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Pain is a negative affective state arising from tissue damage or inflammation. Because pain is aversive and its relief is innately rewarding, animals may learn to avoid a context in which pain is experienced and prefer one where pain relief occurs. It is generally accepted that vertebrate animals experience pain; however, there is currently inconclusive evidence that the affective component of pain occurs in any invertebrate. Here, we show that octopuses, the most neurologically complex invertebrates, exhibit cognitive and spontaneous behaviors indicative of affective pain experience. In conditioned place preference assays, octopuses avoided contexts in which pain was experienced, preferred a location in which they experienced relief from pain, and showed no conditioned preference in the absence of pain. Injection site grooming occurred in all animals receiving acetic acid injections, but this was abolished by local anesthesia. Thus, octopuses are likely to experience the affective component of pain.
Learn More >In the peripheral nervous system, ligand-receptor interactions between cells and neurons shape sensory experience, including pain. We set out to identify the potential interactions between sensory neurons and peripheral cell types implicated in disease-associated pain. Using mouse and human RNA sequencing datasets and computational analysis, we created interactome maps between dorsal root ganglion (DRG) sensory neurons and an array of normal cell types, as well as colitis-associated glial cells, rheumatoid arthritis-associated synovial macrophages, and pancreatic tumor tissue. These maps revealed a common correlation between the abundance of heparin-binding EGF-like growth factor (HBEGF) in peripheral cells with that of its receptor EGFR (a member of the ErbB family of receptors) in DRG neurons. Subsequently, we confirmed that increased abundance of HBEGF enhanced nociception in mice, likely acting on DRG neurons through ErbB family receptors. Collectively, these interactomes highlight ligand-receptor interactions that may lead to treatments for disease-associated pain and, furthermore, reflect the complexity of cell-to-neuron signaling in chronic pain states.
Learn More >The microtubule-stabilizing chemotherapy drug paclitaxel (PTX) causes dose-limiting chemotherapy-induced peripheral neuropathy (CIPN), which is often accompanied by pain. Among the multifaceted effects of PTX is an increased expression of sodium channel NaV1.7 in rat and human sensory neurons, enhancing their excitability. However, the mechanisms underlying this increased NaV1.7 expression have not been explored, and the effects of PTX treatment on the dynamics of trafficking and localization of NaV1.7 channels in sensory axons have not been possible to investigate to date. In this study we used a recently developed live-imaging approach that allows visualization of NaV1.7 surface channels and long-distance axonal vesicular transport in sensory neurons to fill this basic knowledge gap. We demonstrate concentration- and time-dependent effects of PTX on vesicular trafficking and membrane localization of NaV1.7 in real-time in sensory axons. Low concentrations of PTX increase surface channel expression and vesicular flux (number of vesicles per axon). By contrast, treatment with a higher concentration of PTX decreases vesicular flux. Interestingly, vesicular velocity is increased for both concentrations of PTX. Treatment with PTX increased levels of endogenous NaV1.7 mRNA and current density in DRG neurons. However, the current produced by transfection of DRG neurons with Halo-tag NaV1.7 was not increased after exposure to PTX. Taken together, this suggests that the increased trafficking and surface localization of Halo-NaV1.7 that we observed by live imaging in tranfected DRG neurons after treatment with PTX might be independent of an increased pool of NaV1.7 channels. After exposure to inflammatory mediators (IM) to mimic the inflammatory condition seen during chemotherapy, both NaV1.7 surface levels and vesicular transport are increased for both low and high concentrations of PTX. Overall, our results show that PTX treatment increases levels of functional endogenous NaV1.7 channels in DRG neurons and enhances trafficking and surface distribution of NaV1.7 in sensory axons, with outcomes that depend on the presence of an inflammatory milieu, providing a mechanistic explanation for increased excitability of primary afferents and pain in CIPN.
