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Medication overuse headache is estimated to affect 2% of the population, and is ranked in the top 20 most disabling disorders due to its high level of disability. Several therapies used in the treatment of acute migraine are thought to be associated with medication overuse headache, including opioids and triptans. With limited treatment options, it is critical to determine the risk profile of novel therapies prior to their widespread use. The current study explores the potential medication overuse risk of two novel therapeutic drug classes, namely the ditans: 5-HT1F receptor agonists, and the gepants: calcitonin gene-related peptide receptor antagonists, in a preclinical model of medication overuse. Persistent exposure of mice to the 5-HT1F agonist LY344864, but not olcegepant produced a significant reduction in hind paw and orofacial mechanical withdrawal thresholds as a surrogate readout of allodynia. In agreement, only LY344864 induced neuroplastic changes in trigeminal sensory afferents, increasing calcitonin gene-related peptide expression and basal trigeminal nociception. Our data highlight a differential medication overuse headache risk profile for the ditan and gepant classes of drugs that has important implications for their clinical use and patient education to help reduce the burden of medication overuse headache.
Learn More >Chronic pain remains challenging to both diagnose and treat. These challenges, in part, arise from limited systems-level understanding of the basic mechanisms that process nociceptive information and ultimately instantiate a subjectively available experience of pain. Here, I provide a framework, the distributed nociceptive system, for understanding nociceptive mechanisms at a systems level by integrating the concepts of neural population coding with distributed processing. Within this framework, wide-spread engagement of populations of neurons produces representations of nociceptive information that are highly resilient to disruption. The distributed nociceptive system provides a foundation for understanding complex spatial aspects of chronic pain and provides an impetus for nonpharmacological cognitive and physical therapies that can effectively target the highly distributed system that gives rise to an experience of pain.
Learn More >Innovation in the field of brain-machine interfacing offers a new approach to managing human pain. In principle, it should be possible to use brain activity to directly control a therapeutic intervention in an interactive, closed-loop manner. But this raises the question as to whether the brain activity changes as a function of this interaction. Here, we used real-time decoded functional MRI responses from the insula cortex as input into a closed-loop control system aimed at reducing pain and looked for co-adaptive neural and behavioral changes. As subjects engaged in active cognitive strategies orientated toward the control system, such as trying to enhance their brain activity, pain encoding in the insula was paradoxically degraded. From a mechanistic perspective, we found that cognitive engagement was accompanied by activation of the endogenous pain modulation system, manifested by the attentional modulation of pain ratings and enhanced pain responses in pregenual anterior cingulate cortex and periaqueductal gray. Further behavioral evidence of endogenous modulation was confirmed in a second experiment using an EEG-based closed-loop system. Overall, the results show that implementing brain-machine control systems for pain induces a parallel set of co-adaptive changes in the brain, and this can interfere with the brain signals and behavior under control. More generally, this illustrates a fundamental challenge of brain decoding applications-that the brain inherently adapts to being decoded, especially as a result of cognitive processes related to learning and cooperation. Understanding the nature of these co-adaptive processes informs strategies to mitigate or exploit them.
Learn More >How is neuropathic pain regulated in peripheral sensory neurons? Importins are key regulators of nucleocytoplasmic transport. In this study, we found that importin α3 (also known as karyopherin subunit alpha 4) can control pain responsiveness in peripheral sensory neurons in mice. Importin α3 knockout or sensory neuron-specific knockdown in mice reduced responsiveness to diverse noxious stimuli and increased tolerance to neuropathic pain. Importin α3-bound c-Fos and importin α3-deficient neurons were impaired in c-Fos nuclear import. Knockdown or dominant-negative inhibition of c-Fos or c-Jun in sensory neurons reduced neuropathic pain. In silico screens identified drugs that mimic importin α3 deficiency. These drugs attenuated neuropathic pain and reduced c-Fos nuclear localization. Thus, perturbing c-Fos nuclear import by importin α3 in peripheral neurons can promote analgesia.
Learn More >Voltage-gated sodium channel Nav1.7 has been validated as a perspective target for selective inhibitors with analgesic and anti-itch activity. The objective of this study was to discover new candidate compounds with Nav1.7 inhibitor properties. The authors hypothesized that their approach would yield at least one new compound that inhibits sodium currents in vitro and exerts analgesic and anti-itch effects in mice.
Learn More >Neuroscientific research on pleasant touch has focused on the C-tactile pathway for gentle stroking and has successfully explained how these sensory fibers transmit information about affective social touch to the brain and induce sensations of pleasantness. The C-tactile social/affective touch hypothesis even proposes that C-tactile fibers form a privileged pathway underlying social touch. However, deep pressure is a type of touch commonly considered pleasant and calming, occurring in hugs, cuddling, and massage. In this paper we introduce a paradigm for studying pleasant deep pressure and propose that it constitutes another important form of social touch. We describe development of the oscillating compression sleeve (OCS) as one approach to administering deep pressure and demonstrate that this touch is perceived as pleasant and calming. Further, we show that deep pressure can be imaged with functional magnetic resonance imaging (MRI) using the air-pressure-driven OCS and that deep pressure activates brain regions highly similar to those that respond to C-tactile stroking, as well as regions not activated by stroking. We propose that deep pressure constitutes another social touch pathway of evolutionary importance signaling the close proximity of conspecifics.
Learn More >Discrimination toward people living with migraine and other headache disorders is widespread and socially accepted. Stigma toward these diseases is both a manifestation of these discriminatory attitudes and a sustainer of them. For those living with migraine and headache disorders, stigma limits the full expression of their lives, as well as the likelihood of receiving health care to reduce the burden. In the past decade, public advocacy organizations have emerged in the United States and internationally to counter the consequences of this stigma. These organizations have raised public awareness of these diseases, corrected misconceptions, and empowered millions of people affected by them. The Alliance for Headache Disorders Advocacy has focused on addressing the structural stigma inherent in discriminatory policies of employers, government agencies, and public institutions. While notable progress has been made, there is considerable work left to be done to increase resources and equity for people living with headache disorders.
Learn More >Opioids are frequently prescribed for acute musculoskeletal injuries and may result in long-term use and consequent harms.
Learn More >Patients and clinicians can choose from several treatment options to address acute pain from non-low back musculoskeletal injuries.
Learn More >Calcitonin gene-related peptide is recognized as a key player in migraine, yet the mechanisms and sites of calcitonin gene-related peptide action remain unknown. The efficacy of calcitonin gene-related peptide-blocking antibodies as preventative migraine drugs supports a peripheral site of action, such as the trigeminovasculature. Given the apparent disconnect between the importance of vasodilatory peptides in migraine and the prevailing opinion that vasodilation is an epiphenomenon, the goal of this study was to test whether vasodilation plays a role in calcitonin gene-related peptide-induced light aversive behavior in mice.
Learn More >Cryptogenic sensory polyneuropathy (CSPN) is a common generalized slowly progressive neuropathy, second in prevalence only to diabetic neuropathy. Most patients with CSPN have significant pain. Many medications have been tried for pain reduction in CSPN, including antiepileptics, antidepressants, and sodium channel blockers. There are no comparative studies that identify the most effective medication for pain reduction in CSPN.
Learn More >The American College of Physicians (ACP) and American Academy of Family Physicians (AAFP) developed this guideline to provide clinical recommendations on nonpharmacologic and pharmacologic management of acute pain from non-low back, musculoskeletal injuries in adults in the outpatient setting. The guidance is based on current best available evidence about benefits and harms, taken in the context of costs and patient values and preferences. This guideline does not address noninvasive treatment of low back pain, which is covered by a separate ACP guideline that has also been endorsed by AAFP.
Learn More >Fibromyalgia is defined by idiopathic, chronic, widespread musculoskeletal pain. In adults with fibromyalgia, meta-analysis of lower-leg skin biopsy demonstrated 45% pooled prevalence of abnormally low epidermal neurite density (END). END <5th centile of the normal distribution is the consensus diagnostic threshold for small-fiber neuropathy. However, the clinical significance of END findings in fibromyalgia is unknown. The prevalence of small fiber pathology has not yet been studied in juvenile fibromyalgia.
