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Monitoring trends in prescription analgesic use among adults with musculoskeletal conditions provides insight into how changing prescribing practices, guidelines, and policy measures may affect those who need pain management.
Learn More >Gut-innervating nociceptor sensory neurons respond to noxious stimuli by initiating protective responses including pain and inflammation; however, their role in enteric infections is unclear. Here, we find that nociceptor neurons critically mediate host defense against the bacterial pathogen Salmonella enterica serovar Typhimurium (STm). Dorsal root ganglia nociceptors protect against STm colonization, invasion, and dissemination from the gut. Nociceptors regulate the density of microfold (M) cells in ileum Peyer's patch (PP) follicle-associated epithelia (FAE) to limit entry points for STm invasion. Downstream of M cells, nociceptors maintain levels of segmentous filamentous bacteria (SFB), a gut microbe residing on ileum villi and PP FAE that mediates resistance to STm infection. TRPV1+ nociceptors directly respond to STm by releasing calcitonin gene-related peptide (CGRP), a neuropeptide that modulates M cells and SFB levels to protect against Salmonella infection. These findings reveal a major role for nociceptor neurons in sensing and defending against enteric pathogens.
Learn More >Chronic pain affects a significant percentage of the United States population, and available pain medications like opioids have drawbacks that make long-term use untenable. Cannabinoids show promise in the management of pain, but long-term treatment of pain with cannabinoids has been challenging to implement in preclinical models. We developed a voluntary, gelatin oral self-administration paradigm that allowed male and female mice to consume ∆-tetrahydrocannabinol, cannabidiol, or morphine ad libitum. Mice stably consumed these gelatins over 3 weeks, with detectable serum levels. Using a real-time gelatin measurement system, we observed that mice consumed gelatin throughout the light and dark cycles, with animals consuming less THC-gelatin than the other gelatin groups. Consumption of all three gelatins reduced measures of allodynia in a chronic, neuropathic sciatic nerve injury model, but tolerance to morphine developed after 1 week while THC or CBD reduced allodynia over three weeks. Hyperalgesia gradually developed after sciatic nerve injury, and by the last day of testing, THC significantly reduced hyperalgesia, with a trend effect of CBD, and no effect of morphine. Mouse vocalizations were recorded throughout the experiment, and mice showed a large increase in ultrasonic, broadband clicks after sciatic nerve injury, which was reversed by THC, CBD, and morphine. This study demonstrates that mice voluntarily consume both cannabinoids and opioids via gelatin, and that cannabinoids provide long-term relief of chronic pain states. In addition, ultrasonic clicks may objectively represent mouse pain status and could be integrated into future pain models.
Learn More >Placebo treatments even if known to the patient to be placebo, so-called "open label placebo," may be effective in reducing chronic painThe effects of the extent of placebo education are poorly understood WHAT THIS ARTICLE TELLS US THAT IS NEW: Using a well-characterized electrical pain sensitization model in human volunteers, the effects of short versus detailed placebo educational protocols were measuredOpen label placebo treatment reduced pain sensitization in the volunteers, but the extent of placebo education did not modify these responses BACKGROUND:: Open label placebos with patient education are effective in reducing chronic pain, and recent studies on their effect on pain have established interest in this field. Nevertheless, data on their effect on acute pain are scarce, and on hyperalgesia and allodynia, absent. This study assessed the effect of open label placebos on acute pain in healthy adult males and the influence of placebo education.
Learn More >Elucidating the active δ-opioid receptor crystal structure with peptide and small-molecule agonists.
Selective activation of the δ-opioid receptor (DOP) has great potential for the treatment of chronic pain, benefitting from ancillary anxiolytic and antidepressant-like effects. Moreover, DOP agonists show reduced adverse effects as compared to μ-opioid receptor (MOP) agonists that are in the spotlight of the current "opioid crisis." Here, we report the first crystal structures of the DOP in an activated state, in complex with two relevant and structurally diverse agonists: the potent opioid agonist peptide KGCHM07 and the small-molecule agonist DPI-287 at 2.8 and 3.3 Å resolution, respectively. Our study identifies key determinants for agonist recognition, receptor activation, and DOP selectivity, revealing crucial differences between both agonist scaffolds. Our findings provide the first investigation into atomic-scale agonist binding at the DOP, supported by site-directed mutagenesis and pharmacological characterization. These structures will underpin the future structure-based development of DOP agonists for an improved pain treatment with fewer adverse effects.
Learn More >Genetic polymorphisms have been shown to affect opioid requirement for pain relief. However, true genetic effect is often difficult to assess due to underlying pain conditions and placebo effects. The goal of this study was to understand how common polymorphisms affect opioid effects while controlling for these factors. A randomized, double-blind, placebo-controlled study was implemented to assess how opioid effects are modulated by COMT (rs6269, rs4633, rs4848, rs4680), OPRM1 (A118G), and OPRK1 (rs1051660, rs702764, rs16918875). One hundred and eight healthy subjects underwent experimental pain testing before and after morphine, butorphanol, and placebo (saline). Association analysis was performed between polymorphisms/haplotypes and opioid response, while correcting for race, gender, placebo effects, and multiple comparisons. Pressure pain was significantly associated with rs6269 and rs4633 following butorphanol. The AA genotype of rs4680 or A_T_C_A/ A_T_C_A (rs6269_rs4633_ rs4818_rs4680) diplotype of COMT, combined with the AG genotype of OPRM1 A118G, showed significantly increased pressure pain threshold from butorphanol. Opioid effects on pressure, ischemic, heat pain, and side effects were nominally associated with several SNPs and haplotypes. Effects were often present in one opioid but not the other. This indicates that these polymorphisms affect pain relief from opioids, and that their effects are opioid and pain modality specific.
Learn More >Migraine is among the most common and most disabling disorders worldwide, yet its underlying pathophysiology is among the most poorly understood. New information continues to emerge on mechanisms within the central and peripheral nervous systems that may contribute to migraine attacks. Additionally, new therapeutics have recently become available and along with much needed relief for many patients, these drugs provide insight into the disorder based on their mechanism of action. This review will cover new findings within the last several years that add to the understanding of migraine pathophysiology, including those related to the vasculature, calcitonin gene-related peptide (CGRP), and mechanisms within the cortex and meninges that may contribute to attacks. Discussion will also cover recent findings on novel therapeutic targets, several of which continue to show promise in new preclinical studies, including acid-sensing ion channels (ASICs) and the delta-opioid receptor (DOR).
