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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 >Back pain is linked to intervertebral disc (IVD) degeneration, but clinical studies show the relationship is complex. This study assessed whether males and females have distinct relationships between IVD degeneration and pain using an in vivo rat model. Forty-eight male and female Sprague-Dawley rats had lumbar IVD puncture or sham surgery. Six weeks after surgery, IVDs were evaluated by radiologic IVD height, histological grading, and biomechanical testing. Pain was assessed by von Frey assay and dorsal root ganglia (DRG) expression of Calca and Tac1 genes. Network analysis visualized which measures of IVD degeneration most related to pain by sex. In both females and males, annular puncture induced structural IVD degeneration, but functional biomechanical properties were similar to sham. Females and males had distinct differences in mechanical allodynia and DRG gene expression, even though sex differences in IVD measurements were limited. Network analysis also differed by sex, with more associations between annular puncture injury and pain in the male network. Sex differences exist in the interactions between IVD degeneration and pain. Limited correlation between measures of pain and IVD degeneration highlights the need to evaluate pain or nociception in IVD degeneration models to better understand nervous system involvement in discogenic pain.
Learn More >To determine whether erenumab, a new monoclonal antibody to the calcitonin gene-related peptide (CGRP) receptor, exerts functional central effects in migraineurs, we performed functional imaging scans on patients treated with erenumab.
Learn More >Chronic pain is considered a public health crisis due to its high prevalence, impact, costs, and disparities in pain prevalence and treatment. In parallel, drug overdose, particularly due to opioids, has become an epidemic in the United States, prompting a public health crisis concerning harms associated with both prescribed opioid therapy for chronic pain and illicit opioid use. The purpose of this special issue is to highlight state-of-the-art psychological research that addresses the combined issues of chronic pain and harms associated with opioids. Articles included in this special issue focus on 2 related areas. The 1st set of innovative articles focuses on risk factors for chronic pain, characterization of patterns of opioid use and misuse, assessment of opioid risk, and identification of moderating factors in populations ranging from adolescents to older adults. The 2nd set of articles includes exemplary research on psychological approaches for management of chronic pain and opioid risk mitigation; integration of psychological approaches in patient-centered, evidence-based, multimodal and interdisciplinary plans of pain care; and treatment of co-occurring chronic pain and opioid use disorder. Last, the issue includes a guest editorial highlighting psychological research and the participation of psychologists in the National Institutes of Health's Helping to End Addiction Long-Term (HEAL) initiative. In this introduction, the guest editors highlight the objectives in this special issue are to stimulate additional research to develop psychological approaches to reduce opioid misuse behaviors, to help educate providers on opioid prescribing that is equitable and minimizes risk of harms, and to address co-occurring chronic pain and opioid use disorder in vulnerable populations. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
Learn More >The neuroimaging community has shown tremendous interest in exploring the brain's spontaneous activity using functional magnetic resonance imaging (fMRI). On the contrary, the spinal cord has been largely overlooked despite its pivotal role in processing sensorimotor signals. Only a handful of studies have probed the organization of spinal resting-state fluctuations, always using static measures of connectivity. Many innovative approaches have emerged for analyzing dynamics of brain fMRI, but they have not yet been applied to the spinal cord, although they could help disentangle its functional architecture. Here, we leverage a dynamic connectivity method based on the clustering of hemodynamic-informed transients to unravel the rich dynamic organization of spinal resting-state signals. We test this approach in 19 healthy subjects, uncovering fine-grained spinal components and highlighting their neuroanatomical and physiological nature. We provide a versatile tool, the spinal innovation-driven co-activation patterns (SpiCiCAP) framework, to characterize spinal circuits during rest and task, as well as their disruption in neurological disorders.
Learn More >Viscera receive innervation from sensory ganglia located adjacent to multiple levels of the brainstem and spinal cord. Here we examined whether molecular profiling could be used to identify functional clusters of colon afferents from thoracolumbar (TL), lumbosacral (LS), and nodose ganglia (NG) in male and female mice. Profiling of TL and LS bladder afferents was also done. Visceral afferents were back-labeled using retrograde tracers injected into proximal and distal regions of colon or bladder, followed by single cell RT-qPCR and analysis via an automated hierarchical clustering method. Genes were chosen for assay (32 for bladder; 48 for colon) based on their established role in stimulus detection, regulation of sensitivity/function or neuroimmune interaction. A total of 132 colon afferents (from NG, TL, and LS) and 128 bladder afferents (from TL and LS) were analyzed. Retrograde labeling from the colon showed NG and TL afferents innervate proximal and distal regions of the colon whereas 98% of LS afferents only project to distal regions. There were clusters of colon and bladder afferents, defined by mRNA profiling, that localized to either TL or LS ganglia. Mixed TL/LS clustering also was found. In addition, transcriptionally, NG colon afferents were almost completely segregated from colon TL and LS neurons. Furthermore, colon and bladder afferents expressed genes at similar levels, although different gene combinations defined the clusters. These results indicate that genes implicated in both homeostatic regulation and conscious sensations are found at all anatomic levels, suggesting afferents from different portions of the neuraxis have overlapping functions.Visceral organs are innervated by sensory neurons whose cell bodies are located in multiple ganglia associated with the brainstem and spinal cord. For the colon, this overlapping innervation is proposed to facilitate visceral sensation and homeostasis, where sensation and pain is mediated by spinal afferents and fear and anxiety (the affective aspects of visceral pain) are the domain of nodose afferents. Transcriptomic analysis performed here reveals that genes implicated in both homeostatic regulation and pain are found in afferents across all ganglia types, suggesting that conscious sensation and homeostatic regulation is the result of convergence, and not segregation, of sensory input.
Learn More >To improve understanding of the respiratory behavior of oliceridine, a μ-opioid receptor agonist that selectively engages the G-protein-coupled signaling pathway with reduced activation of the β-arrestin pathway, the authors compared its utility function with that of morphine. It was hypothesized that at equianalgesia, oliceridine will produce less respiratory depression than morphine and that this is reflected in a superior utility.
Learn More >Stinging trees from Australasia produce remarkably persistent and painful stings upon contact of their stiff epidermal hairs, called trichomes, with mammalian skin. -induced acute pain typically lasts for several hours, and intermittent painful flares can persist for days and weeks. Pharmacological activity has been attributed to small-molecule neurotransmitters and inflammatory mediators, but these compounds alone cannot explain the observed sensory effects. We show here that the venoms of Australian species contain heretofore unknown pain-inducing peptides that potently activate mouse sensory neurons and delay inactivation of voltage-gated sodium channels. These neurotoxins localize specifically to the stinging hairs and are miniproteins of 4 kDa, whose 3D structure is stabilized in an inhibitory cystine knot motif, a characteristic shared with neurotoxins found in spider and cone snail venoms. Our results provide an intriguing example of inter-kingdom convergent evolution of animal and plant venoms with shared modes of delivery, molecular structure, and pharmacology.
Learn More >Large placebo responses in randomized clinical trials may keep effective medication from reaching the market. Primary outcome measures of clinical trials have shifted from patient-reported to objective outcomes, partly because response to randomized placebo treatment is thought to be greater in subjective compared with objective outcomes. However, a direct comparison of placebo response in subjective and objective outcomes in the same patient population is missing.
Learn More >The occurrence of pain has always been closely related to a break in the balance between excitatory and inhibitory systems, and the internal relationship between these two systems has not been studied in the pathogenesis of chronic migraine (CM). In this study, we explored how inhibitory interneurons specifically modulate the glutamate-induced hyperexcitability in the periaqueductal gray (PAG) of CM rats. The CM model was established by repeated dural infusion of inflammatory soup (IS) in rats. Then, Baclofen, a gamma-aminobutyric acid type B receptor (GABABR) agonist; CGP35348, a GABABR antagonist; H89, a protein kinase A (PKA) inhibitor; and 8-Bromo-cAMP, a PKA agonist, were applied by intraventricular injection to investigate the detailed CM mechanism. Our results showed that GABABR2 mRNA and protein levels were significantly downregulated (P < .01) in the PAG of CM rats. Similarly, gamma-aminobutyric acid (GABA) and its synthetase glutamate decarboxylase 65/67 (GAD65/67) seriously decreased (P < .01), implying a deficit in the function of inhibitory interneurons in the PAG of CM rats. Afterward, the application of Baclofen and H89 alleviated the IS-evoked hyperalgesia and extenuated vesicular glutamate transporter 2 (VGLUT2), glutamate, calcitonin gene-related peptide (CGRP), and c-Fos expression by regulating the GABABR2/PKA/SynCAM1 pathway in the PAG of CM rats, while the application of CGP35348 and 8-Bromo-cAMP exactly exerted the opposite effect. Importantly, CGP35348 induced an elevation of CGRP, and VGLUT2 expression was relieved by H89. These data suggest that the loss in the function of inhibitory interneurons contributes to glutamate-associated central sensitization through the GABABR2/PKA/SynCAM1 pathway in the PAG of CM rats.
Learn More >The role of peripheral mu-opioid receptors (MOPs) in chronic pain conditions is not well understood. Here, we used a combination of mouse genetics, behavioral assays, and pharmacologic interventions to investigate the contribution of primary afferent MOPs to nociceptive, inflammatory, and neuropathic pain, as well as to opioid analgesia.
