,488 were blocked by a single injection of the long-acting antagonist norbinatorphimine (norBNI) (10 mg/kg i.p.) in male mice. Ten to 20-fold lower doses of norBNI were ineffective after a single administration, but daily administration of 1.0 or 0.5 mg/kg for 5 days completely blocked U50,488 antinociceptive effects. Daily administration of 0.1 mg/kg norBNI produced slowly accumulating inhibition and completely blocked the antinociceptive effect of U50,488 after 20-30 days. Estrogen reduces female sensitivity to kappa opioid effects, but 30 days of 0.1 mg/kg norBNI completely blocked U50,488 analgesia in ovariectomized mice. Receptor inactivation in both male and female mice treated for 30 days with 0.1 mg/kg norBNI persisted for at least 1-week. These results suggest that receptor-inactivating kappa antagonists are effective in both males and females when given at 100-fold lower doses than typically administered in preclinical studies. The enhanced safety of this low-dosing protocol has important clinical implications if receptor inactivating kappa antagonists advance in medication development.
Learn More >Current medications inadequately treat the symptoms of chronic pain experienced by over 50 million people in the United States, and may come with substantial adverse effects signifying the need to find novel treatments. One novel therapeutic target is the Transient Receptor Potential A1 channel (TRPA1), an ion channel that mediates nociception through calcium influx of sensory neurons. Drug discovery still relies heavily on animal models, including zebrafish, a species in which TRPA1 activation produces hyperlocomotion. Here, we investigated if this hyperlocomotion follows zebrafish TRPA1 pharmacology and evaluated the strengths and limitations of using TRPA1-mediated hyperlocomotion as potential preclinical screening tool for drug discovery. To support face validity of the model, we pharmacologically characterized mouse and zebrafish TRPA1 in transfected HEK293 cells using calcium assays as well as in vivo. TRPA1 agonists and antagonists respectively activated or blocked TRPA1 activity in HEK293 cells, mice, and zebrafish in a dose-dependent manner. However, our results revealed complexities including partial agonist activity of TRPA1 antagonists, bidirectional locomotor activity, receptor desensitization, and off-target effects. We propose that TRPA1-mediated hyperlocomotion in zebrafish larvae has the potential to be used as in vivo screening tool for novel anti-nociceptive drugs but requires careful evaluation of the TRPA1 pharmacology.
Learn More >To evaluate providers' use and predictors of evidence-based medicine or opioid/barbiturate as first-line acute treatment for children's initial presentation of acute migraine or primary headache.
Learn More >In a previous study exploring central pain modulation with heterotopic stimuli in healthy volunteers, we found that transitions between sustained noxious and innocuous thermal stimulations on the foot activated the "salience matrix". Knowing that central sensory processing is abnormal in migraine, we searched in the present study for possible abnormalities of these salient transitional responses in different forms of migraine and at different time points of the migraine cycle.
Learn More >Symptoms of chronic widespread muscle pain (CWP) meet most of the diagnostic criteria for fibromyalgia syndrome, which is prevalent in females. We used an acid injection-induced muscle pain (AIMP) model to mimic CWP. After female rats received an ovariectomy (OVX), acid saline solution was injected into the left gastrocnemius muscle. Time courses of changes in pain behaviours and p-ERK in the spinal cord were compared between groups. Intrathecal injections of oestradiol (E2) to the OVX group before two acid injections and E2 or progesterone (P4) injections in male rats were compared to evaluate hormone effects. We found that repeated acid injections produced mechanical hypersensitivity and enhanced p-ERK expression in the spinal dorsal horn. OVX rats exhibited significantly less tactile allodynia than did the rats in the other groups. The ERK inhibitor U0126 alleviated mechanical allodynia with lower p-ERK expression in the sham females but did not affect the OVX rats. Intrathecal E2 reversed the attenuated mechanical hypersensitivity in the OVX group, and E2 or P4 induced transient hyperalgesia in male rats. Accordingly, our results suggested that ovarian hormones contribute to AIMP through a spinal p-ERK-mediated pathway. These findings may partially explain the higher prevalence of fibromyalgia in females than males.
Learn More >The T-type calcium channel, Cav3.2, is necessary for acute pain perception, as well as mechanical and cold allodynia in mice. Being found throughout sensory pathways, from excitatory primary afferent neurons up to pain matrix structures, it is a promising target for analgesics. In our study, Cav3.2 was detected in ~60% of the lamina II (LII) neurons of the spinal cord, a site for integration of sensory processing. It was co-expressed with Tlx3 and Pax2, markers of excitatory and inhibitory interneurons, as well as nNOS, calretinin, calbindin, PKCγ and not parvalbumin. Non-selective T-type channel blockers slowed the inhibitory but not the excitatory transmission in LII neurons. Furthermore, T-type channel blockers modified the intrinsic properties of LII neurons, abolishing low-threshold activated currents, rebound depolarizations, and blunting excitability. The recording of Cav3.2-positive LII neurons, after intraspinal injection of AAV-DJ-Cav3.2-mcherry, showed that their intrinsic properties resembled those of the global population. However, Cav3.2 ablation in the dorsal horn of Cav3.2 KI mice after intraspinal injection of AAV-DJ-Cav3.2-Cre-IRES-mcherry, had drastic effects. Indeed, it (1) blunted the likelihood of transient firing patterns; (2) blunted the likelihood and the amplitude of rebound depolarizations, (3) eliminated action potential pairing, and (4) remodeled the kinetics of the action potentials. In contrast, the properties of Cav3.2-positive neurons were only marginally modified in Cav3.1 knockout mice. Overall, in addition to their previously established roles in the superficial spinal cord and in primary afferent neurons, Cav3.2 channel appear to be necessary for specific, significant and multiple controls of LII neuron excitability.