Learn More >Some individuals with chronic pain experience improvement in their pain with treatment, whereas others do not. The neurobiological reason is unclear, but an understanding of brain structure and functional patterns may provide insights into pain's responsivity to treatment. In this investigation, we used magnetic resonance imaging (MRI) techniques to determine grey matter density alterations on resting functional connectivity (RFC) strengths between pain responders and nonresponders in patients with complex regional pain syndrome. Brain metrics of pediatric patients at admission to an intensive pain rehabilitative treatment program were evaluated. Pain responders reported significant pain improvement at discharge and/or follow-up whereas nonresponders reported no improvements in pain, increases in pain, or emergence of new pain symptoms. The pain (responder/nonresponder) groups were compared with pain-free healthy controls to examine predictors of pain responder status via brain metrics. Our results show: (1) on admission, pain nonresponders had decreased grey matter density (GMD) within the nucleus accumbens (NAc) and reduced RFC strength between the NAc and the dorsolateral prefrontal cortex vs. responders; (2) Connectivity strength was positively correlated with change in pain intensity from admission to discharge; (3) Compared with pain-free controls, grey matter and RFC differences emerged only among pain nonresponders; and (4) Using a discriminative model, combining GMD and RFC strengths assessed at admission showed the highest prediction estimate (87%) on potential for pain improvement, warranting testing in a de novo sample. Taken together, these results support the idea that treatment responsiveness on pain is underpinned by concurrent brain structure and resting brain activity.
Learn More >Concerns have been raised regarding the misuse of opioids among patients with chronic pain. Although a number of factors may contribute to opioid misuse, research has yet to examine if the hedonic and calming effects that can potentially accompany the use of opioids contribute to opioid misuse. The first objective of this study was to examine the degree to which the hedonic and calming effects of opioids contribute to opioid misuse in patients with chronic pain. We also examined whether the hedonic and calming effects of opioids contribute to patients' daily levels of opioid craving, and whether these associations were moderated by patients' daily levels of pain intensity, catastrophizing, negative affect, or positive affect. In this longitudinal diary study, patients (n = 103) prescribed opioid therapy completed daily diaries for 14 consecutive days. Diaries assessed a host of pain, psychological, and opioid-related variables. The hedonic and calming effects of opioids were not significantly associated with any type of opioid misuse behavior. However, greater hedonic and calming effects were associated with heightened reports of opioid craving (both P's < 0.005). Analyses revealed that these associations were moderated by patients' daily levels of pain intensity, catastrophizing, and negative affect (all P's < 0.001). Results from this study provide valuable new insights into our understanding of factors that may contribute to opioid craving among patients with chronic pain who are prescribed long-term opioid therapy. The implications of our findings for the management of patients with chronic pain are discussed.
Learn More >This narrative review represents an output from the International Association for the Study of Pain's global task force on the use of cannabis, cannabinoids, and cannabis-based medicines (CBM) for pain management, informed by our companion systematic review and meta-analysis of preclinical studies in this area. Our aims in this review are: 1) to describe the value of studying cannabinoids and endogenous cannabinoid (endocannabinoid) system modulators in preclinical/animal models of pain; 2) to discuss both pain-related efficacy and additional pain-relevant effects (adverse and beneficial) of cannabinoids and endocannabinoid system modulators as they pertain to animal models of pathological or injury-related persistent pain; and 3) to identify important directions for future research. In service of these goals, this review a) provides an overview of the endocannabinoid system and the pharmacology of cannabinoids and endocannabinoid system modulators, with specific relevance to animal models of pathological or injury-related persistent pain; b) describes pharmacokinetics of cannabinoids in rodents and humans; and c) highlights differences and discrepancies between preclinical and clinical studies in this area. Preclinical (rodent) models have advanced our understanding of the underlying sites and mechanisms of action of cannabinoids and the endocannabinoid system in suppressing nociceptive signaling and behaviors. We conclude that substantial evidence from animal models supports the contention that cannabinoids and endocannabinoid system modulators hold considerable promise for analgesic drug development, although the challenge of translating this knowledge into clinically useful medicines is not to be underestimated.
Learn More >We report a systematic review and meta-analysis of studies which assessed the antinociceptive efficacy of cannabinoids, cannabis-based medicines, and endocannabinoid system modulators on pain-associated behavioural outcomes in animal models of pathological or injury-related persistent pain. In April 2019, we systematically searched 3 online databases and used crowd science and machine learning to identify studies for inclusion. We calculated a standardised mean difference (SMD) effect size for each comparison and performed a random effects meta-analysis. We assessed the impact of study design characteristics and reporting of mitigations to reduce the risk of bias. We meta-analysed 374 studies in which 171 interventions were assessed for antinociceptive efficacy in rodent models of pathological or injury-related pain. Most experiments were conducted in male animals (86 %). Antinociceptive efficacy was most frequently measured by attenuation of hypersensitivity to evoked limb withdrawal. Selective CB1, CB2, non-selective cannabinoid receptor agonists (including delta-9-tetrahydrocannabinol; THC), and PPAR-alpha agonists (predominantly palmitoylethanolamide; PEA) significantly attenuated pain-associated behaviours in a broad range of inflammatory and neuropathic pain models. Fatty acid amide hydrolase (FAAH) inhibitors, monoacylglycerol lipase (MGL) inhibitors and cannabidiol (CBD) significantly attenuated pain-associated behaviours in neuropathic pain models but yielded mixed results in inflammatory pain models. The reporting of criteria to reduce the risk of bias was low, therefore the studies have an unclear risk of bias. The value of future studies could be enhanced by improving the reporting of methodological criteria, the clinical relevance of the models and behavioural assessments. Notwithstanding, the evidence supports the hypothesis of cannabinoid-induced analgesia.