Learn More >LPA is one of six known receptors (LPA) for lysophosphatidic acid (LPA). Constitutive Lpar1 null mutant mice have been instrumental in identifying roles for LPA-LPA signaling in neurobiological processes, brain development, and behavior, as well as modeling human neurological diseases like neuropathic pain. Constitutive Lpar1 null mutant mice are protected from partial sciatic nerve ligation (PSNL)-induced neuropathic pain, however, the cell types that are functionally responsible for mediating this protective effect are unknown. Here, we report the generation of an Lpar1 conditional null mutant mouse that allows for cre-mediated conditional deletion, combined with a PSNL pain model. Lpar1 mice were crossed with cre transgenic lines driven by neural gene promoters for nestin (all neural cells), synapsin (neurons), or P0 (Schwann cells). CD11b-cre transgenic mice were also used to delete Lpar1 in microglia. PSNL-initiated pain responses were reduced following cre-mediated Lpar1 deletion with all three neural promoters as well as the CD11b promoter, supporting involvement of Schwann cells, central and/or peripheral neurons, and microglia in mediating pain. Interestingly, rescue responses were nonidentical, implicating distinct roles for Lpar1-expressing cell types. Our results with a new Lpar1 conditional mouse mutant expand an understanding of LPA signaling in the PSNL model of neuropathic pain.
Learn More >Placebo analgesia is hypothesized to involve top-down engagement of prefrontal regions that access endogenous pain inhibiting opioid pathways. Fibromyalgia (FM) patients have neuroanatomical and neurochemical alterations in pathways relevant to placebo analgesia. Thus, it remains unclear whether placebo analgesic mechanisms would differ in FM patients compared to healthy controls (HCs). Here, using placebo-analgesia-inducing paradigms that included verbal suggestions and conditioning manipulations, we examined whether behavioral and neural placebo analgesic responses differed between 32 FM patients and 46 age- and sex-matched HCs. Participants underwent a manipulation scan, where noxious high and low heat were paired with the control and placebo cream, respectively, and a placebo experimental scan with equal noxious heat temperatures. Before the experimental scan, each participant received saline or naloxone, an opioid receptor antagonist. Across all participants, the placebo condition decreased pain intensity and unpleasantness ratings, decreased activity within the right insula and bilateral secondary somatosensory cortex, and modulated the Neurologic Pain Signature. There were no differences between HCs and FM patients in pain intensity ratings or neural responses during the placebo condition. Despite the perceptual and neural effects of the placebo manipulation, prefrontal circuitry was not activated during the expectation period and the placebo analgesia was unaltered by naloxone, suggesting placebo effects were driven more by conditioning than expectation. Together, these findings suggest that placebo analgesia can occur in both HCs and chronic pain FM patients, without the involvement of opiodergic prefrontal modulatory networks.
Learn More >Veterans experience chronic pain at greater rates than the rest of society and are more likely to receive long-term opioid therapy (LTOT), which, at high doses, is theorized to induce maladaptive neuroplastic changes that attenuate self-regulatory capacity and exacerbate opioid dose escalation. Mindfulness meditation has been shown to modulate frontal midline theta (FMT) and alpha oscillations that are linked with marked alterations in self-referential processing. These adaptive neural oscillatory changes may promote reduced opioid use and remediate the neural dysfunction occasioned by LTOT. In this study, we used electroencephalography (EEG) to assess the effects of a mindfulness-based, cognitive training intervention for opioid misuse, mindfulness-oriented recovery enhancement (MORE), on alpha and theta power and FMT coherence during meditation. We then examined whether these neural effects were associated with reduced opioid dosing and changes in self-referential processing. Before and after 8 weeks of MORE or a supportive psychotherapy control, veterans receiving LTOT (N = 62) practiced mindfulness meditation while EEG was recorded. Participants treated with MORE demonstrated significantly increased alpha and theta power (with larger theta power effect sizes) as well as increased FMT coherence relative to those in the control condition-neural changes that were associated with altered self-referential processing. Crucially, MORE significantly reduced opioid dose over time, and this dose reduction was partially statistically mediated by changes in frontal theta power. Study results suggest that mindfulness meditation practice may produce endogenous theta stimulation in the prefrontal cortex, thereby enhancing inhibitory control over opioid dose escalation behaviors.Fig. 1SPECTRAL EEG CHANGES DURING A LABORATORY-BASED MINDFULNESS MEDITATION PRACTICE SESSION BEFORE AND AFTER 8 WEEKS OF MINDFULNESS-ORIENTED RECOVERY ENHANCEMENT (MORE) OR A SUPPORTIVE GROUP (SG) PSYCHOTHERAPY CONTROL CONDITION.: Topoplots are interpolated to cover the entire headspace. dB = decibels.Fig. 2THETA COHERENCE CHANGES DURING A LABORATORY-BASED MINDFULNESS MEDITATION PRACTICE SESSION BEFORE AND AFTER 8 WEEKS OF MINDFULNESS-ORIENTED RECOVERY ENHANCEMENT (MORE) OR A SUPPORTIVE GROUP (SG) PSYCHOTHERAPY CONTROL CONDITION.: Red colors indicate positive coherence while blue colors indicate negative coherence. Saturation of color as well as line thickness represent the strength of coherence between nodes. ROIs are grouped via node color. n.u. = normalized units.Fig. 3Path model indicating that the effect of mindfulness-oriented recovery enhancement (MORE) versus a supportive group (SG) psychotherapy control condition on reducing opioid dose was statistically mediated by increasing frontal theta power mindfulness meditation.Fig. 4Scatterplots depicting associations between treatment-related changes in frontal theta power and a self-transcendence (measured by the Nondual Awareness Dimensional Assessment) and b change in body boundaries (measured by the perceived body boundaries scale), among Veterans treated with mindfulness-oriented recovery enhancement (MORE) or a supportive group (SG) psychotherapy condition.
Learn More >The prototypical member of the receptor-inactivating kappa opioid receptor (KOR) antagonists norbinaltorphimine (norBNI) produces prolonged receptor inactivation by a cJun kinase mechanism. These antagonists have potential therapeutic utility in the treatment of stressdisorders, however additional preclinical characterization is necessary to understand important aspects of their action. In this study, we report that norBNI does not work as effectively in female mice as in males because of estrogen regulation of G-protein receptor kinase (GRK); pretreatment of ovary-intact female mice with the selective GRK2/3 inhibitor, CMPD101, made females equally sensitive to norBNI as males. Prior observations suggested that in vivo treatment with norBNI does not produce long-lasting inhibition of KOR regulation of dopamine release in the nucleus accumbens. We assessed the persistence of norBNI receptor inactivation in subcellular compartments. Fast-scan cyclic voltammetry recordings confirmed that presynaptic inhibition of dopamine release by the KOR agonist U69,593 was not blocked by in vivo pretreatment with norBNI under conditions that prevented KOR mediated aversion and analgesia. We employed a novel in vivo proxy sensor of KOR activation, AAV-DIO-HyPerRed and demonstrated that KOR activation stimulates JNK-dependent ROS production in somatic regions of VTA dopamine neurons, but did not activate ROS production in dopamine terminals. The compartment selective action helps explain how dopamine somatic, but not terminally expressed KORs are inactivated by norBNI. These results further elucidate molecular signaling mechanisms mediating receptor-inactivating KOR antagonist action and advance medication development for this novel class of stress-resilience medications. Kappa opioid receptor (KOR) antagonists are being developed as novel pro-resilience therapeutics for the treatment of mood and substance use disorders. This study showed that the long-acting KOR antagonists are affected by both the sex of the animal and the subcellular compartment in which the receptor is expressed.
Learn More >Neuropathic pain is a debilitating public health concern for which novel non-narcotic therapeutic targets are desperately needed. Using unbiased transcriptomic screening of the dorsal horn spinal cord after nerve injury we have identified that Gpr183 (Epstein-Barr induced gene 2 [EBI2]) is upregulated after chronic constriction injury (CCI) in rats. GPR183 is a chemotactic receptor known for its role in the maturation of B cells and the endogenous ligand is the oxysterol, 7α,25-dihydroxycholesterol (7α,25-OHC). The role of GPR183 in the central nervous system is not well characterized and its role in pain is unknown. The profile of commercially available probes for GPR183 limits their use as pharmacological tools to dissect the roles of this receptor in pathophysiological settings. Using in silico modeling, we have screened a library of 5 million compounds to identify several novel small-molecule antagonists of GPR183 with nanomolar potency. These compounds are able to antagonize 7α,25-OHC-induced calcium mobilization in vitro with IC50 values below 50nM. In vivo intrathecal injections of these antagonists during peak pain after CCI surgery reversed allodynia in male and female mice. Acute intrathecal injection of the GPR183 ligand, 7α,25-OHC in naïve mice induced dose-dependent allodynia. Importantly, this effect was blocked using our novel GPR183 antagonists, suggesting spinal GPR183 activation as pro-nociceptive. These studies are the first to reveal a role for GPR183 in neuropathic pain and identify this receptor as a potential target for therapeutic intervention. We have identified several novel GPR183 antagonists with nanomolar potency. Using these antagonists, we have demonstrated that GPR183 signaling in the spinal cord is pro-nociceptive. These studies are the first to reveal a role for GPR183 in neuropathic pain and identify it as a potential target for therapeutic intervention.
Learn More >Exosomes are extracellular microvesicles implicated in intercellular communication with ability to transfer cargo molecules, including protein, lipids, and nucleic acids, at both close and distant target sites. It has been shown that exosomes are implicated in physiological and pathological processes. In recent years, the interest on exosomes' role in many pain states has increased. Their involvements in pain processes have been demonstrated by studies on different chronic pain diseases, both inflammatory and neuropathic, such as osteoarthritis, rheumatoid arthritis, inflammatory bowel diseases, neurodegenerative pathologies, complex regional pain syndrome, and peripheral nerve injury. Animal and clinical studies investigated exosomes-based treatments, showing their ability to improve painful symptoms with fewer side effects, with potential immunoprotective and anti-inflammatory effect. Specific molecular patterns characterize exosomes' cargo according to the cellular origin, epigenetic modifications, environmental state, and stressor factors. Therefore, the identification of specific cargo's profile associated to pain states may lead to recognize specific pathological states and to consider the use of exosomes as biomarkers of diseases. Furthermore, exosomes' ability to transfer information and their presence in many accessible biological fluids suggest a potential use as novel non-invasive therapeutic tools in pain field.