Learn More >Central disinhibition (CD), as applied to pain, decreases thresholds of endogenous systems. This provokes onset of spontaneous or evoked pain in an individual beyond the ability of the nervous system to inhibit pain resulting from a disease or tissue damage. The original CD concept as proposed by Craig entails a shift from the lateral pain pathway (i.e. discriminative pain processing) towards the medial pain pathway (i.e. emotional pain processing), within an otherwise neurophysiological intact environment. In this review, the original CD concept as proposed by Craig is extended by the primary "nociceptive pathway damage – CD" concept and the secondary "central pathway set point – CD". Thereby, the original concept may be transferred into anatomical and psychological non-functional conditions. We provide examples for either primary or secondary CD concepts within different clinical etiologies as well as present surrogate models, which directly mimic the underlying pathophysiology (A-fiber block) or modulate the CD pathway excitability (thermal grill). The thermal grill has especially shown promising advancements, which may be useful to examine CD pathway activation in the future. Therefore, within this topical review, a systematic review on the thermal grill illusion is intended to stimulate future research. Finally, the authors review different mechanism-based treatment approaches to combat CD pain.
Learn More >Many clinical and preclinical studies report higher prevalence and severity of chronic pain in females. We used hyperalgesic priming with interleukin 6 (IL-6) priming and PGE as a second stimulus as a model for pain chronicity. Intraplantar IL-6 induced hypersensitivity was similar in magnitude and duration in both males and females, while both paw and intrathecal PGE hypersensitivity was more persistent in females. This difference in PGE response was dependent on both circulating estrogen and translation regulation signaling in the spinal cord. In males, the duration of hypersensitivity was regulated by testosterone. Since the prolactin receptor (Prlr) is regulated by reproductive hormones and is female-selectively activated in sensory neurons, we evaluated whether Prlr signaling contributes to hyperalgesic priming. Using ΔPRL, a competitive Prlr antagonist, and a mouse line with ablated Prlr in the Nav1.8 sensory neuronal population, we show that Prlr in sensory neurons is necessary for the development of hyperalgesic priming in female but not male mice. Overall, sex-specific mechanisms in the initiation and maintenance of chronic pain are regulated by the neuroendocrine system and, specifically, sensory neuronal Prlr signaling.Females are more likely to experience chronic pain than males, but the mechanisms that underlie this sex difference are not completely understood. Here, we demonstrate that the duration of mechanical hypersensitivity is dependent on circulating sex hormones in mice – where estrogen caused an extension of sensitivity and testosterone was responsible for a decrease in the duration of the hyperalgesic priming model of chronic pain. Additionally, we demonstrated that Prolactin receptor expression in Nav1.8 neurons was necessary for hyperalgesic priming in female, but not male mice. Our work demonstrates a female-specific mechanism for the promotion of chronic pain involving the neuroendrocrine system and mediated by sensory neuronal prolactin receptor.
Learn More >Non-steroidal anti-inflammatory drugs, cyclo-oxygenase inhibitors, are used routinely in the treatment of primary headache disorders. Indomethacin is unique in its use in the diagnosis and treatment of hemicrania continua and paroxysmal hemicrania. The mechanism of this specific action is not fully understood, although an interaction with nitric oxide signaling pathways has been suggested. Trigeminovascular neurons were activated by dural electrical stimulation, systemic administration of a nitric oxide donor, or local microiontophoresis of L-glutamate. Using electrophysiological techniques, we subsequently recorded the activation of trigeminovascular neurons and their responses to intravenous indomethacin, naproxen and ibuprofen. Administration of indomethacin (5 mgkg), ibuprofen (30 mgkg) or naproxen (30 mgkg) inhibited dural-evoked firing within the trigeminocervical complex with different temporal profiles. Similarly, both indomethacin and naproxen inhibited L-glutamate-evoked cell firing suggesting a common action. In contrast, only indomethacin was able to inhibit nitric oxide-induced firing. The differences in profile of effect of indomethacin may be fundamental to its ability to treat paroxysmal hemicrania and hemicrania continua. The data implicate nitric oxide-related signaling as a potential therapeutic approach to these disorders.
Learn More >Chronic pain reduces life quality and is an important clinical problem associated with emotional and cognitive dysfunction. Epigenetic regulation of DNA methylation is involved in the induction of abnormal behaviors and pathological gene expression. We examined whether acupuncture can restore epigenetic changes caused by chronic pain, and identified the underlying mechanisms in neuropathic pain mice. Acupuncture treatment for 6 months (3 days/week) improved mechanical/cold allodynia and the emotional/cognitive dysfunction caused by left partial sciatic nerve ligation (PSNL)-induced neuropathic pain. The effects of acupuncture were associated with global DNA methylation recovery in the prefrontal cortex (PFC). Analysis of DNA methylation patterns in PFC indicated that 1,364 overlapping genes among 4,442 and 4,416 methylated genes in the PSNL vs. sham and PSNL vs. AP groups, respectively, were highly associated with the DNA methylation process. Acupuncture restored the reduced expression of 5-methylcytosine, methyl-CpG binding protein 2, and DNA methyltransferase family enzymes induced by PSNL in PFC. Methylation levels of Nr4a1 and Chkb associated with mitochondrial dysfunction were decreased in PFC of the PSNL mice, and increased by acupuncture. In contrast, high expression of Nr4a1 and Chkb mRNA in PSNL mice decreased after acupuncture. We also found that acupuncture inhibited the expression of Ras pathway-related genes such as Rasgrp1 and Rassf1. Finally, the expression of Nr4a1, Rasgrp1, Rassf1, and Chkb mRNA increased in the neuronal cells treated with Mecp2 siRNA. These results suggest that acupuncture can relieve chronic pain-induced comorbid conditions by altering DNA methylation of Nr4a1, Rasgrp1, Rassf1, and Chkb in the PFC.
Learn More >Spinal high mobility group box 1 protein (HMGB1) plays crucial roles in arthritis-induced pain, however the involvement of peripheral HMGB1 has not been examined previously. In this study, we addressed the role of peripheral HMGB1 and explored if sex contributes differentially to nociception in arthritis. We found Hmgb1 expression to be elevated in the ankle joints of male and female mice subjected to collagen antibody-induced arthritis (CAIA). Blocking the action of peripheral HMGB1, however, only reversed CAIA-induced hypersensitivity in males. Intra-articular injection of the toll-like receptor (TLR)4-activating, partially reduced disulfide, but not the fully reduced all-thiol, HMGB1 evoked mechanical hypersensitivity in both sexes. A sex-dependent temporal profile in expression of inflammatory factors in the ankle joint was observed in response to intra-articular injection of disulfide HMGB1, with male mice showing a delayed, yet longer lasting increase in mRNA levels for several of the investigated factors. Intra-articular HMGB1 did not induce cellular infiltration in the ankle joint suggesting its action on tissue resident cells. To further explore possible sex differences in cellular involvement, we used the macrophage inhibitor, minocycline, and mice with specific TLR4 depletion in myeloid cells or nociceptors. We found that inhibition of resident macrophages attenuated HMGB1-induced pain-like behavior only in male mice. Interestingly, while the contribution of TLR4 on myeloid cells to nociception was minimal in females compared to males, TLR4 on nociceptors are important for HMGB1-induced pain in both sexes. Collectively, our work highlights sex- and cellular location-dependent roles of HMGB1 and TLR4 in peripheral pain mechanisms.
Learn More >Concerns about adverse outcomes associated with opioid analgesic prescription have led to major guideline and policy changes. Substantial uncertainty remains, however, regarding the association between opioid prescription initiation and increased risk of subsequent substance-related morbidity.