Learn More >Low levels of catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines, and stress, which potentiates catecholamine release from sympathetic nerves, are fundamental to chronic functional pain syndromes (FPS) and comorbid depression, which predominantly affect females. Here, we sought to examine the independent and joint contributions of low COMT and stress to chronic functional pain and depression at the behavioral and molecular level. Male and female C57BL/6 mice received sustained systemic delivery of the COMT inhibitor OR486 over 14 days and underwent a swim stress paradigm on days 8-10. Pain and depressive-like behavior were measured over 14 days and brain-derived neurotrophic factor (BDNF; a factor involved in nociception and depression) and glucocorticoid receptor (GR; a stress-related receptor) expression were measured on day 14. We found that stress potentiates the effect of low COMT on functional pain, and low COMT potentiates the effect of stress on depressive-like behavior. The joint effects of low COMT and stress on functional pain and depressive-like behavior were significantly greater in females versus males. Consistent with behavioral data, we found that stress potentiates COMT-dependent increases in spinal BDNF and low COMT potentiates stress-dependent decreases in hippocampal BDNF in females, but not males. While low COMT increases spinal GR and stress increases hippocampal GR expression, these increases are not potentiated in the OR486 + stress group and are not sex-specific. These results suggest that genetic and environmental factors that enhance catecholamine bioavailability cause abnormalities in BDNF signaling and increase risk of comorbid functional pain and depression, especially among females.
Learn More >This study aims to investigate whether intra-network dynamic functional connectivity and causal interactions of the salience network is altered in the interictal term of migraine. 32 healthy controls, 37 migraineurs without aura and 20 migraineurs with aura were recruited. Participants underwent a T1-weighted scan and resting-state fMRI protocol inside a 1.5T MR scanner. We obtained average spatial maps of resting-state networks using group independent component analysis, which yielded subject-specific time series via a dual regression approach. Salience network ROIs (bilateral insulae and prefrontal cortices, dorsal anterior cingulate cortex) were obtained from the group average map via cluster-based thresholding. To describe intra-network connectivity, average and dynamic conditional correlation was calculated. Causal interactions between the default-mode, dorsal attention and salience network were characterised by spectral Granger's causality. Time-averaged correlation was lower between the right insula and prefrontal cortex in migraine without aura vs. with aura and healthy controls (p<0.038, p<0.037). Variance of dynamic conditional correlation was higher in migraine with aura vs. healthy controls and migraine with aura vs. without aura between the right insula and dorsal anterior cingulate cortex (p<0.011, p<0.026), and in migraine with aura vs. healthy controls between the dorsal anterior cingulate and left prefrontal cortex (p<0.021). Causality was weaker in the <0.05 Hz frequency range between the salience and dorsal attention networks in migraine with aura (p<0.032). Overall, migraineurs with aura exhibit more fluctuating connections in the salience network, which also affect network interactions, and could be connected to altered cortical excitability and increased sensory gain.
Learn More >Several reports support the idea that µ- and δ-opioid receptors (ORs) may exist as heterodimers in brain regions involved in pain signaling. The unique pharmacology of these heteromers may present a novel analgesic target. However, the role of µ-δ heteromers in sensory neurons involved in pain and opioid analgesia remains unclear, particularly during neuropathic pain. We examined the effects of spinal nerve injury on µ-δ heteromer expression in dorsal root ganglion (DRG) neurons and the effects of a µ-δ heteromer-targeting agonist, CYM51010, on neuropathic pain behavior in rats and mice. An L5 spinal nerve ligation (SNL) in rats significantly decreased µ-δ heteromer expression in L5 DRG, but increased heteromer levels in uninjured L4 DRG. Importantly, in SNL rats, subcutaneous (s.c.) injection of CYM51010 inhibited mechanical hypersensitivity in a dose-related manner (EC50: 1.09 mg/kg) and also reversed heat hyperalgesia and attenuated ongoing pain (2 mg/kg, s.c.). HEK-293T cells surface-labeled with µ- and δ-ORs internalized both receptors after exposure to CYM51010. In contrast, in cells transfected with µ-OR alone, CYM51010 was significantly less effective at inducing receptor internalization. Electrophysiologic studies showed that CYM51010 inhibited the C-component and windup phenomenon in spinal wide-dynamic range neurons of SNL rats. The pain inhibitory effects of CYM51010 persisted in morphine-tolerant rats, but was markedly attenuated in µ-OR knockout mice. Our studies show that spinal nerve injury may increase µ-δ heterodimerization in uninjured DRG neurons and that µ-δ heteromers may be a potential therapeutic target for relieving neuropathic pain, even under conditions of morphine tolerance.
Learn More >Selective targeting of sodium channel subtypes Nav1.7, Nav1.8 and Nav1.9, preferentially expressed by peripheral nociceptors, represents a unique opportunity to develop analgesics devoid of central side effects. Several compounds that target Nav1.7 and Nav1.8 with different degrees of selectivity have been developed and are currently being tested in clinical trials for multiple pain indications. Among these chemicals, benzothiazole-like compounds emerged as potent sodium channel blockers.We evaluated the effects of dexpramipexole, a benzothiazole-bearing drug with pleiotypic neuroactive properties and a good safety profile in humans, on sodium conductances of dorsal root ganglia neurons, as well as in multiple nociceptive and neuropathic pain models.Dexpramipexole blocks TTX-resistant sodium conductances in cultured rat dorsal root ganglion neurons with an IC50 of 294.4 nM, suggesting selectivity towards Nav1.8. In keeping with this, dexpramipexole does not affect sodium currents in DRG neurons from Nav1.8 null mice, and acquires binding pose predicted to overlap that of the Nav1.8 channel-selective blocker A-8034637. The drug provides analgesia when parenterally, orally or topically applied in inflammatory and visceral mouse pain models, as well as in mice affected by neuropathic pain induced by oxaliplatin, nerve constriction or diabetes. Pain reduction in mice occurs at doses consistent with those adopted in clinical trials.The present findings confirm the relevance of selective targeting of peripheral Nav1.8 channels to pain therapy. In light of the excellent tolerability of dexpramipexole in humans, our results support its translational potential for treatment of pain.
Learn More >It has been proposed that Complex Regional Pain Syndrome (CRPS) is a post-traumatic autoimmune disease. Previously we observed that B cells are required for the full expression of CRPS-like changes in a mouse tibia fracture model and that serum IgM antibodies from fracture mice have pronociceptive effects in muMT fracture mice lacking B cells. The current study evaluated the pronociceptive effects of injecting CRPS patient serum or antibodies into muMT fracture mice by measuring hindpaw allodynia and unweighting changes. CRPS serum binding was measured against autoantigens previously identified in the fracture mouse model. Both CRPS patient serum or IgM antibodies had pronociceptive effects in the fracture limb when injected systemically in muMT fracture mice, but normal subject serum and CRPS patient IgG antibodies had no effect. Furthermore, CRPS serum IgM antibodies had pronociceptive effects when injected into the fracture limb hindpaw skin or intrathecally in the muMT fracture mice. Early (1-12 months post injury) CRPS patient (n=20) sera were always pronociceptive after systemic injection and chronic (>12 months post injury) CRPS sera were rarely pronociceptive (2/20 patients), while sera from normal subjects (n=20) and from patients with uncomplicated recoveries from orthopedic surgery and/or fracture (n=15) were never pronociceptive. Increased CRPS serum IgM binding was observed for keratin 16, histone 3.2, gamma actin, and alpha enolase autoantigens. We postulate that CRPS patient IgM antibodies bind to neoantigens in the fracture mouse skin and spinal cord to initiate a regionally restricted pronociceptive complement response potentially contributing to the CRPS disease process.