Learn More >Nocebo hyperalgesia refers to increases in perceived pain that putatively result from negative expectations regarding a nocebo stimulus (eg, an inert treatment, compared with no treatment). The precise cognitive-emotional factors contributing to the origins of nocebo effects are poorly understood. We aimed to test the effects of experimentally induced pain-related fear on the acquisition and extinction of nocebo hyperalgesia in healthy participants (N = 72). Acquisition and extinction of nocebo hyperalgesia were compared between a group receiving standard nocebo conditioning (Control group) and 2 groups receiving distinct fear inductions: high intensity of pain stimulations (High-pain group) or a threat manipulation (High-threat group). During nocebo acquisition, the Control and High-threat groups were administered thermal pain stimulations of moderate intensity paired with sham electrical stimulation (nocebo trials), whereas high pain intensity was administered to the High-pain group. During extinction, equivalent pain intensities were administered across all trials. Pain-related fear was measured by eyeblink startle electromyography and self-report. Nocebo hyperalgesia occurred in all groups. Nocebo effects were significantly larger in the High-pain group than those in the Control group. This effect was mediated by self-reported fear, but not by fear-potentiated startle. Groups did not differ in the extinction rate. However, only the High-pain group maintained significant nocebo responses at the end of extinction. Anticipatory pain-related fear induced through a threat manipulation did not amplify nocebo hyperalgesia. These findings suggest that fear of high pain may be a key contributor to the amplification of nocebo hyperalgesia, only when high pain is experienced and not when it is merely anticipated.
Learn More >The social determinants of health (SDH) are known to differentially impact outcomes from many noncommunicable diseases; however, their potential role in low back pain (LBP) is poorly defined. This review endeavours to comprehensively inform the field of their relevance. Our research question was: "How do the broad range of SDH and chronic LBP (CLBP) relate?" The primary aim of this review was to synthesise evidence of relationships between SDH and the frequency or severity of CLBP. Secondary aims were to identify relationships between SDH and LBP-related disability, work absenteeism, and opioid prescription. We included studies involving adult participants that evaluated relationships between one or more of the SDH and CLBP frequency or LBP outcomes (beyond 3 months). Two reviewers screened studies, extracted data, and assessed risk of bias. We synthesized the results narratively and applied PROGRESS to organise our findings. Database searches identified 7018 records. Forty-one studies were included, containing data from 2,161,617 adults from 17 countries. Twenty-four percent and 19% of the relationships included were classified as having a high risk of bias due to confounding and missing data, respectively. We reported 166 relationships representing the majority of the PROGRESS domains. An array of independent and interdependent relationships between the SDH and CLBP were identified with the strongest evidence for associations related to educational attainment and socioeconomic status. Our findings suggest that greater recognition of the contribution of SDH to disparities in LBP outcomes is warranted and this has the potential to usefully inform strategies to impact burden.
Learn More >Pain permeates childhood and remains inadequately and/or inconsistently managed. Existing research and clinical practice guidelines have largely focused on factors influencing the immediate experience of pain. The need for and benefits of preparing children for future pain (e.g., painful procedures) has been well established. Despite being a robust predictor of future pain and distress, memories of past painful experiences remain overlooked in pediatric pain management. Just as autobiographical memories prepare us for the future, children's memories for past pain can be harnessed to prepare children for future painful experiences. Children's pain memories are malleable and can be reframed to be less distressing, thus reducing anticipatory distress and promoting self-efficacy. Parents are powerful agents of change in the context of pediatric pain and valuable historians of children's past painful experiences. They can alter children's pain memories to be less distressing simply by talking, or reminiscing, about past pain. This narrative review summarizes existing research on parent-child reminiscing in the context of acute and chronic pediatric pain and argues for incorporation of parent-child reminiscing elements into preparatory interventions for painful procedures.
Learn More >To develop non-opioid therapies for postoperative incisional pain, we must understand its underlying molecular mechanisms. In this study, we assessed global gene expression changes in dorsal root ganglia neurons in a model of incisional pain to identify pertinent molecular pathways. Male, Sprague-Dawley rats underwent infiltration of 1% capsaicin or vehicle into the plantar hind paw (n = 6-9/group) 30 min before plantar incision. Twenty-four hours after incision or sham (control) surgery, lumbar L4-L6 dorsal root ganglias were collected from rats pretreated with vehicle or capsaicin. RNA was isolated and sequenced by next generation sequencing. The genes were then annotated to functional networks using a knowledge-based database, Ingenuity Pathway Analysis. In rats pretreated with vehicle, plantar incision caused robust hyperalgesia, up-regulated 36 genes and downregulated 90 genes in dorsal root ganglias one day after plantar incision. Capsaicin pretreatment attenuated pain behaviors, caused localized denervation of the dermis and epidermis, and prevented the incision-induced changes in 99 of 126 genes. The pathway analyses showed altered gene networks related to increased pro-inflammatory and decreased anti-inflammatory responses in dorsal root ganglias. Insulin-like growth factor signaling was identified as one of the major gene networks involved in the development of incisional pain. Expression of insulin-like growth factor -2 and IGFBP6 in dorsal root ganglia were independently validated with quantitative real-time polymerase chain reaction. We discovered a distinct subset of dorsal root ganglia genes and three key signaling pathways that are altered 24 h after plantar incision but are unchanged when incision was made after capsaicin infiltration in the skin. Further exploration of molecular mechanisms of incisional pain may yield novel therapeutic targets.
Learn More >Dorsal root ganglion (DRG) neurons detect sensory inputs and are crucial for pain processing. They are often studied in vitro as dissociated cell cultures with the assumption that this reasonably represents in vivo conditions. However, to the best of our knowledge, no study has directly compared genome-wide transcriptomes of DRG tissue in vivo versus in vitro or between laboratories and culturing protocols. Comparing RNA sequencing-based transcriptomes of native to cultured (4 days in vitro) human or mouse DRG, we found that the overall expression levels of many ion channels and G-protein-coupled receptors specifically expressed in neurons are markedly lower although still expressed in culture. This suggests that most pharmacological targets expressed in vivo are present under the condition of dissociated cell culture, but with changes in expression levels. The reduced relative expression for neuronal genes in human DRG cultures is likely accounted for by increased expression of genes in fibroblast-like and other proliferating cells, consistent with their mitotic status in these cultures. We found that the expression of a subset of genes typically expressed in neurons increased in human and mouse DRG cultures relative to the intact ganglion, including genes associated with nerve injury or inflammation in preclinical models such as BDNF, MMP9, GAL, and ATF3. We also found a striking upregulation of a number of inflammation-associated genes in DRG cultures, although many were different between mouse and human. Our findings suggest an injury-like phenotype in DRG cultures that has important implications for the use of this model system for pain drug discovery.
Learn More >The growing demand for improved pain treatments together with expanding legalization of, and access to, cannabinoids, cannabis, and cannabis-based medicines has intensified the focus on risk-benefit considerations in pain management. Given limited harms data from analgesic clinical trials, we conducted an overview of systematic reviews focused on all harms possibly relevant to patients receiving cannabinoids for pain management. This PROSPERO-registered, PRISMA-compliant systematic overview identified 79 reviews, encompassing over 2200 individual reports about psychiatric and psychosocial harms, cognitive/behavioral effects, motor vehicle accidents, cardiovascular, respiratory, cancer-related, maternal/fetal, and general harms. Reviews, and their included studies, were of variable quality. Available evidence suggests variable associations between cannabis exposure (ranging from monthly to daily use based largely on self-report) and psychosis, motor vehicle accidents, respiratory problems, and other harms. Most evidence comes from settings other than that of pain management (eg, nonmedicinal and experimental) but does signal a need for caution and more robust harms evaluation in future studies. Given partial overlap between patients receiving cannabinoids for pain management and individuals using cannabinoids for other reasons, lessons from the crisis of oversupply and overuse of opioids in some parts of the world emphasize the need to broadly consider harms evidence from real-world settings. The advancement of research on cannabinoid harms will serve to guide optimal approaches to the use of cannabinoids for pain management. In the meantime, this evidence should be carefully examined when making risk-benefit considerations about the use of cannabinoids, cannabis, and cannabis-based medicine for chronic pain.
Learn More >Osteoarthritis is characterized by the loss of the articular cartilage, bone remodeling, pain, and disability. No pharmacological intervention can currently halt progression of osteoarthritis. Here, we show that blocking receptor tyrosine kinase-like orphan receptor 2 (ROR2) improves cartilage integrity and pain in osteoarthritis models by inhibiting yes-associated protein (YAP) signaling. ROR2 was up-regulated in the cartilage in response to inflammatory cytokines and mechanical stress. The main ligand for ROR2, WNT5A, and the targets YAP and connective tissue growth factor were up-regulated in osteoarthritis in humans. In vitro, ROR2 overexpression inhibited chondrocytic differentiation. Conversely, ROR2 blockade triggered chondrogenic differentiation of C3H10T/ cells and suppressed the expression of the cartilage-degrading enzymes a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4 and ADAMTS-5. The chondrogenic effect of ROR2 blockade in the cartilage was independent of WNT signaling and was mediated by down-regulation of YAP signaling. ROR2 signaling induced G protein and Rho-dependent nuclear accumulation of YAP, and YAP inhibition was required but not sufficient for ROR2 blockade-induced chondrogenesis. ROR2 silencing protected mice from instability-induced osteoarthritis with improved structural outcomes, sustained pain relief, and without apparent side effects or organ toxicity. Last, ROR2 silencing in human articular chondrocytes transplanted in nude mice led to the formation of cartilage organoids with more and better differentiated extracellular matrix, suggesting that the anabolic effect of ROR2 blockade is conserved in humans. Thus, ROR2 blockade is efficacious and well tolerated in preclinical animal models of osteoarthritis.