Learn More >Chronic non-cancer pain, a disabling and distressing condition, is common in adults. It is a global public health problem and economic burden on health and social care systems and on people with chronic pain. Psychological treatments aim to reduce pain, disability and distress. This review updates and extends its previous version, published in 2012.
Learn More >The neuroanatomical basis behind acupuncture practice is still poorly understood. Here, we used intersectional genetic strategy to ablate NPY noradrenergic neurons and/or adrenal chromaffin cells. Using endotoxin-induced systemic inflammation as a model, we found that electroacupuncture stimulation (ES) drives sympathetic pathways in somatotopy- and intensity-dependent manners. Low-intensity ES at hindlimb regions drives the vagal-adrenal axis, producing anti-inflammatory effects that depend on NPY adrenal chromaffin cells. High-intensity ES at the abdomen activates NPY splenic noradrenergic neurons via the spinal-sympathetic axis; these neurons engage incoherent feedforward regulatory loops via activation of distinct adrenergic receptors (ARs), and their ES-evoked activation produces either anti- or pro-inflammatory effects due to disease-state-dependent changes in AR profiles. The revelation of somatotopic organization and intensity dependency in driving distinct autonomic pathways could form a road map for optimizing stimulation parameters to improve both efficacy and safety in using acupuncture as a therapeutic modality.
Learn More >In this issue of Immunity, Xu et al. reveal that dermal dendritic cells produce interleukin-31, which acts on neurons to promote wound itch. Their findings link itch associated with deeper wounds-wounds that extend beyond the epithelium-to the cells and cytokines that mediate wound healing.
Learn More >To assess the efficacy of monoclonal antibodies targeting calcitonin gene-related peptide (CGRP) or its receptor in chronic cluster headache (CCH) treatment under real world conditions.
Learn More >Since calcitonin gene-related peptide (CGRP) plays an important role in the pathophysiology of migraine via the activation of the trigeminovascular system, the newest prophylactic treatments directly block CGRP or its receptor. However, the safety of these novel antimigraine drugs is not yet sufficiently established.
Learn More >We aimed to systematically assess the effectiveness and tolerability of erenumab in a clinical setting, specifically a tertiary headache center.
Learn More >Administration of ATP-sensitive potassium channel opener levcromakalim triggers headache in healthy volunteers and migraine attacks in migraine patients. Here, we investigated the effect of ATP-sensitive potassium channel blocker glibenclamide on levcromakalim-induced headache in healthy volunteers.
Learn More >Evaluate the safety and tolerability of oral rimegepant when used for acute treatment concomitantly with a monoclonal antibody (mAb) targeting the calcitonin gene-related peptide (CGRP) ligand or receptor (CGRP mAb) for the preventive treatment of migraine.
Learn More >Chronic pain induces a multitude of harmful effects; recently it has been suggested that chronic pain is also associated with premature aging, manifested in shortened telomere length (TL). However, evidence for this hypothesis is scarce and inconsistent. The aim was twofold: 1) Investigate whether chronic pain is associated with premature aging, and 2) Determine whether physical exercise (PE) moderates this association if it exists. Participants were 116 male subjects, with (n=67) and without chronic pain (n=49). Blood samples for TL analysis were collected and participants were interviewed and completed questionnaires. As a part of the cohort, we included people with physical disability; this variable was controlled in the analysis. The TL of individuals with chronic pain was significantly shorter than that of pain-free individuals. Regression analysis revealed a significant moderating effect of PE on chronic pain and TL, above and beyond the effects of disability, age, and weight. Whereas chronic pain was associated with shorter telomeres in participants who did not exercise, this association was non-significant among participants who did exercise. The results suggest that chronic pain is associated with premature ageing; however, PE may mitigate this association and may protect individuals against the harmful effects of chronic pain. PERSPECTIVE: The study suggest that it is important to monitor signs of premature ageing among chronic pain patients as they are at risk. However, chronic pain patients may benefit from regular physical exercise in this respect as it may moderate premature ageing.
Learn More >Sensory information processing in robot skins currently rely on a centralized approach where signal transduction (on the body) is separated from centralized computation and decision-making, requiring the transfer of large amounts of data from periphery to central processors, at the cost of wiring, latency, fault tolerance and robustness. We envision a decentralized approach where intelligence is embedded in the sensing nodes, using a unique neuromorphic methodology to extract relevant information in robotic skins. Here we specifically address pain perception and the association of nociception with tactile perception to trigger the escape reflex in a sensorized robotic arm. The proposed system comprises self-healable materials and memtransistors as enabling technologies for the implementation of neuromorphic nociceptors, spiking local associative learning and communication. Configuring memtransistors as gated-threshold and -memristive switches, the demonstrated system features in-memory edge computing with minimal hardware circuitry and wiring, and enhanced fault tolerance and robustness.
Learn More >Women of childbearing age experience the highest prevalence of irritable bowel syndrome (IBS), yet little is known about their psychosocial and parenting needs, which may influence their children's experience of future gastrointestinal or pain-related conditions. The aims of this study were to conduct qualitative interviews to understand the psychosocial and parenting needs of mothers with IBS who have young school-age children, and to assess mothers' potential interest in and acceptability of a preventive parenting intervention program. Ten mothers with IBS who have young (age 5-10), healthy children were interviewed. Interviews were coded with thematic analysis and three themes were identified: (1) Guilt about how IBS impacts children, (2) Worry that children will develop IBS, and (3) Already on high alert for children's health. All mothers expressed interest in an Internet-based preventive intervention and identified tools and strategies they would want included. Results demonstrate that mothers experience guilt about how IBS has impacted their children in their daily lives, concern that they need to pay attention to children's early signs and symptoms that could indicate gastrointestinal problems, and worry about children developing IBS in the future-suggesting that a preventive intervention may address important concerns for this population.
Learn More >Pathological pain is regulated by a balance between pro-algesic and analgesic mechanisms. Interactions between opioid peptide-producing immune cells and peripheral sensory neurons expressing opioid receptors represent a powerful intrinsic pain control in animal models and in humans. Therefore, treatments based on general suppression of immune responses have been mostly unsuccessful. It is highly desirable to develop strategies that specifically promote neuro-immune communication mediated by opioids. Promising examples include vaccination-based recruitment of opioid-containing leukocytes to painful tissue and the local reprogramming of pro-algesic immune cells into analgesic cells producing and secreting high amounts of opioid peptides. Such approaches have the potential to inhibit pain at its origin and be devoid of central and systemic side effects of classical analgesics. In support of these concepts, in this article, we describe the functioning of peripheral opioid receptors, migration of opioid-producing immune cells to inflamed tissue, opioid peptide release, and the consequent pain relief. Conclusively, we provide clinical evidence and discuss therapeutic opportunities and challenges associated with immune cell-mediated peripheral opioid analgesia.
Learn More >Despite the ability of peripheral nerves to regenerate after injury, failure occurs due to an inability of supporting cells to maintain growth, resulting in long-term consequences such as sensorimotor dysfunction and neuropathic pain. Here, we investigate the potential of engaging the cellular adaptive response to hypoxia, via inhibiting its negative regulators, to enhance the regenerative process. Under normoxic conditions, prolyl hydroxylase domain (PHD) proteins 1, 2, and 3 hydroxylate the key metabolic regulator hypoxia inducible factor 1α (HIF1α), marking it for subsequent proteasomal degradation. We inhibited PHD protein function systemically via either individual genetic deletion or pharmacological pan-PHD inhibition using dimethyloxalylglycine (DMOG). We show enhanced axonal regeneration after sciatic nerve crush injury in PHD1 mice, PHD3 mice, and in DMOG-treated mice, and in PHD1 and DMOG-treated mice a reduction in hypersensitivity to cooling after permanent sciatic ligation. Electromyographically, PHD1 and PHD3 mice showed an increased CMAP amplitude one-month post-injury, probably due to protection against denervation induced muscle atrophy, while DMOG-treated and PHD2 mice showed reduced latencies, indicating improved motor axon function. DMOG treatment did not affect the growth of dorsal root ganglion neurites in vitro, suggesting a lack of direct effects of DMOG on axonal regrowth. Enhanced regeneration in vivo was concurrent with an increase in macrophage density, and a shift in macrophage polarization state ratios (from M1-like toward M2-like) in DMOG-treated animals. These results indicate PHD proteins as a novel therapeutic target to improve regenerative and functional outcomes after peripheral nerve injury without manipulating molecular O.