Learn More >Low back pain (LBP) is a leading cause of global disability. Multiple anatomical, cellular and molecular factors implicated in LBP, including degeneration of lumbar intervertebral discs (IVDs). We previously described a mouse model that displays behavioral symptoms of chronic LBP. Here we investigated the development of pathological innervation and macrophage infiltration into injured IVDs following a puncture injury in mice over 12 months. 2-month old CD1 female mice underwent a single puncture of the ventral L4/5 IVD using a 30G needle, and were sacrificed 4 days and 0.5-, 3-, 6- and 12-months post-injury. Severity of disc degeneration was assessed using colorimetric staining. IVD innervation was measured by PGP9.5-immunoreactivity (-ir) and calcitonin gene-related peptide-ir (CGRP-ir). Macrophage accumulation into IVDs was detected by F4/80-ir. Mechanical IVD injury resulted in severe degeneration and increased PGP9.5-ir nerve fiber density starting at 4 days that persisted for up to 12 months and dorsal herniations began to occur at 3 months. CGRP-ir was also upregulated in injured IVDs, with the largest increase at 12 months post-injury. Infiltration of F4/80-ir macrophages was observed in injured IVDs by day 4 both dorsally and ventrally, with the latter diminishing in the later stage. Persistent LBP is a complex disease with multiple underlying pathologies. By highlighting pathological changes in IVD innervation and inflammation, our study suggests that strategies targeting these mechanisms might be useful therapeutically. This article is protected by copyright. All rights reserved.
Learn More >Recent studies indicate that a significant reorganization of cerebral networks may occur in patients with chronic pain, but how immediate pain experience influences the organization of large-scale functional networks is not yet well characterized. To investigate this question, we used functional magnetic resonance imaging in 106 participants experiencing both noxious and innocuous heat. Painful stimulation caused network-level reorganization of cerebral connectivity that differed substantially from organization during innocuous stimulation and standard resting-state networks. Noxious stimuli increased somatosensory network connectivity with (a) frontoparietal networks involved in context representation, (b) "ventral attention network" regions involved in motivated action selection, and (c) basal ganglia and brainstem regions. This resulted in reduced "small-worldness," modularity (fewer networks), and global network efficiency and in the emergence of an integrated "pain supersystem" (PS) whose activity predicted individual differences in pain sensitivity across 5 participant cohorts. Network hubs were reorganized ("hub disruption") so that more hubs were localized in PS, and there was a shift from "connector" hubs linking disparate networks to "provincial" hubs connecting regions within PS. Our findings suggest that pain reorganizes the network structure of large-scale brain systems. These changes may prioritize responses to painful events and provide nociceptive systems privileged access to central control of cognition and action during pain.
Learn More >Pituitary adenylate cyclase-activating polypeptide (PACAP) occurs as either a 27- or 38-amino acid neuropeptide and belongs to the vasoactive intestinal polypeptide/glucagon/secretin family of peptides. PACAP and vasoactive intestinal polypeptide have a 68% homology of their amino acid sequences and share three B-type G-protein coupled receptors: VPAC, VPAC and PAC receptors.
Learn More >Spinal gastrin-releasing peptide receptor-expressing (GRPR) neurons play an essential role in itch signal processing. However, the circuit mechanisms underlying the modulation of spinal GRPR neurons by direct local and long-range inhibitory inputs remain elusive. Using viral tracing and electrophysiological approaches, we dissected the neural circuits underlying the inhibitory control of spinal GRPR neurons. We found that spinal galanin GABAergic neurons form inhibitory synapses with GRPR neurons in the spinal cord and play an important role in gating the GRPR neuron-dependent itch signaling pathway. Spinal GRPR neurons also receive inhibitory inputs from local neurons expressing neuronal nitric oxide synthase (nNOS). Moreover, spinal GRPR neurons are gated by strong inhibitory inputs from the rostral ventromedial medulla. Thus, both local and long-range inhibitory inputs could play important roles in gating itch processing in the spinal cord by directly modulating the activity of spinal GRPR neurons.
Learn More >The objective of this study was to examine the day-to-day associations between partner support, pain catastrophizing and pain intensity in individuals with end-stage knee osteoarthritis. In this microlongitudinal cohort study, participants (N = 124) with end-stage knee osteoarthritis completed baseline measures of trait pain catastrophizing and negative affect. Participants also provided daily diary assessments of partner support, pain catastrophizing and pain intensity for a period of 7 days using a personal digital assistant. Multilevel analyses revealed that day-to-day fluctuations in pain catastrophizing were associated with pain intensity. Data from multilevel analyses indicated that the main effect of partner support was not significantly associated with pain intensity. Results also indicated the interactions between partner support and both trait and state pain catastrophizing were significant, suggesting that both trait and state pain catastrophizing moderated the relationship between daily partner support and pain intensity. That is, on days when participants experienced low levels of partner support, high catastrophizers reported higher levels of pain intensity than low catastrophizers. In the presence of higher levels of partner support, pain intensity did not differ between high and low catastrophizers. These results are consistent with the Communal Coping Model of pain catastrophizing, and highlight the interpersonal context within which pain catastrophizing impacts pain outcomes. These findings also suggest that future interventions designed to specifically target the dynamic between pain catastrophizing and partner support may improve pain outcomes in individuals with end-stage knee OA.
Learn More >Systematic-reviews of analgesics for low back pain generally include published data only. Obtaining data from unpublished trials is potentially important because they may impact effect sizes in meta-analyses. We determined whether including unpublished data from trial registries changes the effect sizes in meta-analyses of analgesics for low back pain.
Learn More >Over half of youth with chronic pain report sleep deficiency including difficulties falling asleep, maintaining sleep, feeling unrested, and experiencing short sleep duration. Sleep deficiency has been shown to play a causal role in the development or worsening of chronic pain, and is associated with a variety of negative consequences for youth with chronic pain. The purpose of this review is to provide a summary of the literature on the interrelationship of sleep and chronic pain in adolescents. We review the impact and prevalence of sleep disturbances, conceptual models of the interrelationship of sleep and pain, biobehavioral mechanisms and risk factors, sleep assessment, and treatment of sleep deficiency and chronic pain in adolescents. Our recommendations for future research include understanding biobehavioral mechanisms that underlie the link between chronic pain and sleep deficiency to help guide development and testing of treatments for co-occurring pain and sleep disturbance in adolescents.
Learn More >Inflammation is the body's protective reaction to injury and infection. Pain is a hallmark of inflammation and can be either protective or detrimental during acute or chronic phase. Macrophages play a chief role in the pathogenesis of pain and have bilateral communications with nociceptors, the specialized primary sensory neurons that sense pain. Macrophages 'talk to' nociceptors by releasing pro-inflammatory mediators (e.g. pro-inflammatory cytokines) that induce pain via direct activation of nociceptors. Macrophages also 'listen to' nociceptors, by which nociceptors secrete neuropeptides and chemokines which act on macrophages. Activation of toll-like receptors (TLRs) in nociceptors releases CCL2, activating macrophages and potentiating pathological pain. Emerging evidence also points to a pro-resolution role of macrophages in inflammation and pain. Macrophage GPR37 is activated by neuroprotectin D1, a specialized pro-resolving mediator (SPM) and resolves inflammatory pain via phagocytosis and production of IL-10 that inhibits nociceptors. Macrophage-nociceptor interactions are also mediated by microRNAs and microRNA-containing exosomes in chronic pain. Notably, extracellular microRNAs (e.g. let-7b and miR-711) can directly bind and activate nociceptors. Targeting macrophage-nociceptor interactions will help to control inflammation and pain.