Learn More >This study examined a more effective pain management method, without sucrose, on heel lance in preterm infants using the Premature Infant Pain Profile (PIPP).
Learn More >Extracellular ATP activates inflammasome and triggers the release of multiple cytokines in various immune cells, a process primarily mediated by P2X7 receptors. However, the expression and functional properties of P2X7 receptors in native mast cells in tissues such as meninges where migraine pain originates from have not been explored. Here we report a novel model of murine cultured meningeal mast cells and using these, as well as easily accessible peritoneal mast cells, studied the mechanisms of ATP-mediated mast cell activation. We show that ATP induced a time and dose-dependent activation of peritoneal mast cells as analyzed by the uptake of organic dye YO-PRO1 as well as 4,6-diamidino-2-phenylindole (DAPI). Both YO-PRO1 and DAPI uptake in mast cells was mediated by the P2X7 subtype of ATP receptors as demonstrated by the inhibitory effect of P2X7 antagonist A839977. Consistent with this, significant YO-PRO1 uptake was promoted by the P2X7 agonist 2',3'-O-(benzoyl-4-benzoyl)-ATP (BzATP). Extracellular ATP-induced degranulation of native and cultured meningeal mast cells was shown with Toluidine Blue staining. Taken together, these data demonstrate the important contribution of P2X7 receptors to ATP-driven activation of mast cells, suggesting these purinergic mechanisms as potential triggers of neuroinflammation and pain sensitization in migraine.
Learn More >The formation of neuromas involves expansion of the cellular components of peripheral nerves. The onset of these disorganized tumors involves activation of sensory nerves and neuroinflammation. Particularly problematic in neuroma is arborization of axons leading to extreme, neuropathic pain. The most common sites for neuroma are the ends of transected nerves following injury; however, this rodent model does not reliably result in neuroma formation. In this study, we established a rodent model of neuroma in which the sciatic nerve was loosely ligated with two chromic gut sutures [1]. This model formed neuromas reliably (~95%), presumably through activation of the neural inflammatory cascade. Resulting neuromas had a disorganized structure and a significant number of replicating cells. Quantification of changes in perineurial and Schwann cells showed a significant increase in these populations. Immunohistochemical analysis showed the presence of β-tubulin 3 (TUJ1) in the rapidly expanding nerve and a decrease in neurofilament heavy chain compared to the normal nerve, suggesting the axons forming a disorganized structure. Measurement of the permeability of the blood-nerve barrier (BNB) shows that it opened almost immediately and remained open as long as 10 days. Studies using an antagonist of the 3-adrenergic receptor (ADRβ3) (L-748,337) or cromolyn showed a significant reduction in tumor size and cell expansion as determined by flow cytometry, with an improvement in the animal's gait detected using a Catwalk system. Previous studies in our laboratory have shown that heterotopic ossification (HO) is also a result of the activation of neuroinflammation. Since HO and neuroma often occur together in amputees, they were induced in the same limbs of the study animals. More heterotopic bone was formed in animals with neuromas as compared to those without. These data collectively suggest that perturbation of early neuroinflammation with compounds such as L-748,337 and cromolyn may reduce formation of neuromas.
Learn More >Accumulating evidence suggests a potential role of transient receptor potential vanilloid 1 (TRPV1) channels in inflammatory and cancer-related pain. However, the role of TRPV1 in the maintenance of neuropathic pain remains elusive. The current study investigated the effects of transient Trpv1 gene silencing using a small interference RNA (siRNA) on neuropathic pain induced by chronic constriction injury (CCI) of the sciatic nerve in rats. Seven days after CCI, the TRPV1 siRNA was intrathecally administered (5 µg/15 µl, once daily for 2 days). TRPV1 and Ca/calmodulin-dependent protein kinase II (CAMKII) expression and extracellular signal-regulated kinase (ERK) phosphorylation in the spinal cord were detected using western blotting. The thresholds to mechanical and thermal stimuli were determined before and after intrathecal TRPV1 siRNA administration. TRPV1 and CAMKII expression and ERK2 phosphorylation in the spinal cord were upregulated after CCI. Intrathecal administration of the TRPV1 siRNA not only attenuated behavioural hyperalgesia but also reduced the expression of TRPV1 and CAMKII, as well as ERK2 phosphorylation. Based on these results, silencing of the TRPV1 gene in the spinal cord attenuates the maintenance of neuropathic pain by inhibiting CAMKII/ERK2 activation and suggests that TRPV1 represents a potential target in pain therapy.
Learn More >NADPH oxidase (NOX2) is an enzyme that induces reactive oxygen species (ROS) and serves as a switch between the pro-inflammatory and neurorestorative microglial/macrophage phenotypes; such changes play an important role in neuropathic pain and motor dysfunction. Increased NOX2 expression after spinal cord injury (SCI) has been reported, and inhibition of NOX2 improves motor function. However, the underlying mechanisms of NOX2 in post-traumatic pain and motor deficit remain unexplored. In the present study, we report that depletion of NOX2 (NOX2) or inhibition of NOX2 using NOX2ds-tat significantly reduced mechanical/thermal cutaneous hypersensitivity and motor dysfunction after moderate contusion SCI at T10 in male mice. Western blot (WB, 3 mm lesion area) and immunohistochemistry (IHC) showed that SCI elevates NOX2 expression predominantly in microglia/macrophages up to 8 weeks post-injury. Deletion of NOX2 significantly reduced CD11b/CD45F4/80 macrophage infiltration at 24h post-injury detected by flow cytometry and 8-OHG ROS production at 8 weeks post-injury by IHC in both lesion area and lumbar enlargement. NOX2 deficiency also altered microglial/macrophage pro-inflammatory and anti-inflammatory balance towards the neurorestorative response. WB analysis showed robust increase of Arginase-1 and YM1 proteins in NOX2 mice. Furthermore, qPCR analysis showed significant up-regulation of anti-inflammatory cytokine IL-10 levels in NOX2 mice, associated with reduced microRNA-155 expression. These findings were confirmed in CD11b microglia/macrophages isolated from spinal cord at 3 days post-injury. Taken together, our data suggest an important role for IL-10/miR-155 pathway in regulating NOX2-mediated SCI-dysfunction. Thus, specific targeting of NOX2 may provide an effective strategy for treating neurological dysfunction in SCI patients.