Learn More >Recruitment into trials in rare chronic pain conditions can be challenging, so such trials consequently are underpowered or fail.
Learn More >Approximately 50% of individuals with fibromyalgia (a chronic widespread pain condition) have comorbid insomnia. Treatment for these comorbid cases typically target pain, but growing research supports direct interventions for insomnia (eg, cognitive behavioural treatment for insomnia (CBT-I)) in these patients. Previous research suggests sustained hyperarousal mediated by a neural central sensitisation mechanism may underlie insomnia and chronic pain symptoms in fibromyalgia. We hypothesise CBT-I will improve insomnia symptoms, improve clinical pain and reduce central sensitisation. The trial will be the first to evaluate the short-term and long-term neural mechanisms underlying insomnia and pain improvements in fibromyalgia. Knowledge obtained from this trial might allow us to develop new or modify current treatments to better target pain mechanisms, perhaps reversing chronic pain or preventing it.
Learn More >To assess the long-term safety, tolerability, and efficacy of fremanezumab, a fully humanized monoclonal antibody approved for the preventive treatment of migraine.
Learn More >Exercise-induced hypoalgesia (EIH) describes acute reductions in pain that occur following exercise. Current evidence suggests that the magnitude of EIH is small-to-moderate at best, warranting exploration of novel avenues to bolster these effects. Transcranial direct current stimulation (tDCS) has been shown to relieve pain and represents a promising intervention that may enhance EIH. This study aimed to determine whether anodal tDCS of the primary motor cortex (M1) can augment EIH in healthy individuals experiencing experimentally-induced musculoskeletal pain. Twenty-four healthy subjects attended two experimental sessions ('Day 0' and 'Day 2'). On Day 0, subjects were injected with nerve growth factor (NGF) into their right extensor carpi radialis brevis to induce persistent elbow pain. On Day 2, each subject received active or sham tDCS over M1 followed by an isometric grip exercise. Pain intensity, muscle soreness, sensitivity (pressure pain thresholds) and conditioned pain modulation were assessed prior to the NGF injection, on Day 2 before tDCS, immediately post-exercise, and 15 minutes post-exercise. Active tDCS expedited the onset of EIH, inducing immediate reductions in pain intensity that were not present until 15 minutes post-exercise in the sham group. However, active tDCS did not reduce muscle soreness or sensitivity when compared to sham tDCS. Perspective: These findings suggest that active tDCS accelerates the onset of EIH in healthy individuals experiencing experimentally-induced pain. This may represent a promising means of enhancing adherence to exercise protocols. However, larger randomised controlled trials in persistent pain populations are required to confirm the clinical impact of these findings.
Learn More >Loss-adjusting: Young People’s Constructions of a Future Living with Complex Regional Pain Syndrome.
Complex Regional Pain Syndrome (CRPS) is a chronic pain condition that can present specific difficulties when occurring in adolescence. There is limited work exploring future narratives of healthy adolescents, and how these may differ for those who have chronic health conditions, but there is no research on the future narratives of adolescents who have CRPS.
Learn More >In this review, we will explore the use of biomarkers in chronic pain, using the examples of two prototypical facial pain conditions: trigeminal neuralgia and temporomandibular disorder. We will discuss the main categories of biomarkers and identify various genetic/genomic, molecular, neuroradiological, and psychophysical biomarkers in both facial pain conditions, using them to compare and contrast features of neuropathic, non-neuropathic, and mixed pain. By using two distinct model facial pain conditions to explore pain biomarkers, we aim to familiarize readers with different types of biomarkers currently being studied in chronic pain, and explore how these biomarkers may be used to develop new precision medicine approaches to pain diagnosis, prognosis, and management.
Learn More >Alterations beyond joint inflammation such as changes in dorsal horn (DH) excitability contribute to pain in inflammatory arthritis (IA). More complete understanding of specific underlying mechanisms will be important to define novel targets for the treatment of IA pain. Pre-clinical models are useful, but relevant pain assays are vital for successful clinical translation. For this purpose, a method is presented to assess movement-induced pain-related behaviour changes that was subsequently used to investigate DH disinhibition in IA.
Learn More >Diabetic polyneuropathy (DPN) is a common complication of diabetes. Using the Toronto criteria for diabetic polyneuropathy and the grading system for neuropathic pain, the performance of neuropathy scales and questionnaires were assessed by comparing them to a clinical gold standard diagnosis of DPN and painful DPN in a cohort of patients with recently diagnosed type 2 diabetes.
Learn More >There is an unmet need for psychometrically sound instruments to measure pruritus associated with prurigo nodularis (PN).
Learn More >Central sensitization is present in different pain conditions, including chronic whiplash-associated disorders. In the absence of a gold standard method of assessment to determine the presence of central sensitization, quantitative sensory testing is currently understood as an optimal proxy. Laboratory sensory testing is, however, not feasible in clinical practice, and the Central Sensitization Inventory was developed as an alternative. The aim of the current study was to evaluate the convergent validity of the Central Sensitization Inventory in chronic whiplash-associated patients by determining the association between the Central Sensitization Inventory and quantitative sensory testing, pain intensity, fatigue, and psychosocial factors.
Learn More >To describe patterns of perceived stress across stages of the migraine cycle, within and between individuals and migraine episodes as defined for this study.
Learn More >Multisite chronic pain (MSCP) is associated with increased chronic pain impact, but methods for identifying MSCP for epidemiological research have not been evaluated.
Learn More >Temporomandibular disorders (TMD) and migraine can be co-morbid. This can be a significant factor in exacerbating and increasing the prevalence of migraine-like symptoms. However, the underlying putative mechanisms involved are not known. Our objective was to dissect these neural mechanisms, and the role of calcitonin gene-related peptide (CGRP) as a key modulator, in this co-morbidity.
Learn More >Psoriasis (PS) is a chronic inflammatory skin disease accompanied by reduced quality of life. Mindfulness is the ability to focus on the present moment without evaluation. Findings on the effects of 8-week mindfulness trainings in patients with PS reveal positive effects on the severity of the disease and quality of life. However, it remained unclear what distinguishes patients with PS interested in psychological interventions from those without interest and whether also a shorter, namely 2-week mindfulness-based intervention is beneficial in this patient group. This will be investigated with this study.
Learn More >Resting-state functional magnetic resonance imaging (Rs-fMRI) has confirmed sensorimotor network (SMN) dysfunction in migraine without aura (MwoA). However, the underlying mechanisms of SMN effective functional connectivity in MwoA remain unclear. We aimed to explore the association between clinical characteristics and effective functional connectivity in SMN, in interictal patients who have MwoA.
Learn More >Despite the clinical effectiveness of Spinal Cord Stimulation (SCS), potential structural brain modifications have not been explored. Our aim was to identify structural volumetric changes during subsensory SCS, in patients with Failed Back Surgery Syndrome (FBSS).
Learn More >Interstitial cystitis/bladder pain syndrome (IC) is a debilitating condition of chronic pelvic pain with unknown etiology. Recently, we used a genetic approach in a murine model of IC to identify the lipase acyloxyacyl hydrolase (AOAH) as a modulator of pelvic pain. We found that AOAH-deficient mice have elevated pelvic pain responses, and AOAH immunoreactivity was detected along the bladder-brain axis. Lipidomic analyses identified arachidonic acid (AA) and its metabolite PGE2 as significantly elevated in the sacral spinal cord of AOAH-deficient mice, suggesting AA is a substrate for AOAH. Here, we quantified the effects of AOAH on phospholipids containing AA. Spinal cord lipidomics revealed increased AA-containing phosphatidylcholine in AOAH-deficient mice and concomitantly decreased AA-phosphatidylethanolamine, consistent with decreased CoA-independent transferase activity (CoIT). Overexpression of AOAH in cell cultures similarly altered distribution of AA in phospholipid pools, promoted AA incorporation, and resulted in decreased membrane fluidity. Finally, administration of a PGE2 receptor antagonist reduced pelvic pain in AOAH-deficient mice. Together, these findings suggest that AOAH represents a potential CoA-independent AA transferase that modulates CNS pain pathways at the level of phospholipid metabolism.
Learn More >Long-term opioid use has negative health care consequences. Opioid-naïve adults are at risk for prolonged and persistent opioid use after surgery. While these outcomes have been examined in some adolescent and teenage populations, little is known about the risk of prolonged and persistent postoperative opioid use after common surgeries compared to children who do not undergo surgery and factors associated with these issues among pediatric surgical patients of all ages.