Learn More >Understanding the sensory mechanisms innervating the bladder is paramount to developing efficacious treatments for chronic bladder hypersensitivity conditions. The contribution of Mas-gene-related G protein-coupled receptors (Mrgpr) to bladder signalling is currently unknown. Using male and female mice, we show with single-cell RT-PCR that sub-populations of dorsal root ganglion (DRG) neurons innervating the mouse bladder express (14%) and either individually or in combination, with high levels of co-expression with (81-89%). Calcium imaging studies demonstrated MrgprA3 and MrgprC11 agonists (chloroquine, BAM8-22 and neuropeptide FF) activated sub-populations of bladder-innervating DRG neurons, showing functional evidence of co-expression between MrgprA3, MrgprC11 and TRPV1. In bladder-nerve preparations chloroquine, BAM8-22 and neuropeptide FF all evoked mechanical hypersensitivity in sub-populations (20-41%) of bladder afferents. These effects were absent in recordings from mice. whole-cell patch clamp recordings showed that application of an MrgprA3/C11 agonist cocktail induced neuronal hyper-excitability in 44% of bladder-innervating DRG neurons. Finally, instillation of an MrgprA3/C11 agonist cocktail into the bladder of wild-type mice induced a significant activation of dorsal horn neurons within the lumbosacral spinal cord, as quantified by pERK-immunoreactivity. This MrgprA3/C11 agonist-induced activation was particularly apparent within the superficial dorsal horn and the sacral parasympathetic nuclei of wild-type, but not mice. This study demonstrates, for the first time, functional expression of MrgprA3 and MrgprC11 in bladder afferents. Activation of these receptors triggers hypersensitivity to distension, a critically valuable factor for therapeutic target development.Determining how bladder afferents become sensitized is the first step in finding effective treatments for common urological disorders such as overactive bladder and interstitial cystitis/bladder pain syndrome. Here we show that two of the key receptors, MrgprA3 and MrgprC11, that mediate itch from the skin are also expressed on afferents innervating the bladder. Activation of these receptors results in sensitization of bladder afferents, resulting in sensory signals being sent into the spinal cord that prematurely indicate bladder fullness. Targeting bladder afferents expressing MrgprA3 or MrgprC11 and preventing their sensitisation may provide a novel approach for treating overactive bladder and interstitial cystitis/bladder pain syndrome.
Learn More >A recent study by Lee et al. showed that a dynamic functional connectivity pattern induced by tonic experimental pain might serve as a biomarker of chronic pain. The study illustrates key topics in translational neuroscience: the differentiation of biomarker functions, the multimodal integration of biomarkers, and the functional relevance of dynamic connectivity.
Learn More >Early life experience can cause long-term alterations in the nociceptive processes underlying chronic pain, but the consequences of early life arthritic joint inflammation upon the sensory innervation of the joint is not known. Here, we measure pain sensitivity and sensory innervation in a young, juvenile and adult rodent model of arthritic joints and test the consequences of joint inflammation in young animals upon adult arthritic pain and joint innervation.