Learn More >To assess the intraepidermal nerve fiber density in patients diagnosed with fibromyalgia (FM) and to evaluate the role of IgM binding to trisulfated heparin disaccharide (TS-HDS) in these patients.
Learn More >Glutamate is a fundamental excitatory neurotransmitter in the mammalian central nervous system (CNS), playing key roles in memory, neuronal development, and synaptic plasticity. Moreover, excessive glutamate release has been implicated in neuronal cell death. There are both ionotropic and metabotropic glutamate receptors (mGluRs), the latter of which can be divided into eight subtypes and three subgroups based on homology sequence and their effects on cell signaling. Indeed, mGluRs exert fine control over glutamate activity by stimulating several cell-signaling pathways the activation of G protein-coupled (GPC) or G protein-independent cell signaling. The involvement of specific mGluRs in different forms of synaptic plasticity suggests that modulation of mGluRs may aid in the treatment of cognitive impairments related to several neurodevelopmental/psychiatric disorders and neurodegenerative diseases, which are associated with a high economic and social burden. Preclinical and clinical data have shown that, in the CNS, mGluRs are able to modulate presynaptic neurotransmission by fine-tuning neuronal firing and neurotransmitter release in a dynamic, activity-dependent manner. Current studies on drugs that target mGluRs have identified promising, innovative pharmacological tools for the treatment of neurodegenerative and neuropsychiatric conditions, including chronic pain.
Learn More >The aim of this study was to measure brain alterations in patients with herpes zoster (HZ) and postherpetic neuralgia (PHN) and compare their differences using a voxel-based morphometry (VBM) technique.
Learn More >Aggressive breast cancer subtypes utilize system x, a membrane antiporter, to import cystine for glutathione synthesis and maintenance of redox homeostasis, in turn releasing glutamate as a metabolic pro-nociceptive by-product. Metastatic breast cancers establish themselves at distal sites including bone, where changes in extracellular glutamate levels contribute to cancer-induced bone pain. We previously established that stearically blocking system x activity with sulfasalazine delays the onset of nociceptive behaviours and that xCT, the functional antiporter subunit, is positively regulated by signal transducer and activator of transcription 3 (STAT3). In the current investigation, a murine xenograft cancer-induced bone pain model was applied to examine whether pharmacological inhibition of phosphorylated STAT3 (pSTAT3) induces changes in nociception. A high glutamate-releasing, xCT/pSTAT3 over-expressing human breast cancer cell line was selected for injection into the distal epiphysis of the right femur of female nude mice. A 14-day regimen of intraperitoneal injections with either vehicle or the novel STAT3 inhibitor DR-1-55 commenced three weeks after initial intrafemoral bone injection. Nociceptive behaviours were temporally monitored by automated von Frey, dynamic weight bearing and open-field testing for the duration of the study, beginning at the baseline. Prior to sacrifice and at ethical end point, tumour-induced osteolytic lesions were radiographically assessed. Treatment with DR-1-55 significantly delayed the onset and severity of spontaneous and induced nociceptive behaviours, also decreasing human SLC7A11 ( xCT) mRNA levels in tumour-bearing limbs without altering osteolysis. In addition, two pro-inflammatory cytokines released by this cell line, interleukin 6 and interleukin 1β, were also down-regulated at the mRNA level in response to DR-1-55 treatment in vivo, with lower human interleukin 6 levels detected in the host circulation. This study demonstrates that targeting pSTAT3 may be a viable therapeutic means to manage cancer-induced bone pain, alone or in combination with stearic system x blockers.
Learn More >Deep brain stimulation (DBS) has been considered for patients with intractable pain syndromes since the 1950s. Although there is substantial experience reported in the literature, the indications are contested, especially in the United States where it remains off-label. Historically, the sensory-discriminative pain pathways were targeted. More recently, modulation of the affective sphere of pain has emerged as a plausible alternative.
Learn More >Placebo effects benefit a wide range of clinical practice, which can be profoundly influenced by expectancy level and personal characteristics. However, research on the issue of whether these factors independently or interdependently affect the placebo effects is still in its infancy. Here, we adopted a 3-day between-subject placebo analgesia paradigm (2-day conditioning and 1-day test) to investigate the influence of expectancy levels (i.e., No, Low, and High) and personal characteristics (i.e., gender, dispositional optimism, and anxiety state) on placebo effects in 120 healthy participants (60 females). Our results showed that the reduction of pain intensity in the test phase was influenced by the interaction between expectancy and gender, as mainly reflected by greater reductions of pain intensity in females at Low expectancy level than females at No/High expectancy levels, and greater reductions of pain intensity in males than in females at High expectancy level. Additionally, the reduction of pain unpleasantness was not only modulated by the interaction between expectancy and gender, but also by the interaction between expectancy and dispositional optimism, as well as the interaction between expectancy and anxiety state. Specifically, participants who were more optimistic in Low expectancy group, or those who were less anxious in High expectancy group showed greater reductions of pain unpleasantness. To sum up, we emphasized on regulating the expectancy level individually based on the assessment of personal characteristics to maximize placebo effects in clinical conditions.