Learn More >Morphine promotes neuroinflammation after NOD-like receptor protein 3 (NLRP3) oligomerization in glial cells, but the capacity of other opioids to induce neuroinflammation and its relationship to the development of analgesic tolerance is unknown. We studied the effects of morphine and fentanyl on NLRP3 inflammasome activation in glial and neuronal cells in the dorsal raphe nucleus (DRN), a region involved in pain regulation. Male Wistar rats received i.p. injections of morphine (10 mg/kg) or fentanyl (0.1 mg/kg) 3 × daily for 7 days and were tested for nociception. Two hours after the last (19th) administration, we analyzed NLRP3 oligomerization, caspase-1 activation and gasdermin D-N (GSDMD-N) expression in microglia (CD11b positive cells), astrocytes (GFAP-positive cells) and neurons (NeuN-positive cells). Tolerance developed to both opioids, but only fentanyl produced hyperalgesia. Morphine and fentanyl activated NLRP3 inflammasome in astrocytes and serotonergic (TPH-2-positive) neurons, but fentanyl effects were more pronounced. Both opioids increased GFAP and CD11b immunoreactivity, caspase-1 and GSDMD activation, indicating pyroptotic cell death. The opioid receptor antagonist (-)-naloxone, but not the TLR4 receptor antagonist (+)-naloxone, prevented microglia activation and NLRP3 oligomerization. Only (+)-naloxone prevented astrocytes' activation. The anti-inflammatory agent minocycline and the NLRP3 inhibitor MCC950 delayed tolerance to morphine and fentanyl antinociception and prevented fentanyl-induced hyperalgesia. MCC950 also prevented opioid-induced NLRP3 oligomerization. In conclusion, morphine and fentanyl differentially induce cell-specific activation of NLRP3 inflammasome and pyroptosis in the DRN through TLR4 receptors in astrocytes and through opioid receptors in neurons, indicating that neuroinflammation is involved in opioid-induced analgesia and fentanyl-induced hyperalgesia after repeated administrations.
Learn More >Persistent postsurgical pain (PPSP) is a common complication of surgery that significantly affects quality of life. A better understanding of which patients are likely to develop PPSP would help to identify when perioperative and postoperative pain management may require specific attention. Quantitative sensory testing (QST) of a patient's preoperative pain perception is associated with acute postoperative pain, and acute postoperative pain is a risk factor for PPSP. The direct association between preoperative QST and PPSP has not been reviewed to date. In this systematic review, we assessed the relationship of preoperative QST to PPSP. We searched databases with components related to (1) preoperative QST; (2) association testing; and (3) PPSP. Two authors reviewed all titles and abstracts for inclusion. Inclusion criteria were as follows: (1) QST performed before surgery; (2) PPSP assessed ≥3 months postoperatively; and (3) the association between QST measures and PPSP is investigated. The search retrieved 905 articles; 24 studies with 2732 subjects met inclusion criteria. Most studies (22/24) had moderate to high risk of bias in multiple quality domains. Fourteen (58%) studies reported a significant association between preoperative QST and PPSP. Preoperative temporal summation of pain (4 studies), conditioned pain modulation (3 studies), and pressure pain threshold (3 studies) showed the most frequent association with PPSP. The strength of the association between preoperative QST and PPSP varied from weak to strong. Preoperative QST is variably associated with PPSP. Measurements related to central processing of pain may be most consistently associated with PPSP.
Learn More >Erenumab, a calcitonin gene-related peptide (CGRP) receptor monoclonal antibody, has been well tolerated with good efficacy for the preventive treatment of episodic and chronic migraine in phase 2 and phase 3 clinical trials. Limited post-market observations are available to validate these findings in a real-world tertiary headache clinic population with complex comorbidities and refractory migraine.
Learn More >The protein high-mobility group box 1 (HMGB1) is released into the extracellular space in response to many inflammatory stimuli, where it is a potent signaling molecule. Although research has focused on downstream HMGB1 signaling, the means by which HMGB1 exits the cell is controversial. Here we demonstrate that HMGB1 is not released from bone marrow-derived macrophages (BMDM) after lipopolysaccharide (LPS) treatment. We also explore whether HMGB1 is released via the pore-forming protein gasdermin D after inflammasome activation, as is the case for IL-1β. HMGB1 is only released under conditions that cause cell lysis (pyroptosis). When pyroptosis is prevented, HMGB1 is not released, despite inflammasome activation and IL-1β secretion. During endotoxemia, gasdermin D knockout mice secrete HMGB1 normally, yet secretion of IL-1β is completely blocked. Together, these data demonstrate that in vitro HMGB1 release after inflammasome activation occurs after cellular rupture, which is probably inflammasome-independent in vivo.
Learn More >The G protein-gated inwardly rectifying K+ (GIRK) channels play important signaling roles in the central and peripheral nervous systems. However, the role of GIRK channel activation in pain signaling remains unknown mainly due to the lack of potent and selective GIRK channel activators until recently. The present study was designed to determine the effects and mechanisms of ML297, a selective GIRK1/2 activator, on nociception in the spinal cord by using behavioral studies and whole-cell patch-clamp recordings from substantia gelatinosa (SG) neurons. Rats were prepared for chronic lumber catheterization and intrathecal administration of ML297. The nociceptive flexion reflex was tested using an analgesy-meter, and the influence on motor performance was assessed using an accelerating rotarod. We also investigated pre- and post-synaptic actions of ML297 in spinal cord preparations by whole-cell patch-clamp recordings. Intrathecal administration of ML297 increased the mechanical nociceptive threshold without impairing motor function. In voltage-clamp mode of patch-clamp recordings, bath application of ML297 induced outward currents in a dose-dependent manner. The ML297-induced currents demonstrated specific equilibrium potential like other families of potassium channels. At high concentration, ML297 depressed miniature excitatory postsynaptic currents (mEPSCs) but not their amplitude. The ML297-induced outward currents and suppression of mEPSCs were not inhibited by naloxone, a μ-opioid receptor antagonist. These results demonstrated that intrathecal ML297 showed the antinociceptive effect, which was mediated through direct activation of pre- and post-synaptic GIRK channels. Selective GIRK channel activation is a promising strategy for the development of new agents against chronic pain and opioid tolerance.
Learn More >The opioid and pain crises affect every domain of family and community life with two million Americans living with opioid addiction, and 46,802 people dying from opioid overdoses in 2018 alone (National Center for Health Statistics, 2019). In addition, over 50 million Americans experience chronic pain, and half of those people suffer from chronic pain daily. Opioids are widely used to treat acute and chronic pain, and the lack of widespread access to nonpharmacological strategies to manage pain has contributed to the misuse of opioids. In fiscal year 2018, Congress added $500 million to the NIH's base appropriation to generate scientific solutions to the opioid and pain crises in America. The result was the Helping to End Addiction Long-Term Initiative, or NIH HEAL Initiative, a bold transagency effort. The authors of this editorial-psychologists in leadership roles in three NIH institutes- highlight several investments of the NIH HEAL Initiative, note the role of psychologists involved in HEAL, and describe the unprecedented steps the NIH is taking to harmonize data and rapidly and widely disseminate HEAL findings. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
Learn More >The current opioid crisis was fueled by escalation of opioid dosing among patients with chronic pain. Yet, there are few evidence-based psychological interventions for opioid dose reduction among chronic pain patients treated with long-term opioid analgesics. Mindfulness-Oriented Recovery Enhancement (MORE), which was designed to target mechanisms underpinning chronic pain and opioid misuse, has shown promising results in 2 randomized clinical trials (RCTs) and could facilitate opioid sparing and tapering by bolstering self-regulation. Here we tested this hypothesis with secondary analyses of data from a Stage 2 RCT. Chronic pain patients (N = 95) on long-term opioid therapy were randomized to 8 weeks of MORE or a support group (SG) control delivered in primary care. Opioid dose was assessed with the Timeline Followback through 3-month follow-up. Heart rate variability (HRV) during mindfulness meditation was quantified as an indicator of self-regulatory capacity. Participants in MORE evidenced a greater decrease in opioid dosing (a 32% decrease) by follow-up than did the SG, F(2, 129.77) = 5.35, p = .006, d = 1.07. MORE was associated with a significantly greater increase in HRV during meditation than was the SG. Meditation-induced change in HRV partially mediated the effect of MORE on opioid dose reduction (p = .034). MORE may boost self-regulatory strength via mindfulness and thereby facilitate self-control over opioid use, leading to opioid dose reduction in people with chronic pain. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
Learn More >Chronic pain is a common and costly condition, and some people with chronic pain engage in problematic opioid use. There is a critical need to identify factors underlying this co-occurrence, so that treatment can be targeted to improve outcomes. We propose that difficulty with emotion regulation (ER) is a transdiagnostic factor that underlies the co-occurrence of chronic pain and problematic opioid use (CP-POU). In this narrative review, we draw from prominent models of ER to summarize the literature characterizing ER in chronic pain and CP-POU. We conclude that chronic pain is associated with various ER difficulties, including emotion identification and the up- and down-regulation of both positive and negative emotion. Little research has examined ER specifically in CP-POU; however, initial evidence suggests CP-POU is characterized by difficulties with ER that are similar to those found in chronic pain more generally. There is great potential to expand the treatment of ER to improve pain-related outcomes in chronic pain and CP-POU. More research is needed, however, to elucidate ER in CP-POU and to determine which types of ER strategies are optimal for different clinical presentations and categories of problematic opioid use. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
Learn More >Pain rehabilitation’s dual power: Treatment for chronic pain and prevention of opioid-related risks.
The purpose of this article is to provide a data-driven exploration of an interdisciplinary pain rehabilitation program (PRP) as a viable option for addressing the dual crises of chronic pain and opioid use. Psychologists are crucial providers in the PRP, in both intervention and leadership roles. There is well-established literature supporting pain rehabilitation as an effective treatment for chronic pain and functioning, but there are few studies examining the effects of pain rehabilitation on opioid misuse risk. We evaluated data from 60 patients with diverse chronic pain conditions who completed an interdisciplinary PRP to evaluate changes in pain, functioning (self-report and objective physical measure), psychological symptoms, and health-related quality of life. To evaluate the effect of pain rehabilitation on opioid-related risks, we examined opioid use and opioid misuse behaviors (measured by the Current Opioid Misuse Measure; COMM) pre- and posttreatment. Results demonstrated statistically significant improvements in all outcomes, with medium effect sizes for pain severity and large effect sizes for functioning, psychological symptoms, and emotional quality of life. Fifty-eight percent of patients were on opioid medications at entry compared with 15% at discharge. Among patients who entered on opioids, mean COMM scores were significantly reduced from above the cutoff for misuse risk (M = 13.57) to below the cutoff (M = 5.86). Overall, this study provided strong support for pain rehabilitation as an effective treatment for chronic pain and related suffering, while also providing a prevention-based opportunity for reducing opioid-related risk. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
Learn More >To preliminarily examine the psychometric properties (i.e., internal consistency reliability, construct validity) and clinical utility of the Patient-Reported Outcomes Measurement Information System (PROMIS) psychological stress experiences scale in a sample of youth with chronic pain.