Learn More >Peripheral neuropathy is one of the most common complications of both type 1 and type 2 diabetes. Up to half of patients with diabetes develop neuropathy during the course of their disease, which is accompanied by neuropathic pain in to 30-40% of cases. Peripheral nerve injury in diabetes can manifest as progressive distal symmetric polyneuropathy, autonomic neuropathy, radiculo-plexopathies, and mononeuropathies. The most common diabetic neuropathy is distal symmetric polyneuropathy, which we will refer to as DN, with its characteristic glove and stocking like presentation of distal sensory or motor function loss. DN or its painful counterpart, painful DN, are associated with increased mortality and morbidity; thus, early recognition and preventive measures are essential. Nevertheless, it is not easy to diagnose DN or painful DN, particularly in patients with early and mild neuropathy, and there is currently no single established diagnostic gold standard. The most common diagnostic approach in research is a hierarchical system, which combines symptoms, signs, and a series of confirmatory tests. The general lack of long-term prospective studies has limited the evaluation of the sensitivity and specificity of new morphometric and neurophysiological techniques. Thus, the best paradigm for screening DN and painful DN both in research and in clinical practice remains uncertain. Herein, we review the diagnostic challenges from both clinical and research perspectives and their implications for managing patients with DN. There is no established DN treatment, apart from improved glycemic control, which is more effective in type 1 than in type 2 diabetes, and only symptomatic management is available for painful DN. Currently, less than one third of painful DN patients derive sufficient pain relief with existing pharmacotherapies. A more precise and distinct sensory profile from patients with DN and painful DN may help identify responsive patients to one treatment versus another. Detailed sensory profiles will lead to tailored treatment for patient subgroups with painful DN by matching to novel or established DN pathomechanisms and also for improved clinical trials stratification. Large randomized clinical trials are needed to identify the interventions, i.e. pharmacological, physical, cognitive, educational, etc, which leads to the best therapeutic outcomes.
Learn More >The opioid crisis creates challenges for cancer pain management. Acupuncture confers clinical benefits for chronic nonmalignant pain, but its effectiveness in cancer survivors remains uncertain.
Learn More >Although several evidence-based strategies for managing children's vaccination pain exist, many parents report being unaware of them. Knowledge translation (KT) tools present evidence-based information in plain language.
Learn More >Osteopathic manipulative treatment (OMT) is frequently offered to people with nonspecific low back pain (LBP) but never compared with sham OMT for reducing LBP-specific activity limitations.
Learn More >Patients suffering from fibromyalgia syndrome (FMS) are heterogenous. They often present with sensory abnormalities and comorbidities.
Learn More >Despite application of multimodal pain management strategies, patients undergoing spinal fusion surgery frequently report severe postoperative pain. Methadone and ketamine, which are N-methyl-d-aspartate receptor antagonists, have been documented to facilitate postoperative pain control. This study therefore tested the primary hypothesis that patients recovering from spinal fusion surgery who are given ketamine and methadone use less hydromorphone on the first postoperative day than those give methadone alone.
Learn More >People with Parkinson's disease (PD) may live for multiple decades after diagnosis. Ensuring that effective healthcare provision is received across the range of symptoms experienced is vital to the individual's wellbeing and quality of life. As well as the hallmark motor symptoms, PD patients may also suffer from non-motor symptoms including persistent pain. This type of pain (lasting more than 3 months) is inconsistently described and poorly understood, resulting in limited treatment options. Evidence-based pain remedies are coming to the fore but therapeutic strategies that offer an improved analgesic profile remain an unmet clinical need. Since the ability to establish a link between the neurodegenerative changes that underlie PD and those that underlie maladaptive pain processing leading to persistent pain could illuminate mechanisms or risk factors of disease initiation, progression and maintenance, we evaluated the latest research literature seeking to identify causal factors underlying persistent pain in PD through experimental quantification. The majority of previous studies aimed to identify neurobiological alterations that could provide a biomarker for pain/pain phenotype, in PD cohorts. However heterogeneity of patient cohorts, result outcomes and methodology between human psychophysics studies overwhelmingly leads to inconclusive and equivocal evidence. Here we discuss refinement of pain-PD paradigms in order that future studies may enhance confidence in the validity of observed effect sizes while also aiding comparability through standardisation. Encouragingly, as the field moves towards cross-study comparison of data in order to more reliably reveal mechanisms underlying dysfunctional pain processing, the potential for better-targeted treatment and management is high.
Learn More >Racial minorities are disproportionally affected by pain. Compared to non-Hispanic Whites (NHWs), non-Hispanic Blacks (NHBs) report higher pain intensity, greater pain-related disability, and higher levels of mood disturbance. While risk factors contribute to these disparities, little is known regarding how sources of resilience influence these differences, despite the growing body of research supporting the protective role of resilience in pain and disability among older adults with chronic pain. The current study examined the association between psychological resilience and pain, and the moderating role of race across these relationships in older adults with chronic low back pain (cLBP).