Learn More >Neuropathic pain resulting from peripheral nerve lesions is a common medical condition, but current analgesics are often insufficient. The identification of key molecules involved in pathological pain processing is a prerequisite for the development of new analgesic drugs. Hyperexcitability of nociceptive DRG-neurons due to regulation of voltage-gated ion-channels is generally assumed to contribute strongly to neuropathic pain. There is increasing evidence, that T-type Ca-currents and in particular the Ca3.2 T-type-channel isoform play an important role in neuropathic pain, but experimental results are contradicting.
Learn More >Chronic migraine (CM) is the most disabling form of migraine, because pharmacological treatments have low efficacy and cumbersome side effects. New evidence has shown that migraine is primarily a disorder of brain plasticity and migraine chronification depends on a maladaptive process favoring the development of a brain state of hyperexcitability. Due to the ability to induce plastic changes in the brain, researchers started to look at Non-Invasive Brain Stimulation (NIBS) as a possible therapeutic option in migraine field. On one side, NIBS techniques induce changes of neural plasticity that outlast the period of the stimulation (a fundamental prerequisite of a prophylactic migraine treatment, concurrently they allow targeting neurophysiological abnormalities that contribute to the transition from episodic to CM. The action may thus influence not only the cortex but also brainstem and diencephalic structures. Plus, NIBS is not burdened by serious medication side effects and drug-drug interactions. Although the majority of the studies reported somewhat beneficial effects in migraine patients, no standard intervention has been defined. This may be due to methodological differences regarding the used techniques (e.g., transcranial magnetic stimulation, transcranial direct current stimulation), the brain regions chosen as targets, and the stimulation types (e.g., the use of inhibitory and excitatory stimulations on the basis of opposite rationales), and an intrinsic variability of stimulation effect. Hence, it is difficult to draw a conclusion on the real effect of neuromodulation in migraine. In this article, we first will review the definition and mechanisms of brain plasticity, some neurophysiological hallmarks of migraine, and migraine chronification-related (dys)plasticity. Secondly, we will review available results from therapeutic and physiological studies using neuromodulation in CM. Lastly we will discuss the results obtained in these preventive trials in the light of a possible effect on brain plasticity.
Learn More >Cannabinoids are proposed in a wide array of medical indications. Yet, the evaluation of adverse effects in controlled clinical studies, following the evidence-based model, has partly been by-passed. On the other hand, studies on the consequences of recreational use of cannabis and experimental studies bring some insights on the potential long-term consequences of cannabinoids use.
Learn More >Ibuprofen is a widely used non-steroidal anti-inflammatory drug (NSAID) that exerts analgesic and anti-inflammatory actions. The transient receptor potential ankyrin 1 (TRPA1) channel, expressed primarily in nociceptors, mediates the action of proalgesic and inflammatory agents. Ibuprofen metabolism yields the reactive compound, ibuprofen-acyl glucuronide, which, like other TRPA1 ligands, covalently interacts with macromolecules. To explore whether ibuprofen-acyl glucuronide contributes to the ibuprofen analgesic and anti-inflammatory actions by targeting TRPA1, we used in vitro tools (TRPA1-expressing human and rodent cells) and in vivo mouse models of inflammatory pain. Ibuprofen-acyl glucuronide, but not ibuprofen, inhibited calcium responses evoked by reactive TRPA1 agonists, including allyl isothiocyanate (AITC), in cells expressing the recombinant and native human channel and in cultured rat primary sensory neurons. Responses by the non-reactive agonist, menthol, in a mutant human TRPA1 lacking key cysteine-lysine residues, were not affected. In addition, molecular modeling studies evaluating the covalent interaction of ibuprofen-acyl glucuronide with TRPA1 suggested the key cysteine residue C621 as a probable alkylation site for the ligand. Local administration of ibuprofen-acyl glucuronide, but not ibuprofen, in the mouse hind paw attenuated nociception by AITC and other TRPA1 agonists and the early nociceptive response (phase I) to formalin. Systemic ibuprofen-acyl glucuronide and ibuprofen, but not indomethacin, reduced phase I of the formalin response. Carrageenan-evoked allodynia in mice was reduced by local ibuprofen-acyl glucuronide, but not by ibuprofen, whereas both drugs attenuated PGE levels. Ibuprofen-acyl glucuronide, but not ibuprofen, inhibited the release of IL-8 evoked by AITC from cultured bronchial epithelial cells. The reactive ibuprofen metabolite selectively antagonizes TRPA1, suggesting that this novel action of ibuprofen-acyl glucuronide might contribute to the analgesic and anti-inflammatory activities of the parent drug.
Learn More >Bidirectional selection of mice for high (HA) and low (LA) swim stress-induced analgesia (SSIA) is associated with a divergent response to opioids. In the current study, we investigated whether the genetic divergence in opioid system activity between HA and LA mice also affects cannabinoid sensitivity. Additionally, we also investigated whether the endocannabinoid system mediates SSIA in these lines. Numerous reports support the existence of pharmacological and molecular interactions between the opioid and cannabinoid systems along the pain pathways, as both systems utilize the same G-protein subtype for signal transduction. Mice from both lines were treated with a non-selective CB/CB agonist, WIN55,212-2 and their behavior was evaluated according to the tetrad paradigm assessing antinociception, catalepsy, hypothermia and locomotor activity. Surprisingly, the engagement of CB receptors in SSIA was not confirmed. G-protein activation was studied in different brain regions and the spinal cord in the [S]GTPγS assay. It was shown that WIN55,212-2 produced more potent antinociception in HA than in LA mice. Also, HA mice displayed stronger cannabinoid-induced catalepsy in the bar test. However, LA mice were more sensitive to the hypothermic effect of WIN55,212-2. The intensity of behavioral responses to WIN55,212-2 was correlated with increased G-protein activation in the periaqueductal gray matter, frontal cortex, striatum and thalamus in HA mice. A weak response to WIN55,212-2 in LA mice could depend on impaired CB receptor signaling. In conclusion, differences in both opioid and cannabinoid sensitivity between HA and LA mice could stem from alterations in intracellular second messenger mechanisms involving G-protein activation.