Learn More >To investigate sex effects on pain-related behaviors in the medial meniscal transection (MMT) knee osteoarthritis (OA) model.
Learn More >We investigated whether baseline scores for a self-report trait linked to central mechanisms predict 1 year pain outcomes in the Knee Pain In the Community cohort.
Learn More >This updated systematic review evaluated the efficacy, tolerability and safety of opioids compared to placebo in non-malignant chronic low back pain.
Learn More >Pain is considered a hardwired signal of bodily disturbance belonging to a basic motivational system that urges the individual to act and to restore the body's integrity, rather than just a sensory and emotional experience. Given its eminent survival value, pain is a strong motivator for learning. Response to repeated pain increases when harm risks are high (sensitization) and decreases in the absence of such risks (habituation). Discovering relations between pain and other events provides the possibility to predict (Pavlovian conditioning) and control (operant conditioning) harmful events. Avoidance is adaptive in the short term but paradoxically may have detrimental long-term effects. Pain and pain-related responses compete with other demands in the environment. Exposure-based treatments share the aim of facilitating or restoring the pursuit of individual valued life goals in the face of persistent pain, and further improvements in pain treatment may require a paradigm shift toward more personalized approaches. Expected final online publication date for the , Volume 16 is May 7, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Learn More >To assess the efficacy of erenumab across the spectrum of response thresholds (≥50%, ≥75%, 100%) based on monthly migraine days (MMD) reduction in patients with chronic migraine from a 12-week, randomized study (NCT02066415).
Learn More >The serine hydrolase monoacylglycerol lipase (MAGL) is the rate-limiting enzyme responsible for the degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG) into arachidonic acid and glycerol. Inhibition of 2-AG degradation leads to elevation of 2-AG, the most abundant endogenous agonist of the cannabinoid receptors CB1 and CB2. Activation of these receptors have demonstrated beneficial effects on mood, appetite, pain and inflammation. Therefore, MAGL inhibitors have the potential to produce therapeutic effects in a vast array of complex human diseases. The present report describes the pharmacologic characterization of JNJ-42226314, [1-(4-fluorophenyl)indol-5-yl]-[3-[4-(thiazole-2-carbonyl)piperazin-1-yl]azetidin-1-yl]methanone, a reversible and highly selective MAGL inhibitor. JNJ-42226314 inhibits MAGL in a competitive mode with respect to the 2-AG substrate. In rodent brain, the compound time- and dose-dependently bound to MAGL, indirectly led to CB1 occupancy by raising 2-AG levels and raised norepinephrine levels in cortex. In vivo, the compound exhibited antinociceptive efficacy in both the rat complete Freund's adjuvant (CFA)-induced radiant heat hypersensitivity and chronic constriction injury (CCI)-induced cold hypersensitivity models of inflammatory and neuropathic pain, respectively. Although 30 mg/kg induced hippocampal synaptic depression, altered sleep onset and decreased EEG gamma power, 3 mg/kg still provided approximately 80% enzyme occupancy, significantly increased 2-AG and norepinephrine levels and produced neuropathic antinociception without synaptic depression or decreased gamma power. Thus, it is anticipated that the profile exhibited by this compound will allow for precise modulation of 2-AG levels in vivo, supporting potential therapeutic application in several CNS disorders. SIGNIFICANCE STATEMENT: Potentiation of endocannabinoid signaling activity via inhibition of the serine hydrolase monoacylglycerol lipase (MAGL) is an appealing strategy in the development of treatments for several disorders, including ones related to mood, pain and inflammation. JNJ-42226314 is presented in this report to be a novel, potent, selective and reversible non-covalent MAGL inhibitor that demonstrates dose-dependent enhancement of the major endocannabinoid 2-arachidonoylglycerol as well as efficacy in models of neuropathic and inflammatory pain.
Learn More >Chronic postsurgical pain (CPSP) is a surgical complication associated with increased functional disability, psychological distress, and economic costs. The aims of this paper were to prospectively: (1) examine the incidence of CPSP 6 and 12 months after pediatric major surgery; (2) identify pain intensity and pain unpleasantness trajectories before, and up to 12 months after, surgery; (3) identify pre-operative factors that predict pain trajectory group membership; and (4) identify predictors of 12-month functional disability.
Learn More >Despite guidelines, painful neuropathy is often inappropriately treated. We aimed to determine the effectiveness of a clinical decision support system on guideline-recommended medication utilization.
Learn More >Studies have shown a significant association between migraine and endometriosis, but no study has explored the relationship between migraine and endometriosis phenotypes: Superficial peritoneal endometriosis, ovarian endometrioma, and deep infiltrating endometriosis.
Learn More >Allodynia refers to pain evoked by physiologically innocuous stimuli. It is a disabling symptom of neuropathic pain following a lesion within the peripheral or central nervous system. In fact, two different pathophysiological mechanisms of cold allodynia (ie, hypersensitivity to innocuous cold) have been proposed. The peripheral sensitization of nociceptive neurons can produce cold allodynia, which can be induced experimentally by a topical application of menthol. An alternative mechanism involves reduced inhibition of central pain processing by innocuous cold stimuli. A model to induce the latter type of allodynia is the conduction block of peripheral A-fiber input.
Learn More >Chronic pain is a complex neuropsychiatric disorder characterized by sensory, cognitive, and affective symptoms. Over the past 2 decades, researchers have made significant progress toward understanding the impact of mesolimbic dopamine circuitry in acute and chronic pain. These efforts have provided insights into the circuits and intracellular pathways in the brain reward center that are implicated in sensory and affective manifestations of chronic pain. Studies have also identified novel therapeutic targets as well as factors that affect treatment responsiveness. Dysregulation of dopamine function in the brain reward center may further promote comorbid mood disorders and vulnerability to addiction. This review discusses recent clinical and preclinical findings on the neuroanatomical and neurochemical adaptations triggered by prolonged pain states in the brain reward pathway. Furthermore, this discussion highlights evidence of mechanisms underlying comorbidities among pain, depression, and addiction.
Learn More >Chronic neck pain is a highly prevalent condition, affecting 10% to 24% of the general population. Transcutaneous electrical nerve stimulation (TENS) is the noninvasive, transcutaneous use of electrical stimulation to produce analgesia. It is a simple, low-cost and safe intervention used in clinical practice as an adjunct treatment for painful musculoskeletal conditions that have a considerable impact on daily activities, such as chronic neck pain. This review is a split from a Cochrane Review on electrotherapy for neck pain, published in 2013, and focuses specifically on TENS for chronic neck pain.
Learn More >The aim of this study is to investigate the alterations of thalamic nuclei volumes and the intrinsic thalamic network in patients with migraine.
Learn More >The aim of this study was to better understand the role that physical, cognitive and social factors play in pain interference with activities of daily living among individuals with cancer and chronic pain.