Learn More >The bidirectional relationship between pain and working memory (WM) deficits is well-documented but poorly understood. Pain catastrophizing – exaggerated, negative cognitive and emotional responses toward pain – may contribute to WM deficits by occupying finite, shared cognitive resources. The present study assessed the role of pain catastrophizing as both a state-level process and trait-level disposition in the link between acute pain and WM. Healthy, young adults were randomized to an experimentally-induced ischemic pain or control task, during which they completed verbal and non-verbal WM tests. Participants also completed measures of state- and trait-level pain catastrophizing. Simple mediation analyses indicated that participants in the pain group (vs. control) engaged in more state-level catastrophizing about pain, which led to worse verbal and non-verbal WM. Moderated mediation analyses indicated that the indirect (mediation) effect of state-level pain catastrophizing was moderated by trait-level pain catastrophizing for both verbal and non-verbal WM. Participants in the pain group who reported a greater trait-level tendency to catastrophize about pain experienced greater state-level catastrophizing about pain during the ischemic task, which led to worse verbal and non-verbal WM performance. These results provide evidence for pain catastrophizing as an important mechanism and moderating factor of WM deficits in acute pain. Future research should replicate these results in chronic pain samples, investigate other potential mechanisms (e.g., sleep disturbances), and determine if interventions that target pain catastrophizing directly can ameliorate cognitive deficits in people with pain. PERSPECTIVE: This article presents a laboratory study examining the relationships among pain, pain catastrophizing, and working memory in healthy participants. The results shed new light on these relationships and raise the possibility that interventions that reduce catastrophizing may lead to improved cognitive function among people with pain.
Learn More >Persistent pain is common in HIV patients and breast cancer (BC) survivors. The aim of this study was to compare two patient groups with neuropathic pain (NP) regarding several psychological variables and Health-related Quality of Life. Although, treatment of pain is always planned individually, the knowledge of the differences and similarities between the patient groups may help us to understand more precisely the targets of the interventions for pain.
Learn More >Inflammatory Bowel Disease (IBD) is a life-long disorder that often begins between the ages of 15 and 30. Anecdotal reports suggest cannabinoids may be an effective treatment. This study sought to determine whether home cage wheel running is an effective method to assess IBD, and whether THC, the primary psychoactive compound in cannabis, can restore wheel running depressed by IBD. Adolescent and adult female Sprague-Dawley rats were individually housed in a cage with a running wheel. Rats were injected with trinitrobenzene sulphonic acid (TNBS) into the rectum to induce IBD-like symptoms. One day later, both vehicle and TNBS treated rats were injected with a low dose of THC (0.32 mg/kg, s.c.) or vehicle. Administration of TNBS depressed wheel running in adolescent and adult rats. No antinociceptive effect of THC was evident when administered 1 day after TNBS. In fact, administration of THC prolonged TNBS-induced depression of wheel running for over 5 days in adolescent and adult rats. These results show that home cage wheel running is affected by TNBS-induced IBD, making it a useful tool to evaluate the behavioral consequences of IBD, and that administration of THC, instead of producing antinociception, exacerbates TNBS-induced IBD. Perspective This article advances research on inflammatory bowel disease in two important ways: 1) Home cage wheel running is a new and sensitive tool to assess the behavioral consequences of IBD in adolescent and adult rats; and 2) Administration of the cannabinoid THC exacerbates the negative behavioral effects of IBD.
Learn More >While patient perceptions of burden to caregivers is of recognized clinical significance among people with chronic pain, perceived burden to treating physicians has not been studied. This study examined how people with chronic pain perceived levels of medical evidence (low vs high) and pain severity (4,6,8/10) to influence physician burden and how burden then mediated expected clinical judgments. 476 people with chronic pain read vignettes describing a hypothetical patient with varying levels of medical evidence and pain severity from the perspective of a treating physician, rated the burden that patient care would pose, and made a range of clinical judgments. The effect of pain severity on clinical judgments was expected to interact with medical evidence and be conditionally mediated by burden. Although no associations with burden were found for the pain severity x medical evidence interaction or for pain severity alone, low levels of supporting medical evidence yielded higher burden ratings. Burden significantly mediated medical evidence effects on judgments of symptom credibility, clinical improvement, and psychosocial dysfunction. Results indicate that perceived physician burden negatively influenced judgments of patients with chronic pain, beyond the direct effects of medical evidence. Implications are discussed for clinical practice, as well as future research. Perspective People with chronic pain expect physicians to view the care of patients without supporting medical evidence as burdensome. Higher burden is associated with less symptom credibility, more psychosocial dysfunction, and less treatment benefit. Perceived physician burden appears to impact how patients approach treatment, with potentially adverse implications for clinical practice.