Learn More >Chronic pain and opioid misuse occur in pediatric populations and can be associated with a range of negative adverse outcomes that may persist into adulthood. While the association between chronic pain, opioid prescribing, and opioid-related adverse consequences is reasonably well established in adults, the relation in pediatric patients is not well understood and the long-term impact of opioid exposure during childhood is yet to be fully revealed. The present review draws from the available literature on chronic and acute pediatric pain prevalence and treatment, opioid misuse, and adolescent substance use to address knowns and unknowns of comorbid pediatric chronic pain and opioid misuse. Additionally, gaps in knowledge regarding the prevalence and etiology of co-occurring chronic pain and opioid misuse in youth are identified. Hypothesized, modifiable risk factors associated with both pediatric pain and opioid misuse are considered. Due to a lack of empirically supported integrated treatments for comorbid chronic pain and opioid misuse in youth, this review examines the evidence base and best practices from both the chronic pain and opioid treatment literature to guide treatment recommendations for these comorbid conditions in youth. Recommendations are then provided to promote screening and mitigate risk of chronic pain and opioid misuse across a range of pediatric settings. Lastly, a comprehensive agenda to prevent and treat chronic pain and opioid misuse in adolescents and young adults is discussed. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
Learn More >Recent advances in our understanding of the pathophysiology of atopic dermatitis (AD) have revealed that skin microbiome dysbiosis plays an important role in the disease. In this review, we describe how changes in the structure and function of the microbiome are involved in the pathogenesis of AD. We highlight recent data showing that differential changes in microbial diversity, both within and across communities from different body habitats (including the skin, gut, and oral mucosa), are associated with the development and severity of AD. We also describe recent evidence demonstrating that the metabolic activity of the skin microbiome can act as a regulator of inflammation, with alterations in the level of a skin microbiome-derived tryptophan metabolite, indole-3-aldehyde (IAId), being shown to play a role in AD. The various mechanisms by which interactions between the microbiome and components of the non-histaminergic pathway result in itch in AD are also discussed.
Learn More >There is a pressing need to better understand the factors contributing to prescription opioid misuse among patients with chronic pain. Cross-sectional studies have been conducted in this area, but longitudinal studies examining the determinants of prescription opioid misuse repeatedly over the course of opioid therapy have yet to be conducted. The main objective of this study was to examine the relative contribution of pain and psychological factors to the occurrence of opioid misuse among patients with chronic pain prescribed opioids. Of particular interest was to examine whether pain intensity and psychological factors were more strongly associated with certain types of opioid misuse behaviors. Patients with chronic pain (n = 194) prescribed long-term opioid therapy enrolled in this longitudinal observational cohort study. Patients completed baseline measures and were then followed for 6 months. Opioid misuse was assessed once a month using self-report measures, and urine toxicology screens complemented patients' reports of opioid misuse. Heightened pain intensity levels were associated with a greater likelihood of opioid misuse (p = .014). However, pain intensity was no longer significantly associated with opioid misuse when controlling for psychological factors (i.e., negative affect, catastrophizing). Subsequent analyses revealed that higher levels of catastrophizing were associated with a greater likelihood of running out of opioid medication early, even after controlling for patients' levels of pain intensity and negative affect (p = .016). Our findings provide new insights into the determinants of prescription opioid misuse and have implications for the nature of interventions that may be used to reduce specific types of opioid misuse behaviors. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
Learn More >Endometriosis is a chronic inflammatory disease defined as the presence of endometrial tissue outside the uterus that causes pelvic pain and infertility. We used the Global Burden of Disease Study (GBD) 2017 to comprehensively analyze the burden of endometriosis between 1990 and 2017. DisMod-MR 2.1 was used to estimate the incidence and prevalence in some countries/territories with sparse or absent data. Annual percent changes were calculated to quantify endometriosis burden estimate trends. Furthermore, the sociodemographic index (SDI) was used to assess the relationship between endometriosis burden estimates and development level. Between 1990 and 2017, endometriosis age-standardized incidence and prevalence and years of life lived with disability (YLDs) decreased globally by 0.21% (95% confidence interval (CI): -0.23% to -0.20%), 0.29% (95% CI: -0.31% to -0.28%), and 0.28% (95% CI: -0.30% to -0.27%) per year, respectively. Apart from the high SDI quintiles with increasing trends of endometriosis incidence rate, prevalence rate, and YLDs, decreasing trends were observed in all SDI quintiles for all burden estimates. In conclusion, it appears that all endometriosis burden estimates have decreased globally between 1990 and 2017. However, these results are based on limited data and highlight the need for increased data collection on the incidence and prevalence of endometriosis.
Learn More >In 2015, the United States of America (USA) Department of Health and Human Services (HHS) released an issue brief that addressed opioid addiction, opioid overdoses, and opioid-related deaths as a public health concern within the country. After collaboration with state and stakeholder organizations, the HHS identified three target initiatives aimed to mitigate the negative consequences of opioid use within the USA. One initiative included implementation of guidelines to help reduce inappropriate opioid prescribing with a goal to reduce morbidity and mortality. The aim of this commentary is to discuss the misapplication and unintended consequences of the USA CDC Guideline for Prescribing Opioids for Chronic Pain.
Learn More >Fibromyalgia is commonly considered a stress-related chronic pain disorder, and daily stressors are known triggers. However, the relation between stress and pain development remains poorly defined by clinical approaches. Also, the aetiology remains largely unknown.
Learn More >Peer support has found applications beyond the mental health field and is useful for managing several chronic disorders and supporting healthy lifestyle choices. Communication through telephone and the Internet allows for greater access to those who cannot meet in person. Adolescent chronic pain would seem ideally suited to benefit from online peer support groups. Research is lacking, however, to characterize benefit in terms of pain and function, despite a clear desire among adolescents for access to such programs. More rapid development of online applications is needed for peer support, and research into the associated outcomes will be necessary to optimally design such programs.
Learn More >Chronic pruritus has considerable implications for quality of life (QoL). However, its impact on health-related QoL and economic burden is not fully characterized. We administered a cross-sectional survey of 132 patients with chronic pruritus using the Health Utilities Index Mark 3 (HUI3) instrument. Normative data from healthy adults (n=4,187) were obtained from the Joint Canada/U.S. Survey of Health. Quality-adjusted life-year (QALY) loss and economic costs were estimated based on HUI3 scores of chronic pruritus patients vs. controls. Patients with chronic pruritus had lower overall health performance compared to the control (0.56±0.03 vs. 0.86±0.003, p<0.001). In multivariable regression, chronic pruritus was associated with worse overall health performance (coefficient -0.30, 95% CI [-0.33 to -0.27]), most accentuated in the domains of pain (coefficient -0.24, [-0.28 to -0.21]) and emotion (coefficient -0.11, [-0.13 to -0.10]). The reduced HUI3 score correlated to 5.5 average lifetime QALYs lost per patient. Using conservative estimates for willingness-to-pay, the QALY loss translated to an individual lifetime economic burden of $274,921 and a societal burden of $88.8 billion. Chronic pruritus is associated with significant QoL impairment. The economic burden of chronic pruritus highlights the necessity of further research into management options.
Learn More >Paclitaxel is a representative anticancer drug that induces chemotherapy-induced peripheral neuropathy (CIPN), a common side effect that limits many anticancer chemotherapies. Although PINK1, a key mediator of mitochondrial quality control, has been shown to protect neuronal cells from various toxic treatments, the role of PINK1 in CIPN has not been investigated. Here, we examined the effect of PINK1 expression on CIPN using a recently established paclitaxel-induced peripheral neuropathy model in Drosophila larvae. We found that the class IV dendritic arborization (C4da) sensory neuron-specific expression of PINK1 significantly ameliorated the paclitaxel-induced thermal hyperalgesia phenotype. In contrast, knockdown of PINK1 resulted in an increase in thermal hypersensitivity, suggesting a critical role for PINK1 in sensory neuron-mediated thermal nociceptive sensitivity. Interestingly, analysis of the C4da neuron morphology suggests that PINK1 expression alleviates paclitaxel-induced thermal hypersensitivity by means other than preventing alterations in sensory dendrites in C4da neurons. We found that paclitaxel induces mitochondrial dysfunction in C4da neurons and that PINK1 expression suppressed the paclitaxel-induced increase in mitophagy in C4da neurons. These results suggest that PINK1 mitigates paclitaxel-induced sensory dendrite alterations and restores mitochondrial homeostasis in C4da neurons and that improvement in mitochondrial quality control could be a promising strategy for the treatment of CIPN.
Learn More >To describe how chronic low back pain (CLBP) impacts on utility scores and which patients' characteristics most affect these scores in the province of Quebec.
Learn More >The purpose of this narrative review is to discuss the interrelations between pain, stress and executive functions.
Learn More >Acute pain can transition to chronic pain, a potentially debilitating illness.
Learn More >To evaluate secondary outcomes including changes in functioning and disability associated with galcanezumab, a humanized monoclonal antibody to calcitonin gene-related peptide, in patients with chronic migraine.