Learn More >Chronic bladder pain evokes asymmetric behavior in neurons across the left and right hemispheres of the amygdala. An agent-based computational model was created to simulate the firing of neurons over time and in response to painful bladder stimulation. Each agent represents one neuron and is characterized by its location in the amygdala and response type (excited or inhibited). At each time step, the firing rates (Hz) of all neurons are stochastically updated from probability distributions estimated from data collected in laboratory experiments. A damage accumulation model tracks the damage accrued by neurons during long-term, painful bladder stimulation. Emergent model output uses neural activity to measure temporal changes in pain attributed to bladder stimulation. Simulations demonstrate the model's ability to capture acute and chronic pain and its potential to predict changes in pain similar to those observed in the lab. Asymmetric neural activity during the progression of chronic pain is examined using model output and a sensitivity analysis.
Learn More >We want to investigate degenerative changes of white matter volume (WMV) and grey matter volume (GMV) in individuals after a spinal cord injury (SCI). Published studies of whole-brain voxel-based morphometry (VBM) comparing SCI patients with controls published between 2006 and March 1st, 2018 were collected by searching PubMed, Web of Science, and EMBASE databases. Voxel-wise meta-analyses of GMV and WMV differences between SCI patients and controls were performed separately using seed-based d mapping. Twelve studies with 12 GMV datasets and 9 WMV datasets yielded a total of 466 individuals (190 SCI patients and 276 controls) that were included in this meta-analysis. Compared with controls, SCI patients showed GMV atrophy in sensorimotor system regions including the bilateral sensorimotor cortex (S1 and M1), the supplementary motor area (SMA), paracentral gyrus, thalamus, and basal ganglia, as well as WMV loss in the corticospinal tract. GMV aberrancies were also demonstrated in brain regions responsible for cognition and emotion, such as the orbitofrontal cortex (OFC) and the left insula. Additionally, GMV in both the bilateral S1 and the left SMA was positively correlated with the time span after the injury. Anatomical atrophy in cortical-thalamic-spinal pathways suggested that SCIs may result in degenerative changes of the sensorimotor system. Furthermore, OFC and insula GMV abnormalities may explain symptoms such as neuropathic pain and potential cognitive-emotional impairments in chronic SCI patients. These findings indicate that anatomical brain magnetic resonance imaging (MRI) protocols could be neuroimaging biomarkers for interventional studies and treatments.
Learn More >Cortical spreading depression (CSD) is a slowly propagating wave of depolarization of gray matter. This phenomenon is believed to underlie the migraine aura and similar waves of depolarization may exacerbate injury in a number of neurological disease states. CSD is characterized by massive ion dyshomeostasis, cell swelling, and multiphasic blood flow changes. Recently, it was shown that CSD is associated with a closure of the paravascular space (PVS), a proposed exit route for brain interstitial fluid and solutes, including excitatory and inflammatory substances that increase in the wake of CSD. The PVS closure was hypothesized to rely on swelling of astrocytic endfeet due to their high expression of aquaporin-4 (AQP4) water channels. We investigated whether CSD is associated with swelling of endfeet around penetrating arterioles in the cortex of living mice. Endfoot cross-sectional area was assessed by two-photon microscopy of mice expressing enhanced green fluorescent protein in astrocytes and related to the degree of arteriolar constriction. In anesthetized mice CSD triggered pronounced endfoot swelling that was short-lasting and coincided with the initial arteriolar constriction. Mice lacking AQP4 displayed volume changes of similar magnitude. CSD-induced endfoot swelling and arteriolar constriction also occurred in awake mice, albeit with faster kinetics than in anesthetized mice. We conclude that swelling of astrocytic endfeet is a robust event in CSD. The early onset and magnitude of the endfoot swelling is such that it may significantly delay perivascular drainage of interstitial solutes in neurological conditions where CSD plays a pathophysiological role.
Learn More >The current meta-analysis aimed to quantify the effectiveness of hypnosis for reducing pain and identify factors that influence efficacy. Six major databases were systematically searched for trials comparing hypnotic inductions with no-intervention control conditions on pain ratings, threshold and tolerance using experimentally-evoked pain models in healthy participants. Eighty-five eligible studies (primarily crossover trials) were identified, consisting of 3632 participants (hypnosis n = 2892, control n = 2646). Random effects meta-analysis found analgesic effects of hypnosis for all pain outcomes (g = 0.54-0.76, p's<.001). Efficacy was strongly influenced by hypnotic suggestibility and use of direct analgesic suggestion. Specifically, optimal pain relief was obtained for hypnosis with direct analgesic suggestion administered to high and medium suggestibles, who respectively demonstrated 42% (p < .001) and 29% (p < .001) clinically meaningful reductions in pain. Minimal benefits were found for low suggestibles. These findings suggest that hypnotic intervention can deliver meaningful pain relief for most people and therefore may be an effective and safe alternative to pharmaceutical intervention. High quality clinical data is, however, needed to establish generalisability in chronic pain populations.