Learn More >An opioid epidemic is spreading in North America with millions of opioid overdoses annually. Opioid drugs, like fentanyl, target the mu opioid receptor system and induce potentially lethal respiratory depression. The challenge in opioid research is to find a safe pain therapy with analgesic properties but no respiratory depression. Current discoveries are limited by lack of amenable animal models to screen candidate drugs. Zebrafish () is an emerging animal model with high reproduction and fast development, which shares remarkable similarity in their physiology and genome to mammals. However, it is unknown whether zebrafish possesses similar opioid system, respiratory and analgesic responses to opioids than mammals. In freely-behaving larval zebrafish, fentanyl depresses the rate of respiratory mandible movements and induces analgesia, effects reversed by mu-opioid receptor antagonists. Zebrafish presents evolutionary conserved mechanisms of action of opioid drugs, also found in mammals, and constitute amenable models for phenotype-based drug discovery.
Learn More >Common approaches to studying mechanisms of chronic pain and sensory changes in pre-clinical animal models involve measurement of acute, reflexive withdrawal responses evoked by noxious stimuli. These methods typically do not capture more subtle changes in sensory processing nor report on the consequent behavioral changes. In addition, data collection and analysis protocols are often labour-intensive and require direct investigator interactions, potentially introducing bias. In this study, we develop and characterize a low-cost, easily assembled behavioral assay that yields self-reported temperature preference from mice that is responsive to peripheral sensitization. This system uses a partially automated and freely available analysis pipeline to streamline the data collection process and enable objective analysis. We found that after intraplantar administration of the TrpV1 agonist, capsaicin, mice preferred to stay in cooler temperatures than saline injected mice. We further observed that gabapentin, a non-opioid analgesic commonly prescribed to treat chronic pain, reversed this aversion to higher temperatures. In contrast, optogenetic activation of the central terminals of TrpV1 primary afferents via spinal light delivery did not induce a similar change in thermal preference, indicating a possible role for peripheral nociceptor activity in the modulation of temperature preference. We conclude that this easily produced and robust sensory assay provides an alternative approach to investigate the contribution of central and peripheral mechanisms of sensory processing that does not rely on reflexive responses evoked by noxious stimuli.
Learn More >Activation of microglia and astrocytes secondary to inflammatory processes contributes to the development and perpetuation of pain with a neuropathic phenotype. This pain state presents as a chronic debilitating condition and affects a large population of patients with conditions like rheumatoid arthritis and diabetes, or after surgery, trauma, or chemotherapy. Here, we review the regulation of lipid rafts in glial cells and the role they play as a key component of neuroinflammatory sensitization of central pain signaling pathways. In this context, we introduce the concept of an inflammaraft (i-raft), enlarged lipid rafts harboring activated receptors and adaptor molecules and serving as an organizing platform to initiate inflammatory signaling and the cellular response. Characteristics of the inflammaraft include increased relative abundance of lipid rafts in inflammatory cells, increased content of cholesterol per raft, and increased levels of inflammatory receptors, such as toll-like receptor (TLR)4, adaptor molecules, ion channels, and enzymes in lipid rafts. This inflammaraft motif serves an important role in the membrane assembly of protein complexes, for example, TLR4 dimerization. Operating within this framework, we demonstrate the involvement of inflammatory receptors, redox molecules, and ion channels in the inflammaraft formation and the regulation of cholesterol and sphingolipid metabolism in the inflammaraft maintenance and disruption. Strategies for targeting inflammarafts, without affecting the integrity of lipid rafts in noninflammatory cells, may lead to developing novel therapies for neuropathic pain states and other neuroinflammatory conditions.
Learn More >Animal models of pain consist of modeling a pain-like state and measuring the consequent behavior. The first animal models of neuropathic pain (NP) were developed in rodents with a total lesion of the sciatic nerve. Later, other models targeting central or peripheral branches of nerves were developed to identify novel mechanisms that contribute to persistent pain conditions in NP. Objective assessment of pain in these different animal models represents a significant challenge for pre-clinical research. Multiple behavioral approaches are used to investigate and to validate pain phenotypes including withdrawal reflex to evoked stimuli, vocalizations, spontaneous pain, but also emotional and affective behaviors. Furthermore, animal models were very useful in investigating the mechanisms of NP. This review will focus on a detailed description of rodent models of NP and provide an overview of the assessment of the sensory and emotional components of pain. A detailed inventory will be made to examine spinal mechanisms involved in NP-induced hyperexcitability and underlying the current pharmacological approaches used in clinics with the possibility to present new avenues for future treatment. The success of pre-clinical studies in this area of research depends on the choice of the relevant model and the appropriate test based on the objectives of the study.