Learn More >Little is known about how primary care clinicians (PCCs) approach chronic pain management in the current climate of rapidly changing guidelines and the growing body of research about risks and benefits of opioid therapy.
Learn More >Spinal cord stimulation (SCS) is an important treatment modality used to treat chronic neuropathic pain. However, reported success rates of 26%-70% entail an increased focus on patient selection. An area of core interest is psychological evaluation, often using scales such as the Pain Catastrophizing Scale (PCS). The aim of this study was to assess the relation between baseline PCS scores obtained before implantation and SCS outcomes defined as (1) Rating on Patients' Global Impression of Change scale (PGIC), (2) Pain relief on the Numeric Rating Scale (NRS), (3) Cessation of pain medication, and (4) Risk of permanent explantation.
Learn More >Chronic migraine (CM) can be associated with aberrant long-range connectivity of MRI-derived resting-state networks (RSNs). Here, we investigated how the fractal dimension (FD) of blood oxygenation level dependent (BOLD) activity may be used to estimate the complexity of RSNs, reflecting flexibility and/or efficiency in information processing in CM patients respect to healthy controls (HC).
Learn More >Cytochrome P450 2D (CYP2D) mediates the activation and inactivation of several classes of psychoactive drugs, including opioids, which can alter drug response. Tramadol is a synthetic opioid with analgesic activity of its own as well as being metabolically activated by CYP2D to O-desmethyltramadol (ODMST) an opioid receptor agonist. We investigated the impact of brain CYP2D metabolism on central tramadol and ODSMT levels, and resulting analgesic response after oral tramadol administration in rats. CYP2D inhibitors propranolol and propafenone were administered intracerebroventricularly prior to oral tramadol administration and analgesia was measured by tail-flick latency. Drug levels of tramadol and its metabolites, ODSMT and N-desmethyltramadol, were assessed in plasma and in brain by microdialysis using LC-ESI-MS/MS. Inhibiting brain CYP2D with propafenone pretreatment increased analgesia after oral tramadol administration (ANOVA p = 0.02), resulting in a 1.5-fold increase in area under the analgesia-time curve (AUC, p < 0.01). This effect was associated with changes in the brain levels of tramadol and its metabolites consistent with brain CYP2D inhibition. In conclusion, under oral tramadol dosing pretreatment with a central administration of the CYP2D inhibitor propafenone increased analgesia (without altering plasma drug or metabolite levels), indicating that tramadol itself (and activity of CYP2D within the brain) contributed to analgesia.
Learn More >Fibromyalgia (FM) is a common chronic pain disease, whose pathogenic mechanism still remains elusive. Oxidative stress markers and impaired bioenergetics homeostasis have been proposed as relevant events in the pathogenesis of the disease. Hence, the aim of the study is to analyse the potential biomarkers of mitochondrial imbalance in FM patients along with coenzyme Q10 (CoQ10) as a possible treatment.
Learn More >Chronic pelvic pain (CPP), often defined as non-cyclical pelvic pain lasting for 6 months or longer, affects approximately 2-24% of women, depending on the CPP definition used (Daniels et al. BMJ 2010;341:c4834). While CPP can be a symptom associated with a variety of health conditions (including endometriosis, irritable bowel syndrome, and interstitial cystitis), at least 30% of women undergoing laparoscopic surgery have no associated disease diagnosis or clear pathologic cause for their pain.
Learn More >The primary aim was to quantify and compare the location and extent of pain in people with either episodic migraine, chronic migraine, or cervicogenic headache. A secondary aim was to examine the associations between pain extent and headache features, quality of life, and psychological distress for each headache type.
Learn More >One in five patients undergoing total knee arthroplasty (TKA) experience unchanged or worse pain and physical function 1 year after surgery. Identifying risk factors for unfavourable outcomes is necessary to develop tailored interventions to minimise risk. There is a need to review more current literature with updated methodology that addresses the limitations of earlier systematic reviews and meta-analyses. We present a Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols compliant protocol for a systematic review and meta-analysis of predictors of chronic pain and impaired function after TKA.
Learn More >In response to the dual public health crises of chronic pain and opioid use, providers have become more vigilant about assessing patients for risk of opioid-related problems. Little is known about how providers are making these risk assessments. Given previous studies indicating that Black patients are at increased risk for suboptimal pain care, which may be related to stereotypes about drug abuse, the current study examined how patient race and previous opioid misuse behaviors impact providers' risk assessments for future prescription opioid-related problems. Physician residents and fellows (N = 135) viewed videos and read vignettes about 8 virtual patients with chronic pain who varied by race (Black/White) and history of prescription opioid misuse (absent/present). Providers rated patients' risk for future prescription opioid-related adverse events, misuse/abuse, addiction, and diversion, and also completed measures of implicit racial attitudes and explicit beliefs about race differences in pain. Two significant interactions emerged indicating that Black patients were perceived to be at greater risk for future adverse events (when previous misuse was absent) and diversion (when previous misuse was present). Significant main effects indicated that Black patients and patients with previous misuse were perceived to be at greater risk for future misuse/abuse of prescription opioids, and that patients with previous misuse were perceived to be at greater risk of addiction. These findings suggest that racial minorities and patients with a history of prescription opioid misuse are particularly vulnerable to any unintended consequences of efforts to stem the dual public health crises of chronic pain and opioid use. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
Learn More >Occipital nerve stimulation (ONS) is used to treat therapy-resistant chronic migraine. Clinical use has resulted in a wide intraindividual and interindividual variation of clinical efficacy. The aim of this study was to analyze a potential relationship between sociodemographic variables, headache parameters, perceived sensory quality, perceived sensory location, as well as clinical efficacy.
Learn More >The venom of jellyfish triggers severe dermal pain along with inflammation and tissue necrosis, and occasionally, induces internal organ dysfunction. However, the basic mechanisms underlying its cytotoxic effects are still unknown. Here, we report one of the mechanisms involved in peripheral pain modulation associated with inflammatory and neurotoxic oxidative signaling in rats using the venom of jellyfish, Chrysaora pacifica (CpV). This jellyfish is identified by brown tentacles carrying nematocysts filled with cytotoxic venom that induces severe pain, pruritus, tentacle marks, and blisters. The subcutaneous injection of CpV into rat forepaws in behavioral tests triggered nociceptive response with a decreased threshold for mechanical pain perception. These responses lasted up to 48 h and were completely blocked by verapamil and TTA-P2, T-type Ca channel blockers, or HC030031, a transient receptor potential cation ankyrin 1 (TRPA1) channel blocker, while another Ca channel blocker, nimodipine, was ineffective. Also, treatment with Ca chelators (EGTA and BaptaAM) significantly alleviated the CpV-induced pain response. These results indicate that CpV-induced pain modulation may require both Ca influx through the T-type Ca channels and activation of TRPA1 channels. Furthermore, CpV induced Ca-mediated oxidative neurotoxicity in the dorsal root ganglion (DRG) and cortical neurons dissociated from rats, resulting in decreased neuronal viability and increased intracellular levels of ROS. Taken together, CpV may activate Ca-mediated oxidative signaling to produce excessive ROS acting as an endogenous agonist of TRPA1 channels in the peripheral terminals of the primary afferent neurons, resulting in persistent inflammatory pain. These findings provide strong evidence supporting the therapeutic effectiveness of blocking oxidative signaling against pain and cytotoxicity induced by jellyfish venom.
Learn More >Post-thoracotomy pain syndrome (PTPS) is defined as persistent pain following a thoracotomy and has an incidence of 21-61%. Dorsal root ganglion stimulation (DRG-S) is a form of neuromodulation that modulates pain signal transmission to the spinal cord. The aims of this study were to investigate the efficacy of DRG-S for the management of PTPS and to assess the role of thoracic paravertebral blocks (t-PVB) as a tool for prediction of success of DRG-S.
Learn More >Two factors related to the continuation of persistent pain are pain catastrophizing and illness perceptions. Pain neuroscience education is known to positively influence both in patients with persistent pain. As the integration of pain neuroscience education in monodisciplinary physiotherapy treatments is effective, integration in transdisciplinary cognitive-behavioral treatments seems recommendable. When doing so, the moderating effect of pain catastrophizing and perceptions on treatment results have to be examined, as these provide valuable information under which conditions treatment works. A bottom-up retrospective observational study evaluated the changes in clinical outcomes, and relationships between clinical outcomes and cognitive and emotional factors in patients with persistent pain. Multiple regression analysis, PROCESS macro, explored the moderating effects of pain catastrophizing on the relationship between illness perceptions and self-reported symptoms of central sensitization. In total, 78 patients were included in the study. A correlation between pretreatment scores and change scores in illness perceptions and self-reported symptoms of central sensitization following treatment were found (resp. R-sq 0.407, F(10,99) = 0.638, P = 0.000; R-sq 0.361, F(5, 54) = 0.609, P = 0.000; and R-sq 0.314, F(4,55) = 0.560, P = 0.00), however, moderation of pain catastrophizing scores on these correlations was not found. Even though an association between changes in pain catastrophizing and illness perceptions in patients with persistent pain was found, the direction or strength between the changes in illness perceptions and changes in self-reported symptoms of central sensitization was not influenced by pretreatment scores of pain catastrophizing.