Learn More >A substantial fraction of the human population suffers from chronic pain states, which often cannot be sufficiently treated with existing drugs. This calls for alternative targets and strategies for the development of novel analgesics. There is substantial evidence that the G protein-coupled GABA receptor is involved in the processing of pain signals and thus has long been considered a valuable target for the generation of analgesics to treat chronic pain. In this review, the contribution of GABA receptors to the generation and modulation of pain signals, their involvement in chronic pain states as well as their target suitability for the development of novel analgesics is discussed.
Learn More >Statistical analysis plans describe the planned data management and analysis for clinical trials. This supports transparent reporting and interpretation of clinical trial results. This paper reports the statistical analysis plan for the RESOLVE clinical trial. The RESOLVE trial assigned participants with chronic low back pain to graded sensory-motor precision training or sham-control.
Learn More >The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) alleviate symptoms of experimental neuropathy, protect and stimulate regeneration of sensory neurons in animal models of neuropathic pain, and restore their functional activity. However, clinical development of GFL proteins is complicated by their poor pharmacokinetic properties and multiple effects mediated by several receptors. Previously, we have identified a small molecule that selectively activates the major signal transduction unit of the GFL receptor complex, receptor tyrosine kinase RET, as an alternative to GFLs, for the treatment of neuropathic pain. We then introduced a series of chemical changes to improve the biological activity of these compounds and tested an optimized compound named BT44 in a panel of biological assays. BT44 efficiently and selectively stimulated the GFL receptor RET and activated the intracellular mitogene-activated protein kinase/extracellular signal-regulated kinase pathway in immortalized cells. In cultured sensory neurons, BT44 stimulated neurite outgrowth with an efficacy comparable to that of GFLs. BT44 alleviated mechanical hypersensitivity in surgery- and diabetes-induced rat models of neuropathic pain. In addition, BT44 normalized, to a certain degree, the expression of nociception-related neuronal markers which were altered by spinal nerve ligation, the neuropathy model used in this study. Our results suggest that the GFL mimetic BT44 is a promising new lead for the development of novel disease-modifying agents for the treatment of neuropathy and neuropathic pain.
Learn More >Headache diaries and recall questionnaires are frequently used to assess headache frequency and severity in clinical and research settings.
Learn More >Epidermolysis bullosa (EB) is a highly diverse group of inherited skin disorders, resulting from mutations in genes encoding proteins of the dermal-epidermal junction (DEJ). Itch (pruritus) is one of the commonest symptoms across all EB subtypes. It occurs in blistered or wounded sites, or manifests as a generalized phenomenon, thereby affecting both intact skin and healing wounds. The mechanism of pruritus in EB is unclear. It is likely that skin inflammation secondary to barrier disruption, wound healing cascades and dysregulated activation of epidermal sensory nerve endings are all involved in its pathophysiology on the molecular and cellular level. Understanding these mechanisms in depth is crucial in developing optimised treatments for people with EB and improving quality of life. This review summarises current evidence on the prevalence, mechanisms and management of itch in EB.
Learn More >Previous studies have shown that CCL2 (C-C motif chemokine ligand 2) induces chronic pain, but the exact mechanisms are still unknown. Here, we established models to explore the potential mechanisms. Behavioral experiments revealed that an antagonist of extracellular signal-regulated kinase (ERK) inhibited not only CCL2-induced inflammatory pain, but also pain responses induced by complete Freund's adjuvant. We posed the question of the intracellular signaling cascade involved. Subsequent experiments showed that CCL2 up-regulated the expression of phosphorylated ERK (pERK) and N-methyl D-aspartate receptor [NMDAR] subtype 2B (GluN2B); meanwhile, antagonists of CCR2 and ERK effectively reversed these phenomena. Whole-cell patch-clamp recordings revealed that CCL2 enhanced the NMDAR-induced currents via activating the pERK pathway, which was blocked by antagonists of GluN2B and ERK. In summary, we demonstrate that CCL2 directly interacts with CCR2 to enhance NMDAR-induced currents, eventually leading to inflammatory pain mainly through the CCL2-CCR2-pERK-GluN2B pathway.
Learn More >Although mid back pain (MBP) is a common condition that causes significant disability, it has received little attention in research and knowledge about trajectories and prognosis of MBP is limited. The purpose of this study was to identify trajectories of MBP and baseline risk factors for an unfavorable outcome in MBP patients undergoing chiropractic treatment.
Learn More >This review examines recent (2016 onwards) neuroscientific findings on the mechanisms supporting mindfulness-associated pain relief. To date, its clear that mindfulness lowers pain by engaging brain processes that are distinct from placebo and vary across meditative training level. Due to rapid developments in the field of contemplative neuroscience, an update review on the neuroimaging studies focused on mindfulness, and pain is merited.
Learn More >Opioid dose escalation to effectively control pain is often linked to the current prescription opioid abuse epidemic. This creates social as well as medical imperatives to better understand the mechanistic underpinnings of opioid tolerance to develop interventions that minimize it, thereby maximizing the analgesic effectiveness of opioids. Profound opioid analgesic tolerance can be observed in the absence of mu-opioid receptor (MOR) downregulation, aggregate MOR G protein uncoupling, and MOR desensitization, in the absence of impaired G protein coupled receptor kinase phosphorylation, arrestin binding, or endocytosis. Thus, we have explored alternative biochemical sequelae that might better account for opioid analgesic tolerance. Our findings indicate that substantial plasticity among upstream and downstream components of opioid receptor signaling and the emergence of alternative signaling pathways are major contributors to opioid analgesic tolerance. An exemplar of this plasticity is our findings that chronic morphine upregulates the MOR variants MOR-1B2 and MOR-1C1 and phosphorylation of their C-terminal sites not present in MOR-1, events causally associated with the chronic morphine-induced shift in MOR G protein coupling from predominantly GG inhibitory to G-stimulatory adenylyl cyclase signaling. The unique feature(s) of these variants that underlies their susceptibility to adapting to chronic morphine by altering the nature of their G protein coupling reveals the richness and pliability of MOR signaling that is enabled by generating a wide diversity of MOR variants. Furthermore, given differential anatomical expression patterns of MOR variants, MOR splice variant-dependent adaptations to chronic morphine could enable mechanistic underpinnings of tolerance and dependence that are CNS region- and cell-specific.
Learn More >Astrocytes are the most abundant glial cells in the central nervous system (CNS), including the spinal cord. Neuronal damage induces astrocytes to become reactive and contribute to various CNS pathologies. Recent studies have demonstrated that astrocytes in the spinal dorsal horn (SDH) become reactive in a transcription factor signal transducer and activator of transcription 3-dependent manner without neuronal damage under chronic itch conditions, causing release of the factor lipocalin-2, leading to induction of sensitization of gastrin releasing peptide-induced chemical itch signaling in the SDH. In this review, we describe recent advances in our understanding of SDH neuronal pathways for itch transmission, the mechanisms of SDH astrocytic activation and its contribution to abnormal itch processing and discuss the role of reactive astrocytes in the SDH in abnormal sensory processing under chronic itch conditions.