Learn More >The purpose of this review is to evaluate evidence from the last 3 years on complementary and integrative medicine treatment options for episodic migraine. Using Pubmed, Embase, and Cochrane databases, research published from 2015-2018 evaluating the modalities of mind/body therapies, supplements, and manual therapies for treatment of migraine were assessed.
Learn More >Approximately half of the population will experience either low back pain or neck pain, at some point in their lives. Previous studies suggest that people with diabetes are more likely to present with chronic somatic pain, including shoulder, knee and spinal pain. This study aimed to systematically review and appraise the literature to explore the magnitude as well as the nature of the association between diabetes and back, neck, or spinal (back and neck) pain.
Learn More >To assess national trends in selected prescription opioid risk mitigation practices and associations with prescriber type, state-specific opioid overdose severity, and required pain education.
Learn More >To assess the prevalence and characteristics of chronic neck pain, chronic low back pain, and migraine or frequent headaches among Spanish adults in 2014 according to gender, to identify predictors for each of these types of pains, and to compare the prevalence with those found in 2009.
Learn More >Background and aims Complex Regional Pain Syndrome (CRPS) often recovers spontaneously within the first year, but when it becomes chronic, available rehabilitative therapies (pharmacological management, physiotherapy, and psychological intervention) have limited effectiveness. This study examined the effect of a 12-week intensive outpatient rehabilitation on pain relief and function in chronic CRPS patients. Rehabilitation program included memantine and morphine treatment (added to patient's prior pain medication) and concurrent psychological and physiotherapeutic intervention. Primary outcome measure was a change in CRPS symptom count and secondary outcomes were motor performance, psychological factors, pain intensity, and quality of life. Methods Ten patients with chronic upper limb CRPS I (median 2.9 years, range 8 months to 12 years) were recruited to the study and were assessed before and after the intervention. Hand motor function of the patients was evaluated by an independent physiotherapist. There were standardized questionnaires for depression, pain anxiety, pain acceptance, quality of life, and CRPS symptom count. In addition, psychological factors were evaluated by a semi-structured interview. Severity of experienced pain was rated at movement and at rest. In addition, a video experiment of a hand action observation was conducted pre- and post-intervention to study possible change in neuronal maladaptation. Intervention consisted of pharmacological, psychological and physiotherapeutic treatment. First, 10 mg daily morphine was started and increased gradually to 30 mg daily, if tolerated. After 30 mg/day or tolerated dose of morphine was achieved, 5 mg daily memantine was started and increased gradually to 40 mg, if tolerated. Psychological intervention consisted of weekly group sessions, using cognitive and behavioral methods (relaxation, behavioral activation, and exposure) and acceptance and commitment therapy (ACT) and daily home practice. Physiotherapeutic intervention consisted of graded motor imagery and physiotherapy exercises with weekly group sessions and/or individual guidance by the physiotherapist, and individual exercise of the affected upper limb. Results Multimodal intensive intervention resulted in significant decrease in CRPS symptom count. The effect was strongest in motor and trophic symptoms (19% decrease after intervention) and in sensory symptoms (18% decrease). Additionally, improvement was seen in some, but not all, secondary outcomes (movement pain, motor symptoms, change in perceptions during video experiment of hand actions, and summary index with motor functioning, pain, and psychological factors). There were no dropouts. Conclusions Intensive 12-week multimodal intervention reduced some CRPS symptoms but was not sufficient to alter patients' rest pain, distress, or quality of life. Implications These results support the efficacy of an interdisciplinary rehabilitation program for pain and function in chronic CRPS patients. After intervention, some CRPS symptoms reduced and function improved, but distress and quality of life were unchanged. This may be due to the relatively short duration of this program; to delayed effects; to particular cognitive problems of CPRS patients; and/or to low distress levels at baseline that make statistically significant reduction less likely.
Learn More >In the central nervous system (CNS), astrocytes form networks interconnected by gap junctions made from connexins of the subtypes Cx30 and Cx43. When unopposed by an adjoining hemichannel, astrocytic connexins can act as hemichannels to control the release of small molecules such as ATP and glutamate into the extracellular space. Accruing evidence indicates that astrocytic connexins are crucial for the coordination and maintenance of physiologic CNS activity. Here we provide an update on the role of astrocytic connexins in neurodegenerative disorders, glioma, and ischemia. In addition, we address the regulation of Cx43 in chronic pain.
Learn More >Radicular pain, caused by a lesion or autologous nucleus pulposus (NP) implantation, is associated with alteration in gene expression of the pain-signaling pathways. lncRNAs have been shown to play critical roles in neuropathic pain. However, the mechanistic function of lncRNAs in lumbar disc herniation (LDH) remains largely unknown. Identifying different lncRNA expression under sham and NP-implantation conditions in the spinal cord is important for understanding the molecular mechanisms of radicular pain.
Learn More >Animal experiment: a rat model of lumbar disc herniation (LDH) induced painful radiculopathies.
Learn More >To determine whether the intensity, spread and sensitivity of chronic pain can be predicted using demographic features, socioeconomic conditions and comorbidities.
Learn More >Despite being routinely used for pain management, opioid use is limited due to adverse effects such as development of tolerance and paradoxical pain, including thermal hyperalgesia and mechanical allodynia. Evidence indicates that continued morphine administration causes increased expression of proinflammatory mediators such as tumor necrosis factor-alpha (TNF-α). The objectives of the present study were to determine the effects of B1 (-[(1-benzimidazol-2-yl)methyl]-4-methoxyaniline) and B8 (-{4-[(1-benzimidazol-2-yl)methoxy]phenyl}acetamide), benzimidazole derivatives, on thermal nociception and mechanical allodynia during repeated morphine (intraperitoneal; 5 mg/kg twice daily for 6 days)-induced paradoxical pain and TNF-α expression in the spinal cord in mice. Our data indicate that administration of benzimidazole derivatives attenuated morphine-induced thermal hyperalgesia and mechanical allodynia. Benzimidazole derivatives also reduced TNF-α expression in mice. Taken together, these results suggest that benzimidazole derivatives might be useful for the treatment of neuroinflammatory consequences of continued morphine administration and could be potential drug candidates for the management of opioid-induced paradoxical pain.