Learn More >Mechanisms of neuropathic pain are not fully understood. Molecular changes in spinal dorsal horn take part in the initiation and development of neuropathic pain.
Learn More >The objective of this review was to determine the unmet needs for migraine in East Asian adults and children.
Learn More >The aim of the present study was to compare the efficacy of burst-like conditioning electrical stimulation versus continuous stimulation of cutaneous nociceptors for inducing increased pinprick sensitivity in the surrounding unstimulated skin (a phenomenon referred to as secondary hyperalgesia). In a first experiment (N=30) we compared the increase in mechanical pinprick sensitivity induced by 50 Hz burst-like stimulation (N=15) versus 5 Hz continuous stimulation (N=15), while maintaining constant the total number of stimuli and the total duration of stimulation. We found a significantly greater increase in mechanical pinprick sensitivity in the surrounding unstimulated skin after 50 Hz burst-like stimulation compared to 5 Hz continuous stimulation (=.013, Cohen's =.970). Importantly, to control for the different frequency of stimulation we compared in a second experiment (N=40) 5 Hz continuous stimulation (N=20) versus 5 Hz burst-like stimulation (N=20), this time while keeping the total number of stimuli as well as the frequency of stimulation identical. Again we found a significantly greater increase in pinprick sensitivity after 5 Hz burst-like stimulation compared to 5 Hz continuous stimulation (=.009, Cohen's =.868). To conclude, our data shows indicate that burst-like conditioning electrical stimulation is more efficacious than continuous stimulation for inducing secondary hyperalgesia.
Learn More >Oxytocin (OT), a hormone synthesized within the paraventricular nucleus and supraoptic nucleus of the hypothalamus, when given intracerebroventricularly, induces strong scratching behaviors. However, it is not clear whether intradermal injection (ID) of OT elicits itch sensation. Herein, we found that OT (0.02 mg/ml) did not elicit an itch-scratching response in mice but aggravated chloroquine (CQ, 3 mmol/L)-elicited scratching behavior. Similar to OT, arginine vasopressin (AVP, 0.02 mg/ml), which is structurally related to OT, also enhanced CQ-induced scratching behavior but did not directly induce scratching behavior in mice. Mechanistically, OT-mediated enhancement of CQ-induced scratching behavior was significantly suppressed by conivaptan (0.05 mg/ml), a vasopressin-1a receptor (V1AR) antagonist and 1,400 W (3 mg/kg), inhibitor of inducible nitric oxide synthase (iNOS), but not OT receptor (OTR) antagonist L-368,899 (0.05 mg/ml). Notably, conivaptan also directly decreased CQ-induced scratching. In conclusion, OT plays a role in CQ-induced scratching behavior V1AR binding events. V1AR antagonists could be used as possible treatments for CQ-induced itch.
Learn More >Spinal cord injury (SCI) causes loss of normal sensation and often leads to debilitating neuropathic pain (NeP). Chronic NeP develops at or below the SCI lesion in as many as 80% of patients with SCI and may be induced by modulators of neuronal excitability released from activated microglia and macrophages. In the inflammatory response after SCI, different microglia/macrophage populations that are classically activated (M1 phenotype) or alternatively activated (M2 phenotype) have become of great interest. Chemokines have also recently attracted attention in neuron-microglia communication. CCL21 is a chemokine that activates microglia in the central nervous system (CNS) and is expressed only in neurons with an insult or mechanical injury. In this study using an SCI model in mutant () mice with deficient CCL21 expression, we assessed post-SCI NeP and expression of microglia/macrophages and inflammatory cytokines at the injured site and lumbar enlargement. SCI-induced hypersensitivities to mechanical and thermal stimulation were relieved in mice compared with those in wild-type (C57BL/6) mice, although there was no difference in motor function. Immunohistochemistry and flow cytometry analysis showed that the phenotype of microglia/macrophages was M1 type-dominant in both types of mice at the lesion site and lumbar enlargement. A decrease of M1-type microglia/macrophages was seen in mice compared with wild-type, while the number of M2-type microglia/macrophages did not differ between these mice. In immunoblot analysis, expression of M1-induced cytokines [tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ)] was decreased in mice, while that of M2-induced cytokines interleukin-4 (IL-4, IL-10) did not differ in the two types of mice. The results of this study indicate that suppression of expression of inflammatory cytokines by decreasing the number of M1-type microglia/macrophages at the injured site and lumbar enlargement is associated with provision of an environment for reduction of NeP. These findings may be useful for the design of new therapies to alleviate NeP after SCI.
Learn More >Acid-sensing ion channels (ASICs) are important acid sensors involved in neural modulation in the central nervous system and pain-associated tissue acidosis in the peripheral system. Among ASIC subtypes, ASIC1b is the most selectively expressed in peripheral sensory neurons. However, the role of ASIC1b is still elusive in terms of its functions and expression profile. In this study, we probed the role of ASIC1b in acid-induced muscle pain in -knockout () and transgenic ( ) mice. We tested the effect of ASIC1b knockout in a mouse model of fibromyalgia induced by dual intramuscular acid injections. In this model, a unilateral acid injection to the gastrocnemius muscle induced transient bilateral hyperalgesia in wild-type () but not mice; a second acid injection, spaced 1 or 5 days apart, to the same muscle induced chronic hyperalgesia lasting for 4 weeks in mice, but the duration of hyperalgesia was significantly shortened in mice. Mambalgin-1, an ASIC1b-containing channel inhibitor that was mixed with acid saline at the first injection, dose-dependently blocked the acid-induced transient and chronic hyperalgesia in mice. In contrast, psalmotoxin 1 (PcTx1), an ASIC1a-selective antagonist, had no effect on acid-induced transient or chronic hyperalgesia. We used whole-cell patch clamp recording to study the properties of acid-induced currents in ASIC1b-expressing dorsal root ganglia (DRG) neurons from -TdTomato reporter mice. Medium- to large-sized ASIC1b-expressing DRG neurons mainly exhibited an amiloride-sensitive ASIC-like biphasic current () in response to acid stimulation, whereas small- to medium-sized ASIC1b-expressing DRG neurons predominantly exhibited an amiloride-insensitive sustained current. Specifically, mambalgin-1 selectively inhibited the in most ASIC1b-expressing DRG neurons. However, PcTx1 or APETx2 (an ASIC3-selective antagonist) had only a mild inhibitory effect on in about half of the ASIC1b-expressing DRG neurons. hybridization revealed that ASIC1b-positive DRG neurons co-expressed highly with ASIC1a and ASIC2a mRNA and partially with ASIC3 and ASIC2b. Thus, ASIC1b might form a wide variety of heteromeric channels. ASIC1b-containing heteromeric channels might be promising targets for the therapeutic treatment of acid-induced chronic muscle pain.