Learn More >Osteoarthritis results in chronic pain and loss of function. Proinflammatory cytokines create both osteoarthritis pathology and pain. Current treatments are poorly effective, have significant side effects, and have not targeted the cytokines central to osteoarthritis development and maintenance. Interleukin-10 is an anti-inflammatory cytokine that potently and broadly suppresses proinflammatory cytokine activity. However, interleukin-10 protein has a short half-life in vivo and poor joint permeability. For sustained IL-10 activity, we developed a plasmid DNA-based therapy that expresses a long-acting human interleukin-10 variant (hIL-10var). Here, we describe the 6-month GLP toxicology study of this therapy. Intra-articular injections of hIL-10var pDNA into canine stifle joints up to 1.5 mg bilaterally were well-tolerated and without pathologic findings. This represents the first long-term toxicologic assessment of intra-articular pDNA therapy. We also report results of a small double-blind, placebo-controlled study of the effect of intra-articular hIL-10var pDNA on pain measures in companion (pet) dogs with naturally occurring osteoarthritis. This human IL-10-based targeted therapy reduced pain measures in the dogs, based on veterinary and owner ratings, without any adverse findings. These results with hIL-10var pDNA therapy, well-tolerated and without toxicologic effects, establish the basis for clinical trials of a new class of safe and effective therapies for OA.
Learn More >Chronic pain negatively affects psychological functioning including self-perception. Self-compassion may improve self-related functioning in patients with chronic pain but understanding of the neural mechanisms is limited. In this study, twenty patients with chronic low back pain read negative self-related situations and were instructed to be either self-reassuring or self-critical while undergoing fMRI. Patients rated their feelings of self-reassurance and self-criticism during each condition, and brain responses were contrasted with neutral instructions. Trait self-compassion measures (SCS) were also acquired. Brain activations during self-criticism and self-reassurance were localized to prefrontal, self- and emotion-processing areas, such as medial prefrontal cortex, dorsolateral prefrontal cortex (dlPFC), dorsal anterior cingulate cortex and posterior cingulate cortex. Self-reassurance resulted in more widespread and stronger activations relative to self-criticism. Patients then completed a brief self-compassion training (8 contact hours, 2 weeks home practice). Exploratory pre-post comparisons in thirteen patients found that feelings of self-criticism were significantly reduced and brain activations were greater in the anterior insula and prefrontal cortical regions such as dlPFC. Pre-post increases in dlPFC activation correlated with increased self-compassion (SCS), suggesting that early self-compassion skills might primarily target self-criticism via dlPFC upregulation. Future controlled studies on self-compassion training in chronic pain populations should extend these results.
Learn More >Patients with back pain can show one or more features of spinal osteoarthritis (OA), such as morning stiffness, limited or painful range of motion (ROM), and lumbar disc degeneration (LDD). However, whether these features are prognostic of long-term back pain has not been investigated.
Learn More >The concentration of the multifunctional protein clusterin is reduced in the plasma of subjects with degenerative scoliosis and carpal tunnel syndrome but elevated in the cerebrospinal fluid of neuropathic pain patients successfully treated with spinal cord stimulation. The present work tries to increase the knowledge of pain-associated changes of plasma and brain clusterin by using an animal model of neuropathy. We studied the effects of sciatic nerve ligation on mechanical allodynia (von Frey test), anxiety (elevated plus maze test), plasma clusterin (enzyme-linked immunosorbent assay) and clusterin expression in the nucleus accumbens and prefrontal cortex of adult male Wistar rats (western blot). The possible modulatory role of high fat dieting was also studied, bearing in mind that obesity has been also reported to influence nociception, clusterin levels and prefrontal cortex activation. Animals with nerve ligation showed mechanical allodynia, anxiety and a marked downregulation of clusterin in the mitochondrial fraction of the prefrontal cortex. Animals fed on high fat also exhibited a slight increase of the sensitivity to mechanical stimuli and anxiety; however, the diet did not potentiate the effects of nerve ligation. The results did not confirm a parallelism between neuropathy, obesity and alterations of plasma levels of clusterin, but strongly suggest that the protein could be involved in the functional reorganization of the prefrontal cortex which has been recently reported in chronic pain conditions.
Learn More >Hamstring injuries in athletes can lead to significant time away from competition as a result of persistent posterior thigh pain. These cases are often difficult to treat as the state of the tissues alone cannot explain symptoms. In non-athletic populations with persistent pain, disruptions to tactile, proprioceptive, and spatial cortical representations exist, which has led to promising brain-based treatments. Here, we explored whether athletes with persistent posterior thigh pain also display impairments in these cortical representations.
Learn More >Central sensitization represents a key pathophysiological mechanism underlying the development of neuropathic pain, often manifested clinically as mechanical allodynia and hyperalgesia. Adopting a mechanism-based treatment approach relies highly on the ability to assess the presence of central sensitization. The aim of the study was to investigate potential pain-autonomic readouts to operationalize experimentally induced central sensitization in the area of secondary hyperalgesia.
Learn More >In the search for safer, non-addictive analgesics, kappa opioid receptor (KOPr) agonists are a potential target, as unlike mu-opioid analgesics, they do not have abuse potential. Salvinorin A (SalA) is a potent and selective KOPr agonist, however, clinical utility is limited by the short duration of action and aversive side effects. Biasing KOPr signaling toward G-protein activation has been highlighted as a key cellular mechanism to reduce the side effects of KOPr agonists. The present study investigated KOPr signaling bias and the acute antinociceptive effects and side effects of two novel analogs of SalA, 16-Bromo SalA and 16-Ethynyl SalA. 16-Bromo SalA showed G-protein signaling bias, whereas 16-Ethynyl SalA displayed balanced signaling properties. In the dose-response tail-withdrawal assay, SalA, 16-Ethynyl SalA and 16-Bromo SalA were more potent than the traditional KOPr agonist U50,488, and 16-Ethynyl SalA was more efficacious. 16-Ethynyl SalA and 16-Bromo SalA both had a longer duration of action in the warm water tail-withdrawal assay, and 16-Ethynyl had greater antinociceptive effect in the hot-plate assay, compared to SalA. In the intraplantar 2% formaldehyde test, 16-Ethynyl SalA and 16-Bromo SalA significantly reduced both nociceptive and inflammatory pain-related behaviors. Moreover, 16-Ethynyl SalA and 16-Bromo SalA had no anxiogenic effects in the marble burying task, and 16-Bromo SalA did not alter behavior in the elevated zero maze. Overall, 16-Ethynyl SalA significantly attenuated acute pain-related behaviors in multiple preclinical models, while the biased KOPr agonist, 16-Bromo SalA, displayed modest antinociceptive effects, and lacked anxiogenic effects.
Learn More >: Sugar is routinely used to comfort neonates undergoing painful procedures, and animal studies have shown that sucrose increases the time to withdrawal from painful stimuli. However, there are no published studies examining the effects of sweet substances on heat pain thresholds and percept in adult humans. : Healthy adult volunteers (n=27, aged 18-48 years) were recruited to a controlled, double-blind, randomised, cross-over study to characterise the effect of tasting solutions of equivalent sweetness (10% sucrose and 0.016% sucralose) on warm detection and heat pain thresholds and the percept ratings of painfully hot stimuli. The effect of anticipation of a sweet taste on heat pain threshold was also assessed. : Tasting either sucrose or sucralose had no significant effect on the percept of an individually titrated hot stimulus (54.5±4.2 and 54.9±3.2 vs 53.2±3.5 for water, 0-100 visual analogue scale), on the warm detection or heat pain threshold (43.3±0.8, 43.2±0.8 vs 43.0±0.8°C). Anticipation of a sweet substance similarly did not affect heat pain thresholds. : Sucrose and sucralose solutions had no analgesic effect when assessed using heat detection thresholds and percept ratings of painfully hot stimuli despite being perceived as sweeter and more pleasant than water. These findings are in contrast to results reported from previous animal studies in which thermal analgesia from sweet solutions is robust. Given the ubiquitous availability of sugar rich drinks in the modern environment, the lack of observable effect may be due to an insufficient hedonic value of the test solutions when compared to the experience of a laboratory rodent. Alternatively, sweet tastes may have a specific effect on pain tolerance rather than the threshold and acute percept measures assayed in this study.