Learn More >This article reviews the complexities of the opioid epidemic, considering recent research involving the current state of the opioid epidemic; chronic pain and its role in the crisis; the properties of opioids and how they interact with human neurobiology; the effectiveness and risks of opioids as a treatment for chronic pain; opioid addiction and dependence; and pharmacological and psychological interventions for opioid addiction, opioid dependence, and chronic pain management. Opioid abuse can be reduced with the availability and access to treatment facilities for opioid detoxification; using interdisciplinary treatment models for chronic pain, opioid addiction and dependence; conducting more research in the areas of opioid addiction and opioid dependence; and shifting to an increase in nonpharmacological, less invasive treatments for pain.
Learn More >: Central neuropathic pain represents one of the most common symptoms in multiple sclerosis (MS) and it seriously affects quality of life. Spinal mechanisms may contribute to the pathogenesis of neuropathic pain in MS. Converging evidence from animal models and neurophysiological and clinical studies in humans suggests a potential effect of transcranial direct current stimulation (tc-DCS) on neuropathic pain. Spinal application of DCS, i.e., transcutaneous spinal DCS (ts-DCS), may modulate nociception through inhibition of spinal reflexes. Therefore, ts-DCS could represents an effective, safe and well-tolerated treatment for neuropathic pain in MS, a largely unexplored topic. This study is a pilot randomized double-blind sham-controlled trial to evaluate the efficacy of ts-DCS on central neuropathic pain in MS patients. : Thirty-three MS patients with central neuropathic pain were enrolled and randomly assigned to two groups in a double-blind sham-controlled design: anodal ts-DCS group ( = 19, 10 daily 20-min sessions, 2 mA) or sham ts-DCS group ( = 14, 10 daily 20-min sessions, 0 mA). The following clinical outcomes were evaluated before ts-DCS treatment (T0), after 10 days of treatment (T1) and 1 month after the end of treatment (T2): neuropathic pain symptoms inventory (NPSI), Ashworth Scale (AS) for spasticity and Fatigue Severity Scale (FSS). A subgroup of patients treated with anodal ts-DCS ( = 12) and sham ts-DCS ( = 11) also underwent a parallel neurophysiological study of the nociceptive withdrawal reflex (NWR) and the NWR temporal summation threshold (TST), two objective markers of pain processing at spinal level. : Anodal ts-DCS group showed a significant improvement in NPSI at T1, which persisted at T2, while we did not detect any significant change in AS and FSS. Sham ts-DCS group did not show any significant change in clinical scales. We observed a non-significant trend towards an inhibition of NWR responses in the anodal ts-DCS group at T1 and T2 when compared to baseline. : Anodal ts-DCS seems to have an early and persisting (i.e., 1 month after treatment) clinical efficacy on central neuropathic pain in MS patients, probably through modulation of spinal nociception. www.ClinicalTrials.gov, identifier #NCT02331654.
Learn More >Conditioned Pain Modulation (CPM) and Manipulation Induced Analgesia (MIA) may activate similar neurophysiological mechanisms to mediate their analgesic effects. This study assessed the association between CPM and MIA responses in people with lateral epicondylalgia (LE).
Learn More >Migraine is the seventh most disabling disorder globally, with prevalence of 11.7% worldwide. One of the prevailing mechanisms is the activation of the trigeminovascular system, and calcitonin gene-related peptide (CGRP) is an important therapeutic target for migraine in this system. Recent studies suggested an emerging role of pituitary adenylate cyclase-activating peptide (PACAP) in migraine. However, the relation between CGRP and PACAP and the role of PACAP in migraine remain undefined. In this study, we established a novel repetitive (one, three, and seven days) electrical stimulation model by stimulating dura mater in conscious rats. Then, we determined expression patterns in the trigeminal ganglion and the trigeminal nucleus caudalis of the trigeminovascular system. Electrical stimulation decreased facial mechanical thresholds, and the order of sensitivity was as follows: vibrissal pad >inner canthus >outer canthus (P < 0.001). The electrical stimulation group exhibited head-turning and head-flicks (P < 0.05) nociceptive behaviors. Importantly, electrical stimulation increased the expressions of CGRP, PACAP, and the PACAP-preferring type 1 (PAC1) receptor in both trigeminal ganglion and trigeminal nucleus caudalis (P < 0.05). The expressions of two vasoactive intestinal peptide (VIP)-shared type 2 (VPAC1 and VPAC2) receptors were increased in the trigeminal ganglion, whereas in the trigeminal nucleus caudalis, their increases were peaked on Day 3 and then decreased by Day 7. PACAP was colocalized with NEUronal Nuclei (NeuN), PAC1, and CGRP in both trigeminal ganglion and the trigeminal nucleus caudalis. Our results demonstrate that the repetitive electrical stimulation model can simulate the allodynia during the migraine chronification, and PACAP plays a role in the pathogenesis of migraine potentially via PAC1 receptor.