Learn More >Schwann cells (SC) are essential to the growth, maintenance and regeneration of peripheral nerves, but the proteome of normal human SC is poorly defined. Here, we performed a proteomic analysis by liquid chromatography tandem mass spectrometry (LC-MS/MS) to define the protein expression profile of primary human SC. A total of 19,557 unique peptides corresponding to 1,553 individual proteins were identified. Ingenuity Pathway Analysis (IPA), Gene Ontology (GO) and Database for Annotation, Visualization and Integrated Discovery (DAVID) were used to assign protein localization and function, and to define enriched pathways. EIF2, mTOR and integrin signalling were among the most enriched pathways and the most enriched biological function was cell-cell adhesion, which is in agreement with the supportive role of SC in peripheral nerves. In addition, several nociceptors and synaptic proteins have been identified and may contribute to the recently discovered role of SC in pain sensation and cancer progression. This proteome analysis of normal human SC constitutes a reference for future molecular explorations of physiological and pathological processes where SC are involved. This article is protected by copyright. All rights reserved.
Learn More >Ion channels, due to their prominent localization in primary sensory neurons and other key structures in pain processing, are regarded as a major class of drug targets for modulating pain sensation and controlling chronic pain. Here, we review the implications of some ion channels in pain transduction and the preclinical and clinical investigations on drugs that target such channels in pain studies. The discussion will be limited to voltage-gated calcium channels, transient receptor potential channels, acid-sensing ion channels, and PIEZO channels. Descriptions of other important channels in pain signaling, including voltage-sensitive sodium channels, are reported elsewhere in this volume.
Learn More >This paper presents and discusses recent evidence on the pathophysiological mechanisms of pain. The role of tapentadol-an analgesic molecule characterized by an innovative mechanism of action (i.e., µ-opioid receptor [MOR] agonism and inhibition of noradrenaline [NA] reuptake [NRI])-in the modulation of pain, and the most recent pharmacological evidence on this molecule (e.g., the µ-load concept) are also presented and commented upon. Narrative review. Solid evidence has highlighted the importance of central sensitization in the transition from acute to chronic pain. In particular, the noradrenergic system holds a major role in limiting central sensitization and the progression to chronic pain. Therefore, pharmacological modulation of the noradrenergic system appears to be a well-grounded strategy for the control of chronic pain. Tapentadol is characterized by a to-date-unique mechanism of action, since it acts both as a MOR agonist and as an inhibitor of NA reuptake. The synergistic interaction of these two mechanisms allows a strong analgesic effect by acting on both ascending and descending pathways. Of note, the reduced µ-load of tapentadol has two important consequences: first, it limits the risk of opioid-related adverse events, as well as the risk of dependence; second, the NA component becomes predominant at least in some types of pain with consequent specific clinical efficacy in the treatment of neuropathic and chronic pain. According to these characteristics, tapentadol appears suitable in the treatment of chronic pain conditions characterized by both a nociceptive and a neuropathic component, such as osteoarthritis or back pain.
Learn More >Temporal summation (TS) refers to the increased perception of pain with repetitive noxious stimuli. While thermal TS is generally considered a behavioral correlate of spinal windup, noxious heat pulses also trigger additional sensory processes which were modeled in this study.
Learn More >Measuring patients' experiences of health services has become an essential part of quality of care reporting and a means for identifying opportunities for improvement. This study aimed to evaluate change in patient experience in an interdisciplinary primary care program and to estimate the impact on patient experience of sociodemographic, function, pain and general health status, resource utilization, and process variables.
Learn More >Many aspects of study conduct impact the observed effect size of treatment. Data were utilized from a recently published meta-analysis of randomized, double-blind, placebo-controlled, clinical trials performed for the United States Food and Drug Administration (FDA) approval of full mu-agonist opioids for the treatment of chronic pain.
Learn More >The emerging role of inflammation in the initiation and maintenance of neuropathic pain has been confirmed. Previous studies have reported that miR138 has neuroprotective and anti-inflammatory effects in animal models of spinal cord injury and in human coronary artery endothelial cell injury, while its effect on neuropathic pain is still not known. As the mechanism of neuropathic pain remains unclear, we investigated whether miR138 is involved in the development of neuropathic pain and the role of miR138 in the modulation of inflammation in the spinal cord in a mouse model of neuropathic pain induced by spared sciatic nerve injury (SNI).
Learn More >Pediatric functional abdominal pain disorders (FAPD) are associated with adverse outcomes including increased somatization (e.g., heightened physiological sensations that include gastroenterological and non-gastroenterological symptoms) and increased functional disability. Caregiver distress and child anxiety are separately associated with the adverse outcomes of pediatric FAPD. However, the cumulative role of caregiver (i.e., stress, anxiety, and depression) and child psychological functioning (anxiety) in relation to adverse outcomes associated with FAPD, and particularly somatization, is unclear. Thus, the present investigation sought to examine the role of caregiver distress and child anxiety in relation to pain-related functioning (i.e., somatization, pain intensity, functional disability) in youth with FAPD. Data were gathered as part of a larger study examining a psychological treatment for youth with FAPD. Participants (ages 9-14) with FAPD completed measures of child anxiety, pain, and pain-related functioning. Caregivers completed a measure of caregiver distress (e.g., stress, anxiety, depressive symptoms). Pearson correlations revealed significant positive associations between child anxiety and child functional disability. Additionally, caregiver anxiety, child anxiety, and child somatization were all significantly and positively correlated with one another. Therefore, we assessed whether child anxiety may potentially mediate the relationship between caregiver anxiety and child somatization in this cross-sectional study. The indirect association between caregiver anxiety and child somatization via child anxiety was not significant. Future research including longitudinal designs to further understand the relationship between caregiver anxiety, child anxiety, and child pain-related functioning, would enhance understanding of how these potentially modifiable psychological factors may impact adverse outcomes of FAPD.
Learn More >Pain management with conventional opioids can be challenging due to dose-limiting adverse events (AEs), some of which may be related to the simultaneous activation of β-arrestin (a signaling pathway associated with opioid-related AEs) and G-protein pathways. The investigational analgesic oliceridine is a G-protein-selective agonist at the µ-opioid receptor with less recruitment of β-arrestin. The objective of this phase 3, open-label, multi-center study was to evaluate the safety and tolerability, of IV oliceridine for moderate to severe acute pain in a broad, real-world patient population, including postoperative surgical patients and non-surgical patients with painful medical conditions.
Learn More >While the prevalence of pain increases with age, too much medication can lead to negative side effects. Complementary approaches, such as clinical hypnosis, could be relevant in pain management. While evidence in the literature has shown that clinical hypnosis is effective in child and adult populations, there have been few studies in aging populations. Furthermore, the feasibility and effectiveness of clinical hypnosis in preventive home care in elderly populations with pain have never been established. The goal of this within-subject study was to determine the feasibility and the effects of three 15-min hypnosis sessions delivered during home care interventions over a 12-week period in 15 elderly women with chronic pain (mean age, 81 years; range, 65-87 years).