Learn More >To conduct a systematic literature review of dorsal root ganglion (DRG) stimulation for pain.
Learn More >Highly active antiretroviral therapy (HAART) works effectively in inhibiting HIV replication in patients. However, the use of nucleoside reverse transcriptase inhibitors (NRTIs) often causes side effects of neuropathic pain, and its mechanism remains to be elucidated. Therefore, we aim to explore the mechanism of NRTIs-induced neuropathic pain at the transcriptome level. C57BL/6 J mice were given intraperitoneal injection of zalcitabine (ddC) or saline (control) for 2 weeks, during which the mechanical pain threshold of the mice was detected by von Frey test. Then the L3~L5 spinal segments of the mice were isolated and subsequently used for RNA sequencing (RNA-seq) on the last day of treatment. The mechanical pain threshold of mice given ddC decreased significantly. Compared with the control group, ddC caused significant changes in the expression of 135 genes, of which 66 upregulated and 69 downregulated. Enrichment analysis showed that the functions of these genes are mainly enriched in regulation of transcription, multicellular organism development, and cell differentiation, and the pathway is mainly enriched in the cGMP-PKG signaling pathway and AMPK signaling pathway. Furthermore, key genes such as Gabrd, Kcnd3, Npcd, Insr, Lypd6, Scd2, and Mef2d were also identified. These may serve as drug targets for the prevention or treatment of NRTI-induced neuropathic pain.
Learn More >To examine the change in the Patient Activation Measure and physical and psychosocial outcome measures in a military interdisciplinary intensive outpatient program for persistent pain. Pre- and post-intervention measures, which were also stratified by gender and baseline activation, included patient-reported outcomes and physical function assessment, obtained from 2017 to 2018 program database. The majority of the participants were male (70.9%), with an average age of 29.18 years and pain duration of 4.78 years (n = 103). Patient activation, majority of the patient reported outcomes and functional assessments improved in the overall sample with fewer changes in females on the Defense and Veterans Pain Rating Scale. Improvements were noted on the Patient Activation Measure and majority of the other outcome measures suggesting that service members with persistent pain at any level of patient activation or baseline function, may benefit from an intensive outpatient program.
Learn More >The mechanisms by which mobility function and neuropathic pain are mutually influenced by supraspinal plasticity in motor- and pain-related brain networks following spinal cord injury (SCI) remains poorly understood.
Learn More >Cortical disinhibition is the underlying pathological alteration contributing to neuropathic pain associated with peripheral nerve injury. Nerve injury resulting in disinhibition of the anterior cingulate cortex has been reported. However, the effect of optogenetic inhibition of the anterior cingulate cortex (ACC) on the sensory component of nerve injury-induced neuropathic pain has not been well studied. To investigate the feasibility of optogenetic ACC modulation, we injected an optogenetic virus or a null virus into the ACC of a nerve injury-induced neuropathic pain model. The unilateral ACC was modulated, and the optogenetic effect was measured by mechanical and thermal sensitivity tests. The assessment was performed in "pre-light off," "stimulation-yellow light on," and "post-light off" states. Optogenetic inhibition of the ACC in injury models revealed improved mechanical and thermal latencies with profound pain-relieving effects against nerve injury-induced neuropathic pain. The sensory thalamic discharge in electrophysiological in vivo recordings was also altered during laser stimulation. This finding indicates that hyperactivity of the ACC in nerve injury increases output to the spinothalamic tract through direct or indirect pathways. The direct photoinhibition of ACC neurons could play a vital role in restoring equilibrium and provide novel insight into techniques that can assuage peripheral nerve injury-induced neuropathic pain.
Learn More >The trigemino-vascular system (TVS) plays a key role in migraine pathophysiology. Glial cells are abundant in the TVS system and mainly in the trigeminal ganglion. S100B protein is a calcium-binding protein, found in the cytoplasm of glial cells in the central nervous system, which is released in response to inflammatory stimuli. Previous works analyzing S100B in migraineurs have offered contradictory results.
Learn More >The anti-nociceptive properties of ghrelin have been demonstrated in alleviating inflammatory and neuropathic pain. Whether a ghrelin receptor-mediated mechanism attenuates visceral and somatic pain in the absence of active inflammation remains to be explored. Here, we investigate the efficacy of peripherally restricted (ipamorelin) and a globally active (HM01) selective ghrelin receptor agonist in an experimental model of non-inflammatory visceral hypersensitivity and somatic mechanical allodynia.
Learn More >Effective treatment of neuropathic pain is challenging as its underlying mechanism remains largely unknown. Recently, the participation of brain-derived neurotrophic factor (BDNF) in neuropathic pain has been attracting increased attention. BDNF binds to a member of the tyrosine kinase receptor family, the TrkB receptor, that is specific for BDNF and is the transmembrane receptor on the posterior horn of spinal cord. In the present study, we purified two proteins that included the BDNF-binding domain of TrkB (eTrkB) and eTrkB coupled with a liposomal outer surface (liposomal eTrkB) in order to inhibit the BDNF-TrkB pathway in neuropathic pain. Results of the pull-down assay showed that eTrkB was bound to BDNF. We investigated the neuropathic pain suppression effect of this purified protein by its intrathecal administration in a rat neuropathic pain model. Mechanical and thermal hyperalgesia induced by L5 lumbar nerve ligation was markedly suppressed by treatment with eTrkB protein. Furthermore, we showed a prolonged algetic inhibition by liposomal eTrkB protein treatment. In conclusion, this study suggests that eTrkB, which sequesters endogenous BDNF and inhibits the BDNF-TrkB pathway, may prove to be a novel analgesic to treat neuropathic pain.
Learn More >Although migraine is one of the most common primary headaches, its therapy is still limited in many cases. The use of animal models is crucial in the development of novel therapeutic strategies, but unfortunately, none of them show all aspects of the disease, therefore, there is a constant need for further improvement in this field. The application of inflammatory agents on the dura mater is a widely accepted method to mimic neurogenic inflammation in rodents, which plays a key role in the pathomechanism of migraine. Complete Freund's Adjuvant (CFA), and a mixture of inflammatory mediators, called inflammatory soup (IS) are often used for this purpose.
Learn More >The central medial nucleus (CM), a prominent cell group of the intralaminar nuclei (ILN) of the thalamus, and the ventrolateral periaqueductal gray matter (vlPAG) are two major components of the medial pain system. Whether vlPAG and CM are input sources of nociceptive information to the basolateral amygdala (BLA) and whether they are involved in neuropathic pain regulation remain unclear. Clarifying the hierarchical organization of these subcortical nuclei (vlPAG, CM, and BLA) can enhance our understanding on the neural circuits for pain regulation. Behavioral test results showed that a CM lesion made by kainic acid (KA) injection could effectively alleviate mechanical hyperalgesia 4, 6, and 8 days after spared nerve injury (SNI) surgery, with the symptoms returning after 10 days. Morphological studies revealed that: (1) the CM received afferents from vlPAG and sent efferents to BLA, indicating that an indirect vlPAG-CM-BLA pathway exists; (2) such CM-BLA projections were primarily excitatory glutamatergic neurons as revealed by fluorescence hybridization; (3) the fibers originated from the CM-formed close contacts with both excitatory and inhibitory neurons in the BLA; and (4) BLA-projecting CM neurons expressed Fos induced by SNI and formed close contacts with fibers from vlPAG, suggesting that the vlPAG-CM-BLA indirect pathway was activated in neuropathic pain conditions. Finally, the vlPAG-CM-BLA indirect pathway was further confirmed using anterograde and monosynaptic virus tracing investigation. In summary, our present results provide behavioral and morphological evidence that the indirect vlPAG-CM-BLA pathway might be a novel pain pathway involved in neuropathic pain regulation.