Learn More >Chronic visceral pain is one of the primary symptoms of patients with irritable bowel syndrome (IBS), which affects up to 15% of the population world-wide. The detailed mechanisms of visceral pain remain largely unclear. Our previous studies have shown that neonatal maternal deprivation (NMD) followed by adult multiple stress (AMS) advances the occurrence of visceral pain, likely due to enhanced norepinephrine (NE)-β adrenergic signaling. This study was designed to explore the roles of P2X3 receptors (P2X3Rs) in the chronic visceral pain induced by combined stress. Here, we showed that P2X3Rs were co-expressed in β adrenergic receptor (β-AR)-positive dorsal root ganglion neurons and that NE significantly enhanced ATP-induced Ca signals. NMD and AMS not only significantly increased the protein expression of P2X3Rs, but also greatly enhanced the ATP-evoked current density, number of action potentials, and intracellular Ca concentration of colon-related DRG neurons. Intrathecal injection of the P2X3R inhibitor A317491 greatly attenuated the visceral pain and the ATP-induced Ca signals in NMD and AMS rats. Furthermore, the β-AR antagonist butoxamine significantly reversed the expression of P2X3Rs, the ATP-induced current density, and the number of action potentials of DRG neurons. Overall, our data demonstrate that NMD followed by AMS leads to P2X3R activation, which is most likely mediated by upregulation of β adrenergic signaling in primary sensory neurons, thus contributing to visceral hypersensitivity.
Learn More >Bone cancer pain (BCP) remains a difficult clinical problem. This study examined whether pioglitazone, a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, is effective for attenuating BCP, and investigated the interaction between activation of PPARγ and phosphatase and tensin homolog deleted from chromosome 10 (PTEN) / mammalian target of rapamycin (mTOR) signal in the spinal dorsal horn (SDH) of BCP rats.
Learn More >We describe the pervasiveness of headache diseases across the globe and the need for healthcare advocacy, define healthcare advocacy, and identify how providers can incorporate healthcare advocacy into clinical practice and beyond.
Learn More >. Thermo transient receptor potential (thermoTRP) channels are some of the most intensely pursued therapeutic targets of the past decade. They are considered promising targets of numerous diseases including chronic pain and cancer. Modulators of these proteins, in particular TRPV1-4, TRPM8 and TRPA1, have reached clinical development, but none have been approved for clinical practice yet.
Learn More >High-frequency spinal cord stimulation (HFSCS) at 10 kHz provides paresthesia-free treatment for chronic pain. However, the underlying mechanisms of its action have not been fully elucidated. The aim of the present study was to investigate the effect of HFSCS treatment on spinal glutamate release and uptake in spared nerve injury (SNI) rats. HFSCS was applied to the T10/T11 spinal cord 3 days after SNI. The concentration of spinal glutamate, glutamate transporter activity and miniature excitatory postsynaptic currents (mEPSCs) from neurons in lamina II were evaluated. HFSCS treatment alleviated SNI pain induced by mechanical and cold allodynia. HFSCS treatment also partially restored altered spinal glutamate uptake activity, the levels of spinal glutamate, and the frequency of mEPSCs following SNI. In conclusion, HFSCS treatment attenuated SNI-induced neuropathic pain and partially restored the altered glutamate uptake after SNI.
Learn More >To build a national Headache Medicine fellowship opportunities website that promotes a unified application timeline and a more transparent application process.
Learn More >Opioid analgesics are effective pain therapeutics but they cause various adverse effects and addiction. For safer pain therapy, biased opioid agonists selectively target distinct μ opioid receptor (MOR) conformations, while the potential of biased opioid antagonists has been neglected. Agonists convert a dormant receptor form (MOR-μ) to a ligand-free active form (MOR-μ*), which mediates MOR signaling. Moreover, MOR-μ converts spontaneously to MOR-μ* (basal signaling). Persistent upregulation of MOR-μ* has been invoked as a hallmark of opioid dependence. Contrasting interactions with both MOR-μ and MOR-μ* can account for distinct pharmacological characteristics of inverse agonists (naltrexone), neutral antagonists (6β-naltrexol), and mixed opioid agonist-antagonists (buprenorphine). Upon binding to MOR-μ*, naltrexone but not 6β-naltrexol suppresses MOR-μ*signaling. Naltrexone blocks opioid analgesia non-competitively at MOR-μ*with high potency, whereas 6β-naltrexol must compete with agonists at MOR-μ, accounting for ~100-fold lower in vivo potency. Buprenorphine's bell-shaped dose-response curve may also result from opposing effects on MOR-μ and MOR-μ*. In contrast, we find that 6β-naltrexol potently prevents dependence, below doses affecting analgesia or causing withdrawal, possibly binding to MOR conformations relevant to opioid dependence. We propose that 6β-naltrexol is a biased opioid antagonist modulating opioid dependence at low doses, opening novel avenues for opioid pain therapy and use management.
Learn More >Chronic headache pain is one of the most commonly reported comorbid pain conditions with post-traumatic stress disorder (PTSD) patients and resistant to effective treatment, yet no combined preclinical model of the two disorders has been reported. Here, we used a modified chronic headache pain model to investigate the contribution of single prolonged stress (SPS) model of PTSD with sodium nitroprusside (SNP)-induced hyperalgesia. Injection of SNP (2 mg/kg, i.p.) occurred every other day from day 7 to day 15 after initiation of SPS in rats. Paw withdrawal threshold (PWT) to von Frey stimuli and tail flick latencies (TFL) dramatically decreased as early as 7 days after SPS and lasted until at least day 21. Basal PWT and TFL also significantly decreased during the SNP treatment period. The lower nociceptive thresholds recovered in 6 days following the final SNP injection in SNP group, but not in SPS + SNP group. Elevated nociceptin/OFQ (N/OFQ) levels observed in cerebrospinal fluid of SPS rats were even higher in SPS + SNP group. Glial fibrillary acidic protein (GFAP) and N/OFQ peptide (NOP) receptor mRNA expression increased in dorsal root ganglia (DRG) 21 days after SPS exposure; mRNA increases in the SPS/SNP group was more pronounced than SPS or SNP alone. GFAP protein expression was upregulated in trigeminal ganglia by SPS. Our results indicate that traumatic stress exaggerated chronic SNP-induced nociceptive hypersensitivity, and that N/OFQ and activated satellite glia cells may play an important role in the interaction between both conditions.
Learn More >Chronic pain can disrupt everyday life and shatter beliefs about the world. Shattered beliefs may be rebuilt, either positively or negatively, leading to posttraumatic growth (PTG) or posttraumatic depreciation (PTD). According to a transdiagnostic emotion regulation perspective, these phenomena are associated with coping strategies and emotions related to the body, self, others, and the world. Because PTG and PTD can coexist, this study aims to compare different profiles of rebuilt beliefs based on emotions, emotion regulation, and psychopathology.
Learn More >The present study was undertaken to further investigate the spinal anti-allodynic effects of endomorphins (EMs) and their C-terminal hydrazide modified analogs EM-1-NHNH and EM-2-NHNH in the spared nerve injury (SNI) model of neuropathic pain in mice. Our results demonstrated that intrathecal (i.t.) administration of endomorphin-1 (EM-1), endomorphin-2 (EM-2), EM-1-NHNH and EM-2-NHNH produced potent anti-allodynic effects ipsilaterally in neuropathic pain model. Judging from the area under the curve (AUC) values, these two analogs exhibited higher antinociception than their parent peptides. Moreover, they also displayed significant antinociceptive effects in the contralateral paw administered intrathecally. Interestingly, EM-1 and its analog EM-1-NHNH displayed their antinociception probably by μ-opioid receptor subtype since the μ-opioid receptor antagonist naloxonazine didn't significantly block the anti-allodynia of EM-1 and EM-1-NHNH, which implied a same opioid mechanism. However, the anti-allodynia induced by EM-2, but not EM-2-NHNH was significantly reduced by both μ-opioid antagonist, naloxonazine and κ-antagonist, nor-binaltorphamine (nor-BNI), indicating multiple opioid receptors were involved in the anti-allodynic effects of EM-2. Most importantly, EM-1-NHNH decreased the antinociceptive tolerance, and EM-2-NHNH displayed non-tolerance-forming antinociception. Therefore, C-terminal amide to hydrazide conversion changed the spinal antinociceptive profiles of EMs in neuropathic pain. The present investigation is of great value in the development of novel opioid therapeutics against neuropathic pain.
Learn More >The neuropeptide FF2 (NPFF) receptor, predominantly expressed in the central nervous system, plays an important role in the modulation of sensory input and opioid analgesia, as well as in locomotion, feeding, intestinal motility, reward, and the control of obesity. The NPFF receptor belongs to the RFamide peptide receptor family and to the G protein coupled receptor (GPCR) super family, but contrary to many other class A GPCRs, no 3D structure has been solved. Thus, it is essential to perform mutagenesis to gain information on the fine functioning of the NPFF receptor. In this study, we examined the role of aspartic acid (D) from the "D/ERY/F" motif found in the second intracellular loop (ICL2) and the role of the C-terminal end of the receptor in ligand binding and signal transduction. We found that mutation D3.49A does not impair binding capacities but inhibits G protein activation as well as adenylyl cyclase regulation. Truncation of the C terminal part of the receptor has different effects depending on the position of truncation. When truncation was realized downstream of the putative acylation site, ligand binding and signal transduction capabilities were not lost, contrary to total deletion of the C terminus, which totally impairs the activity of the receptor.
Learn More >Several single-nucleotide polymorphisms (SNPs) are associated with restless legs syndrome (RLS). This study investigated whether or not additional SNP variants increase the risk of RLS in migraineurs and in migraine with aura (MA) and migraine without aura (MoA) subgroups.
Learn More >Neuropathic pain (NP) is common in patients presenting with low back related leg pain. Accurate diagnosis of NP is fundamental to ensure appropriate intervention. In the absence of a clear gold standard, expert opinion provides a useful methodology to progress research and clinical practice. The aim of this study was to achieve expert consensus on a list of clinical indicators to identify NP in low back related leg pain.
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