Learn More >Trauma is one of the most common causes of morbidity and mortality in people of working age. Following surgery, approximately 10% of patients develop persistent postsurgical pain. Chronic pain is a complex phenomenon that can adversely affect quality of life and is associated with psychiatric conditions such as anxiety and depression. Pharmacological treatment is normally insufficient to fully alleviate chronic pain and improve functional capacity, especially in the long term. The appropriateness of opioid treatment in chronic non-cancer pain has become increasingly examined with high numbers of serious side effects including drug dependency and death. The present study was based on clinical observations suggesting that a problematic opioid use can be initiated during trauma care, which implies the importance of evaluating opioid therapy and its effect on trauma patients. Specific attention is given to patients with known psychiatric conditions which may render them more vulnerable to develop problematic opioid use. The aim of this observational study was to broadly characterize patients referred to a pain specialist after severe trauma regarding their trauma type, psychiatric co-morbidity, and opioid prescription pattern. This was done to tentatively investigate possible risk factors for long-term opioid use following trauma.
Learn More >Migraine affects over a billion people worldwide in any year and is the second most common cause of years lost due to disability. Not "just a headache", morbidity washes though society and carries a substantial economic and social cost. Understanding of migraine pathophysiology has progressed significantly. Animal models and functional neuroimaging have yielded significant insight into brain structures that mediate migraine symptoms. The role of small peptides as neurotransmitters within this network has been elucidated, allowing the generation of novel therapeutic approaches that have been validated by randomised placebo-controlled trials. Migraine is underdiagnosed and undertreated. Treatment of migraine should be proactive. An acute and, when indicated, preventive strategy should be formulated with the patient. Comorbid medication overuse must be supportively managed. Migraine-specific medications are making their way from bench to bedside. They promise an improved safety profile and ease of use in comparison to older, repurposed medications. Devices promise a non-drug alternative should patients prefer. The migraine understanding and treatment landscape is changing rapidly.
Learn More >To assess the effectiveness and reporting standards of psychological interventions for improving outcomes after total knee replacement (TKR).
Learn More >We bilaterally injected 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle of rats and developed bilateral Parkinson's disease (PD) model rats in order to experimentally investigate the neural mechanisms underlying the alteration of nociception in the orofacial region of patients with PD. We explored the effects of dopamine depletion on nociception by investigating behavioral responses (face rubbing) triggered by subcutaneous administration of formalin into the vibrissa pad. We also assessed the number of c-Fos-immunoreactive (c-Fos-IR) cells in the superficial layers of the trigeminal spinal subnucleus caudalis (Vc). Subcutaneous formalin administration evoked a two-phase increase in face rubbing. We observed the first increase 0-5 min after formalin administration (first phase) and the second increase 10-60 min after administration (second phase). The number of face rubbing behaviors of 6OHDA-injected rats did not significantly change compared with saline-injected rats in both phases. Significant increase of c-Fos-IR cells in the Vc was found in 6-OHDA-injected rats after formalin administration compared with those in saline-injected rats after formalin administration. We also assessed expression of c-Fos-IR cells in the paraventricular nucleus (PVN), and significant decrease of c-Fos-IR cells in the PVN of 6-OHDA-injected rats was found. Taken together, these findings suggest that bilateral dopaminergic denervation evoked by 6-OHDA administration causes hyperalgesia in the trigeminal region and the PVN may be involved in the hyperalgesia.
Learn More >Intrathecal opioid pumps have been used in the management of severe chronic pain for more than 40 years. Numerous studies have shown significant therapeutic effects alongside tolerable side effects. In the last decades, life expectancy has increased in many countries in the world. With an aging population, the question arises whether effects equal to those in younger patients can also be achieved in elderly patients.
Learn More >This study estimated the prevalence of cancer-related pain in working-age cancer survivors (age 25-64 years) and evaluated differences in demographic and clinical variables in those with and without pain. We also investigated the impact of cancer-related pain on health-related quality of life (HRQoL) and employment outcomes in this population.
Learn More >To examine the clinical outcomes of intentional overdoses involving triptans and ergotamines with a retrospective review of the National Poison Data System (NPDS).
Learn More >Time perception is an important ability that is related closely to humans' and animals' daily activities. It can be distorted by various emotional states. In human studies, experimental pain has been shown to prolong the perception of time. However, related animal studies are lacking. In this study, we used a temporal bisection task to investigate how acute inflammatory pain (induced by hind-paw formalin injection) and chronic neuropathic pain [induced by spinal nerve ligation (SNL)] affected time perception in rats. Rats were trained to recognize "short" (1200-ms) and "long" (2400-ms) anchor-duration pure tones and were rewarded for corresponding lever presses. During testing, rats perceived a series of intermediate-duration and anchor-duration pure tones, and selected levers corresponding to the "short" and "long" tones. After formalin injection, rats gave more "long" lever-press responses than after saline injection. The point of subjective equality after formalin injection also increased, suggesting that formalin-induced acute pain extended time perception. In contrast, rats that had undergone SNL gave fewer "long" lever-press responses compared with the sham surgery group. This animal study suggests that formalin-induced pain and neuropathic pain may have different effects on time perception.
Learn More >Pain and its alleviation are currently a highly studied issue in human health. Research on pain and response to analgesia has evolved to include the effects of genetics, heritability, and sex as important components in both humans and animals. The laboratory mouse is the major animal studied in the field of pain and analgesia. Studying the inbred mouse to understand how genetic heritable traits and/or sex influence pain and analgesia has added valuable information to the complex nature of pain as a human disease. In the context of biomedical research, identifying pain and ensuring its control through analgesia in research animals remains one of the hallmark responsibilities of the research community. Advancements in both human and mouse genomic research shed light not only on the need to understand how both strain and sex affect the mouse pain response but also on how these research achievements can be used to improve the humane use of all research animal species. A better understanding of how strain and sex affect the response to pain may allow researchers to improve study design and thereby the reproducibility of animal research studies. The need to use both sexes, along with an improved understanding of how genetic heritability affects nociception and analgesic sensitivity, remains a key priority for pain researchers working with mice. This review summarizes the current literature on how strain and sex alter the response to pain and analgesia in the modern research mouse, and highlights the importance of both strain and sex selection in pain research.
Learn More >Headaches and pain-related symptoms are the most disabling somatic complaints following mild traumatic brain injury (mTBI). In this study, we reviewed the existing literature examining structural differences in brain morphology and axonal connections, as well as functional differences in brain activity and connectivity associated with pain or post-traumatic headache following mTBI. We searched MEDLINE, EMBASE, PubMed, CINAHL, Cochrane Central Register of Controlled Trials, and Web of Science databases for: 1) TBI, concussion or post-concussion syndrome, 2) pain or headache, and 3) magnetic resonance imaging, functional MRI or diffusion tensor imaging. Inclusion criteria were original studies written in English on participants with mTBI or concussion diagnosis with results reported on pain and/or headache. Exclusion criteria: Review papers, case studies, documentaries and studies related to moderate to severe TBI. Quality was assessed using Newcastle-Ottawa Scale (NOS) quality assessment tool. Results: Nineteen out of 3439 studies satisfied the inclusion and exclusion criteria. Participants with pain-related symptoms had lower cortical thickness in frontal and parietal cortical areas and spinothalamic tract volume. Differences in axonal connectivity were displayed in the corpus callosum, spinothalamic tract, fornix-septohippocampal circuit, and periaqueductal gray. Less activation in pain-related regions during a heat-pain task-based fMRI was reported in participants with PTH. In conclusion, individuals with pain following mTBI display differences in brain structure and brain function suggesting irregularities in descending pain modulatory system. These findings primarily provide information on neuroimaging differences in adults; there is limited research in pediatric populations.