Learn More >A core outcome set (COS) represents the agreed minimum set of domains and measurement instruments that should be measured and reported in any clinical trial for a given condition. In BMS randomized controlled trials (RCTs), the outcomes identified in the existing literature regarding the efficacy of therapeutic interventions are numerous and diverse. Although the standardized IMMPACT core outcome domains has been developed for measurement of outcomes in chronic pain RCTs, no BMS-specific COS have been adopted and validated. With the evolving landscape of BMS management end points and the development of new therapies, a consensus on a COS for use in future BMS trials is paramount to reduce heterogeneity in outcome reporting. The aim of this study was to reach a consensus for adopting the standardized Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) outcome domains, and their tools of assessment, for burning mouth syndrome (BMS) clinical trials and clinical practice.
Learn More >Tetrodotoxin (TTX) is a highly specific voltage-gated sodium channel (VGSC) blocker in clinical evaluation as a peripheral-acting analgesic for chronic pain. This study presents the first published results of the safety including cardiac liability of TTX at therapeutic-relevant concentrations in twenty-five healthy adults. Randomized, double-blind, placebo-, and positive- (moxifloxacin) controlled study evaluated single ascending doses of 15 µg, 30 µg, and 45 µg TTX over 3 periods with a 7-day washout between each period. Subcutaneous injections of TTX were readily absorbed, reaching maximum plasma concentration (C) within 1.5 h. Both extent of exposure (AUC) and C increased in proportion to dose. No QT prolongation was identified by concentration-QTc analysis and the upper bounds of the two-sided 90% confidence interval of predicted maximum baseline and placebo corrected QTcF (ΔΔQTcF) value did not exceed 10 ms for all tetrodotoxin doses, thereby meeting the criteria of a negative QT study. Safety assessments showed no clinically relevant changes with values similar between all groups and no subject withdrawing due to adverse events. Paresthesia, oral-paresthesia, headache, dizziness, nausea, and myalgia were the most common TEAEs (overall occurrence ≥5%) in the TTX treatment groups. TTX doses investigated in this study are safe, well-tolerated, and lack proarrhythmic proclivity.
Learn More >The cone snails (family Conidae) are the best known and most intensively studied venomous marine gastropods. However, of the total biodiversity of venomous marine mollusks (superfamily Conoidea, >20,000 species), cone snails comprise a minor fraction. The venoms of the family Drilliidae, a highly diversified family in Conoidea, have not previously been investigated. In this report, we provide the first biochemical characterization of a component in a Drilliidae venom and define a gene superfamily of venom peptides. A bioactive peptide, cdg14a, was purified from the venom of Fedosov and Puillandre, 2020. The peptide is small (23 amino acids), disulfide-rich (4 cysteine residues) and belongs to the J-like drillipeptide gene superfamily. Other members of this superfamily share a conserved signal sequence and the same arrangement of cysteine residues in their predicted mature peptide sequences. The cdg14a peptide was chemically synthesized in its bioactive form. It elicited scratching and hyperactivity, followed by a paw-thumping phenotype in mice. Using the Constellation Pharmacology platform, the cdg14a drillipeptide was shown to cause increased excitability in a majority of non-peptidergic nociceptors, but did not affect other subclasses of dorsal root ganglion (DRG) neurons. This suggests that the cdg14a drillipeptide may be blocking a specific molecular isoform of potassium channels. The potency and selectivity of this biochemically characterized drillipeptide suggest that the venoms of the Drilliidae are a rich source of novel and selective ligands for ion channels and other important signaling molecules in the nervous system.
Learn More >Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are associated with various sequelae. Chronic pain, one of these sequelae, has never been systematically evaluated.
Learn More >To conduct a systematic literature review of peripheral nerve stimulation (PNS) for pain.
Learn More >Most patients treated with erenumab in clinical practice have chronic migraine (CM). We assessed the rate and possible predictors of conversion from CM to episodic migraine (EM) in a real-life study.
Learn More >In this study we aimed to evaluate the frequency of the main red flags in patients with headache who do have Covid-19.
Learn More >Frailty and chronic pain are prevalent among older adults. However, no study has systematically reviewed the association between frailty and chronic pain in older adults. Therefore, we aimed to estimate the prevalence of frailty and prefrailty among older adults with chronic pain and review the longitudinal association between frailty status and chronic pain.
Learn More >With the advancement of technology, peripheral nerve stimulation (PNS) has been increasingly used to treat various chronic pain conditions. Its origin is based on the gate control theory postulated by Wall and Melzack in 1965. However, the exact mechanism behind PNS' analgesic effect is largely unknown. In this article, we performed a comprehensive literature review to overview the PNS mechanism of action.
Learn More >Although previous reports described the beneficial role of angiotensin-converting enzyme inhibitors (ACE-Is) or AT1 receptor blockers (ARBs) in attenuating neuropathic pain (NP), no study has yet explored the exact underlying mechanisms, as well as the superiority of using centrally versus peripherally acting renin-angiotensin-aldosterone system (RAAS) drugs in NP. We investigated the effects of 14 days of treatment with centrally (telmisartan and ramipril) or peripherally (losartan and enalapril) acting ARBs and ACE-Is, respectively, in attenuating peripheral NP induced by sciatic nerve chronic constriction injury (CCI) in rats. We also compared these with the effects of pregabalin, the standard treatment for NP. Behavioral changes, inflammatory markers (NFкB, TNF-α, COX-2, PGE2, and bradykinin), oxidative stress markers (NADPH oxidase and catalase), STAT3 activation, levels of phosphorylated P38-MAPK, ACE, AT1 receptor (AT1R), and AT2 receptor (AT2R), as well as histopathological features, were assessed in the brainstem and sciatic nerve. CCI resulted in clear pain-related behavior along with increased levels of inflammatory and oxidative stress markers, and STAT3 activity, as well as increased levels of phosphorylated P38-MAPK, ACE, AT1R, and AT2R, along with worsened histopathological findings in both the brainstem and sciatic nerve. ARBs improved both animal behavior and all measured parameters in CCI rats and were more effective than ACE-Is. At the tested doses, centrally acting ARBs or ACE-Is were not superior to the peripherally acting drugs of the same category. These findings suggest that ARBs (centrally or peripherally acting) are an effective treatment modality for NP.
Learn More >Some chronic pain conditions in the orofacial region are common and the mechanisms underlying orofacial pain are unresolved. Nerve growth factor (NGF) is a member of a family of neurotrophins and regulates the growth, maintenance and development of neurons. Increasing evidence suggests that NGF plays a crucial role in the generation of pain and hyperalgesia in different pain states. This review investigates the role of NGF in orofacial pain and their underlying cellular mechanisms, which may provide essential guidance to drug-discovery programmes. A systemic literature search was conducted in Pubmed focusing on NGF and orofacial pain. Articles were reviewed, and those discussing in vitro studies, animal evidence, clinical course, and possible mechanisms were summarized. We found a hyperalgesic effect of NGF in peripheral sensitization in orofacial pain models. We also summarize the current knowledge regarding NGF-dependent pain mechanism, which is initiated by retrograde transport of the ligand-receptor complex, ensuing transcriptional regulation of many important nociceptor genes involved in nociceptive processing. Phase III trials suggest that anti-NGF drug is endorsed with anti-inflammatory and pain-relieving effects with good tolerance in a variety of pain conditions, including pain associated with osteoarthritis and chronic lower back pain. Based on the data reviewed herein, NGF is believed to be an important hyperalgesic mediator in orofacial pain. The identification of underlying mechanisms and pathways of orofacial pain opens new frontiers for pain management.
Learn More >We intended to clarify the effect of gender and A118G polymorphism of Opioid Receptor μ1 (OPRM1) on the required morphine for patients to maintain Visual Analogue Scale ≦ 3 for post-operative pain control after total knee replacement (TKR).
Learn More >Postoperative pain after total knee arthroplasty (TKA) and total hip arthroplasty (THA) influence patients' rehabilitation and life quality. Although gabapentin has been widely used for analgesia, its efficacy is still controversial in TKA and THA. This meta-analysis was performed to assess the efficacy and safety of gabapentin following TKA and THA.