Learn More >Hyperalgesia often occurs in alcoholics, especially during abstinence, yet the underlying mechanisms remain elusive. The lateral habenula (LHb) has been implicated in the pathophysiology of pain and alcohol use disorders. Suppression of m-type potassium channels (M-channels) has been found to contribute to the hyperactivity of LHb neurons of rats withdrawn from chronic alcohol administration. Here, we provided evidence that LHb M-channels may contribute to hyperalgesia. Compared to alcohol naïve counterparts, in male Long-Evans rats at 24-hours withdrawal from alcohol administration under the intermittent access paradigm for eight weeks, hyperalgesia was evident (as measured by paw withdrawal latencies in the Hargreaves Test), which was accompanied with higher basal activities of LHb neurons in brain slices, and lower M-channel protein expression. Inhibition of LHb neurons by chemogenetics, or pharmacological activation of M-channels, as well as overexpression of M-channels' subunit KCNQ3, relieved hyperalgesia and decreased relapse-like alcohol consumption. In contrast, chemogenetic activation of LHb neurons induced hyperalgesia in alcohol-naive rats. These data reveal a central role for the LHb in hyperalgesia during alcohol withdrawal, which may be due in part to the suppression of M-channels and, thus, highlights M-channels in the LHb as a potential therapeutic target for hyperalgesia in alcoholics.
Learn More >Over 70% of older adults report chronic or acute pain, and pain threatens affective wellbeing. The strategies older adults use to maintain affective wellbeing following acute pain remain unknown. Specific strategies that can be used to manage pain include recalling, recognizing, and responding to positive stimuli and prioritizing close over knowledgeable social partners. The study tested whether older adults used positivity-enhancing strategies and maintained affective wellbeing following acute pain better than younger adults. Fifty older (ages 65-85) and 50 younger (ages 18-30) pain-free adults experienced a control and a pain condition and were given the chance to employ positivity-enhancing strategies. Older and younger adults similarly used positivity-enhancing strategies following pain. Younger adults demonstrated reduced preference for knowledgeable social partners after experiencing pain. Pain-related affective changes were similar between age groups. Older and younger adults may cope with acute pain similarly, highlighting future directions for exploring age differences in pain coping.
Learn More >In this review, we discussed the types and frequencies of trigger factors of primary headache [migraine and tension-type headache (TTH)] among adult patients. We assessed the influence of geographical location, ethnicity and gender on the various trigger factors of a migraine and a TTH. We also evaluated the trigger factors among the multi-ethnic Southeast Asian adult patients. In a recent study, odor triggered more migrainous headaches compared to the other primary headaches. Odor was observed to be specific of migraines. Moreover, stress is one of the most common trigger factors for patients with migraines and TTHs worldwide. Migrainous patients have an increased sensitivity in comparison to non-migrainous patients. Furthermore, these patients have much difficulty in adapting to the high level of sensitivity, and the sensitized brain is therefore more vulnerable to trigger factors. In addition, the presence of one trigger factor may increase the exposure of other trigger factors. This phenomenon is more marked in the patients with migraines who have stress and menstruation as triggers, predisposing them to be more sensitive to other triggers. In conclusion, the geographical location factor has an influence on the trigger factors of headaches. Ethnicity may have an effect due to the cultural differences. Change in weather and sunlight are important commonly identified trigger factors for headaches. Moreover, gender differences in some trigger factors are present among the patients with headaches, especially sunlight and sleep deprivation. More research studies can be conducted to have a better understanding on trigger factors in the future. This will enable proper identification of trigger factors, leading to a decrease in the number of headache episodes and an improvement in quality of life for patients.
Learn More >Chronic neuropathic pain is a debilitating condition that remains challenging to treat. Glutamate N-methyl-D-aspartate receptor (NMDAR) antagonists have been used to treat neuropathic pain, but the exact sites of their actions have been unclear until recently. Although conventionally postsynaptic, NMDARs are also expressed presynaptically, particularly at the central terminals of primary sensory neurons, in the spinal dorsal horn. However, presynaptic NMDARs in the spinal cord are normally quiescent and are not actively involved in physiological nociceptive transmission. In this review, we describe the emerging role of presynaptic NMDARs at the spinal cord level in chronic neuropathic pain and the implications of molecular mechanisms for more effective treatment. Recent studies indicate that presynaptic NMDAR activity at the spinal cord level is increased in several neuropathic pain conditions but not in chronic inflammatory pain. Increased presynaptic NMDAR activity can potentiate glutamate release from primary afferent terminals to spinal dorsal horn neurons, which is crucial for the synaptic plasticity associated with neuropathic pain caused by traumatic nerve injury and chemotherapy-induced peripheral neuropathy. Furthermore, α2δ-1, previously considered a calcium channel subunit, can directly interact with NMDARs through its C-terminus to increase presynaptic NMDAR activity by facilitating synaptic trafficking of α2δ-1-NMDAR complexes in neuropathic pain caused by chemotherapeutic agents and peripheral nerve injury. Targeting α2δ-1-bound NMDARs with gabapentinoids or α2δ-1 C-terminus peptides can attenuate nociceptive drive form primary sensory nerves to dorsal horn neurons in neuropathic pain.
Learn More >Non-invasive stimulation of the vagus nerve has been proposed as a new neuromodulation therapy to treat primary headache disorders, as the vagus nerve is hypothesized to modulate the headache pain pathways in the brain. Vagus nerve stimulation can be performed by placing an electrode on the ear to stimulate the tragus nerve, which contains about 1% of the vagus fibers. Non-invasive vagus nerve stimulation (nVNS) conventionally refers to stimulation of the cervical branch of the vagus nerve, which is made up entirely of vagal nerve fibers. While used interchangeably, most of the research to date has been performed with nVNS or an implanted vagus nerve stimulation device. However, the exact mechanism of action of nVNS remains hypothetical and no clear overview of the effectiveness of nVNS in primary headache disorders is available.
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