Learn More >Imidazoline receptors historically referred to a family of nonadrenergic binding sites that recognize compounds with an imidazoline moiety, although this has proven to be an oversimplification. For example, none of the proposed endogenous ligands for imidazoline receptors contain an imidazoline moiety but they are diverse in their chemical structure. Three receptor subtypes (I, I, and I) have been proposed and the understanding of each has seen differing progress over the decades. I receptors partially mediate the central hypotensive effects of clonidine-like drugs. Moxonidine and rilmenidine have better therapeutic profiles (fewer side effects) than clonidine as antihypertensive drugs, thought to be due to their higher I/-adrenoceptor selectivity. Newer I receptor agonists such as LNP599 [3-chloro-2-methyl-phenyl)-(4-methyl-4,5-dihydro-3-pyrrol-2-yl)-amine hydrochloride] have little to no activity on -adrenoceptors and demonstrate promising therapeutic potential for hypertension and metabolic syndrome. I receptors associate with several distinct proteins, but the identities of these proteins remain elusive. I receptor agonists have demonstrated various centrally mediated effects including antinociception and neuroprotection. A new I receptor agonist, CR4056 [2-phenyl-6-(1-imidazol-1yl) quinazoline], demonstrated clear analgesic activity in a recently completed phase II clinical trial and holds great promise as a novel I receptor-based first-in-class nonopioid analgesic. The understanding of I receptors is relatively limited. Existing data suggest that I receptors may represent a binding site at the Kir6.2-subtype ATP-sensitive potassium channels in pancreatic -cells and may be involved in insulin secretion. Despite the elusive nature of their molecular identities, recent progress on drug discovery targeting imidazoline receptors (I and I) demonstrates the exciting potential of these compounds to elicit neuroprotection and to treat various disorders such as hypertension, metabolic syndrome, and chronic pain.
Learn More >Pain can interfere with the daily functioning of persons with multiple sclerosis (PwMS). Furthermore, beliefs about pain and activity engagement are reliably associated with persons' experience of chronic pain. This study aimed to explore the extent to which different aspects of PwMS' activity engagement is related to pain-related illness intrusiveness, and whether certain coping and support systems mediate that relationship.
Learn More >In recent years, studying the central mechanism of itch has gained momentum. However, a proper meta-analysis has not been conducted in this domain. In this study, we tried to respond to this need. A systematic search and a meta-analysis were carried out to estimate the central mechanism of itch. The itch matrix comprises the thalamus and the parietal, secondary somatosensory, insular and cingulate cortices. We have shown that the basal ganglia (BG) play an important role in itch reduction. Finally, we explored itch processing in AD patients and observed that the itch matrix in these patients was different. In conclusion, this is the first meta-analysis on the central mechanisms of itch perception and processing. Our study demonstrated that different modalities of itch induction can produce a common pattern of activity in the brain and provided further insights into understanding the underlying nature of itch central perception.
Learn More >MicroRNAs (miRNAs) play crucial roles in the pathogenesis of neuropathic pain. The present study investigated the effects of miR-448 on the progression of neuropathic pain in a rat model of chronic constriction injury (CCI) of the sciatic nerve. Reverse-transcription quantitative polymerase chain reaction was conducted to detect the gene expression. The paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) were used to assess the pain threshold. The protein expression levels of interleukin (IL)-6, IL-1β and tumor necrosis factor-α (TNF-α) were detected by ELISA. The target of miR-448 was predicted by TargetScan software. The Student's t-test or one-way ANOVA were used to identify statistical differences among groups. miR-448 was persistently upregulated in CCI rats, and both mechanical allodynia and thermal hyperalgesia in CCI rats were decreased following miR-448 downregulation. The expression levels of IL-1β, IL-6 and TNF-α were significantly increased in CCI rats compared with controls, and these effects were reversed following treatment with a miR-448 inhibitor. A luciferase reporter assay revealed that sirtuin 1 (SIRT1) was a target gene of miR-448. SIRT1 was found to abrogate the effect of miR-448 on neuropathic pain development. Collectively, the results of the present study revealed that miR-448 promoted neuropathic pain in CCI rats by regulating neuroinflammation via SIRT1. Therefore, SIRT1 may be considered as a novel biomarker for neuropathic pain.
Learn More >Mechanical Allodynia (MA), a frequent chronic pain symptom caused by innocuous stimuli, constitutes an unmet medical need, as treatments using analgesics available today are not always effective and can be associated with important side-effects. A series of 3,5-disubstituted pyridin-2(1H)-ones was designed, synthesized and evaluated in vivo toward a rat model of inflammatory MA. We found that the series rapidly and strongly prevented the development of MA. 3-(2-Bromophenyl)-5-(phenylamino)pyridin-2(1H)-one 69, the most active compound of the series, was also able to quickly reverse neuropathic MA in rats. Next, when 69 was evaluated toward a panel of 50 protein kinases (PK) in order to identify its potential biological target(s), we found that 69 is a p38α MAPK inhibitor, a PK known to contribute to pain hypersensitivity in animal models. 3,5-Disubstituted pyridin-2(1H)-ones thus could represent a novel class of analgesic for the treatment of MA.
Learn More >Opioid Dose and Benzodiazepine Use Among Commercially Insured Individuals on Chronic Opioid Therapy.
To examine morphine milligram equivalent (MME) trends, use of concurrent opioids and benzodiazepines, and opioid-related emergency department (ED) visits or hospitalizations in a national cohort of patients on chronic opioid therapy.
Learn More >Brachial plexus avulsion (BPA) represents the most devastating nerve injury in the upper extremity and is always considered as a sophisticated problem due to its resistance to most standard pain relief medications or neurosurgical interventions. There is also a lack of understanding on the underlying mechanisms. Our study aimed to investigate whether spinal CCL2-CCR2 signaling contributed to the development of neuropathic pain following BPA via modulating glutamate N-methyl-d-aspartate receptor (NMDAR). A rat model of BPA on lower trunk (C8-T1) was established, and the sham- and BPA-operated animals were intrathecally injected with saline, CCR2 inhibitor INCB3344 and NMDAR antagonist DL-AP5 one week postoperatively, the behavioral performance of the treated animals and expressions of CCL2, CCR2, and NR2B in spinal cord sections of each group were examined. It was shown that BPA injury significantly reduced mechanic withdrawal thresholds the next day after surgery until the end of the observation. Both CCL2 and CCR2 expressions increased in BPA rats compared to those in sham rats. CCL2 was mainly localized in astrocytes, and CCR2 was preferably expressed on astrocytes and neurons. Besides, NMDAR subunit NR2B increased in BPA-operated rats, which was reversed in response to CCR2 and NR2B inhibition. However, these inhibitors didn't change the spinal NMDAR level in sham rats. CCR2 and NMDAR inhibition efficiently alleviated mechanical allodynia caused by BPA either at early or late phase of neuropathic pain. Collectively, CCL2-CCR2 axis is associated with mechanical pain after BPA by elevating NMDAR signaling.
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