Learn More >Src family kinases (SFK) are a group of non-receptor tyrosine kinases which play a pivotal role in cellular responses and oncogenesis. Accumulating evidence suggest that SFK also act as a key component in signalling pathways of the central nervous system (CNS) in both physiological and pathological conditions. Despite the crucial role of SFK in signal transduction of the CNS, the relationship between SFK and molecules implicated in pain has been relatively unexplored. This article briefly reviews the recent advances uncovering the interplay of SFK with diverse membrane proteins and intracellular proteins in the CNS and the importance of SFK in the pathophysiology of migraine and neuropathic pain. Mechanisms underlying the role of SFK in these conditions and potential clinical applications of SFK inhibitors in neurological diseases are also summarised. We propose that SFK are the convergent point of signalling pathways in migraine and neuropathic pain and may constitute a promising therapeutic target for these diseases.
Learn More >Protein kinase type C-ε (PKCε) plays important roles in the sensitization of primary afferent nociceptors, such as ion channel phosphorylation, that in turn promotes mechanical hyperalgesia and pain chronification. In these neurons, PKCε is modulated through the local release of mediators by the surrounding Schwann cells (SCs). The progesterone metabolite allopregnanolone (ALLO) is endogenously synthesized by SCs, whereas it has proven to be a crucial mediator of neuron-glia interaction in peripheral nerve fibers. Biomolecular and pharmacological studies on rat primary SCs and dorsal root ganglia (DRG) neuronal cultures were aimed at investigating the hypothesis that ALLO modulates neuronal PKCε, playing a role in peripheral nociception. We found that SCs tonically release ALLO, which, in turn, autocrinally upregulated the synthesis of the growth factor brain-derived neurotrophic factor (BDNF). Subsequently, glial BDNF paracrinally activates PKCε via trkB in DRG sensory neurons. Herein, we report a novel mechanism of SCs-neuron cross-talk in the peripheral nervous system, highlighting a key role of ALLO and BDNF in nociceptor sensitization. These findings emphasize promising targets for inhibiting the development and chronification of neuropathic pain.
Learn More >Growing evidence demonstrates circadian rhythms of pain hypersensitivity in various chronic disorders. In chemotherapy-induced peripheral neuropathy (CIPN), agents such as paclitaxel are known to elicit chronic neuropathic pain in cancer patients and seriously compromise their quality of life. Here, we report that the mechanical threshold for allodynia in paclitaxel-treated rats exhibited a robust circadian oscillation, reaching the nadir during the daytime (inactive phase). Using Per2::LucSV circadian reporter mice expressing a PER2::LUC fusion protein, we isolated dorsal root ganglia (DRG), the primary sensory cell body for peripheral nerve injury generated hypersensitivity, and monitored ex vivo reporter bioluminescence. We observed strong circadian reporter rhythms in DRG neurons which are highly entrainable by external cues. Paclitaxel treatment significantly lengthened DRG circadian periods, with little effects on the amplitude of oscillation. We further observed the core protein BMAL1 and PER2 in DRG neurons and satellite cells. Using DRG and dorsal horn (DH; another key structure for CIPN pain response) tissues from vehicle and paclitaxel treated rats, we performed RNA-sequencing and identified diurnal expression of core clock genes as well as clock-controlled genes in both sites. Interestingly, 20.1% and 30.4% of diurnal differentially expressed genes (DEGs) overlapped with paclitaxel-induced DEGs in the DRG and the DH respectively. In contrast, paclitaxel-induced DEGs displayed only a modest overlap between daytime and nighttime (Zeitgeber Time 8 and 20). Furthermore, paclitaxel treatment induced de novo diurnal DEGs, suggesting reciprocal interaction of circadian rhythms and chemotherapy. Our study therefore demonstrates a circadian oscillation of CIPN and its underlying transcriptomic landscape.
Learn More >This narrative review addresses common clinical questions and concerns of both physicians and patients about migraine during and after the perimenopausal transition, specifically (1) How does the perimenopausal transition affect migraine prevalence and does this vary by migraine type? (2) Does the magnitude of stroke risk associated with migraine increase with hormone therapy (HT)?, and (3) What are best practices as regards migraine treatment in perimenopausal women?
Learn More >The diagnosis of trigeminal neuralgia (TN) is challenging due to the lack of objective diagnostics. Corneal confocal microscopy (CCM) is a non-invasive ophthalmic imaging technique, which allows quantification of corneal nerve fibers arising from the trigeminal ganglion and may allow the assessment of neurodegeneration in TN. CCM was undertaken in 11 patients with TN and 11 age-matched healthy controls. Corneal nerve fiber density (CNFD), corneal nerve branch density, corneal nerve fiber length (CNFL), corneal nerve fiber width, corneal nerve fiber area, and dendritic cell and non-dendritic cell density with or without nerve fiber contact were quantified. Patients with TN had significantly lower CNFD and CNFL but no difference for any other corneal nerve or dendritic cell parameter in the ipsilateral and the contralateral cornea compared to the control group. There was no significant difference in corneal nerve and cell parameters between patients with TN with and without involvement of the ophthalmic nerve (V1) or with nerve vessel conflict. Corneal confocal microscopy is a rapid non-invasive imaging technique that identifies symmetrical corneal nerve loss in patients with TN.
Learn More >Transient receptor potential melastatin 8 (TRPM8) ion channel represents a valuable pharmacological option for several therapeutic areas. Here, a series of conformationally restricted derivatives of the previously described TRPM8 antagonist N,N'-dibenzyl tryptophan were prepared and characterized in vitro by Ca-imaging and patch-clamp electrophysiology assays. Molecular modeling studies led to identification of a broad and well-defined interaction network of these derivatives inside the TRPM8-agonist binding site, underlying their antagonist activity. The (5R,11aS)-5-(4-chlorophenyl)-2-(4-fluorobenzyl)-5,6,11,11a-tetrahydro-1H-imidazo[1',5':1,6]pyrido[3,4-b]indole-1,3(2H)-dione () emerged as a potent (IC50 4.10 ± 1.2 nM), selective, and metabolically stable TRPM8 antagonist. In vivo, showed significant target coverage in an icilin-induced WDS (at 11.5 mg/kg i.p.), an oxaliplatin-induced cold allodynia (at 10-30 μg s.c.), and CCI-induced thermal hyperalgesia (at 11.5 mg/kg i.p.) mice models. These results confirm the tryptophan moiety as a solid pharmacophore template for the design of highly potent modulators of TRPM8-mediated activities.
Learn More >A relationship between chronic pain and frailty has been reported. The early detection and prevention of frailty are recommended, in part because community-dwelling older adults in a pre-frailty state may return to a healthy state. The relationship between chronic pain and pre-frailty is not known. Toward the goal of promoting a reversible return to health from pre-frailty, we investigated the relationship between chronic pain and pre-frailty among community-dwelling older adults. We assessed the frailty and chronic pain of 107 older adults who were participating in community health checks. The status of physical frailty was based on the five components described by Fried (2001): muscle weakness shown by handgrip strength, slowness of gait speed, weight loss, low physical activity, and exhaustion. Chronic pain was assessed based on pain intensity, the Pain Catastrophizing Scale (PCS), the Japanese version of the Geriatric Depression Scale-15 (GDS-15), and the Central Sensitization Inventory (CSI). The prevalence of chronic pain with pre-frailty was 40.2%. A hierarchical analysis revealed that PCS-measured helplessness (odds ratio [OR]: 0.88) and the CSI (OR: 0.87) were significant factors associated with the presence of chronic pain with pre-frailty. The prevalence of chronic pain with pre-frailty was high, and chronic pain and pre-frailty were strongly related. New intervention or prevention programs that take into account both chronic pain and pre-frailty must be created as soon as possible.
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