Learn More >Neuropathic pain negatively affects quality of life among people living with HIV (PLWH). This study examined the feasibility of conducting a full-scale randomized-controlled trial of online acceptance and commitment therapy ("ACT OPEN") for neuropathic pain in PLWH.
Learn More >Cannabis has been used for centuries for its medicinal properties. Given the dangerous and unpleasant side effects of existing analgesics, the chemical constituents of Cannabis have garnered significant interest for their antinociceptive, anti-inflammatory and neuroprotective effects. To date, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) remain the two most widely studied constituents of Cannabis in animals. These studies have led to formulations of THC and CBD for human use; however, chronic pain patients also use different strains of Cannabis (sativa, indica and ruderalis) to alleviate their pain. These strains contain major cannabinoids, such as THC and CBD, but they also contain a wide variety of cannabinoid and noncannabinoid constituents. Although the analgesic effects of Cannabis are attributed to major cannabinoids, evidence indicates other constituents such as minor cannabinoids, terpenes and flavonoids also produce antinociception against animal models of acute, inflammatory, neuropathic, muscle and orofacial pain. In some cases, these constituents produce antinociception that is equivalent or greater compared to that produced by traditional analgesics. Thus, a better understanding of the extent to which these constituents produce antinociception alone in animals is necessary. The purposes of this review are to (1) introduce the different minor cannabinoids, terpenes, and flavonoids found in Cannabis and (2) discuss evidence of their antinociceptive properties in animals.
Learn More >Primary nociceptors are a heterogeneous class of peripheral somatosensory neurons, responsible for detecting noxious, pruriceptive, and thermal stimuli. These neurons are further divided into several molecularly defined subtypes that correlate with their functional sensory modalities and morphological features. During development, all nociceptors arise from a common pool of embryonic precursors, and then segregate progressively into their mature specialized phenotypes. In this review, we summarize the intrinsic transcriptional programs and extrinsic trophic factor signaling mechanisms that interact to control nociceptor diversification. We also discuss how recent transcriptome profiling studies have significantly advanced the field of sensory neuron development.
Learn More >Monoclonal antibodies targeting CGRP or its receptor (anti-CGRP mAbs) are proven to be effective treatments in migraine prevention. Real-world evidence studies assessing their efficacy are scarce.
Learn More >The presence or absence of clearly defined symptoms and underlying pathophysiology may be a crucial variable related to variability in wellbeing and stigmatization in individuals with chronic pain (ICPs). In the context of pain, absence of clearly defined symptoms and pathophysiology deviates from the widely endorsed biomedical model and as such, may lead to stigmatization, which in turn could be related to ICPs' wellbeing.
Learn More >Painful distal symmetrical polyneuropathy (DPN) is a frequent complication of type-2 diabetes mellitus (T2DM) that commonly presents as neuropathic pain and loss of skin nerve fibers. However, there are limited therapies to effectively treat DPN and many of the current animal models of T2DM-induced DPN do not appear to mirror the human disease. Thus, we validated a DPN mouse model induced by a cafeteria-style diet plus low-doses of streptozotocin (STZ). Female C57BL/6J mice were fed either standard (STD) diet or obesogenic cafeteria (CAF) diet for 32 weeks, starting at 8 weeks old. Eight weeks after starting diets, CAF or STD mice received either four low-doses of STZ or vehicle. Changes in body weight, blood glucose and insulin levels, as well as oral glucose- and insulin-tolerance tests (OGTT and ITT) were determined. The development of mechanical hypersensitivity of the hindpaws was determined using von Frey filaments. Moreover, the effect of the most common neuropathic pain drugs was evaluated on T2DM-induced mechanical allodynia. Finally, the density of PGP -9.5 (a pan-neuronal marker) axons in the from the hindpaw glabrous skin was quantified. At 22-24 weeks after STZ injections, CAF + STZ mice had significantly higher glucose and insulin levels compared to CAF + VEH, STD + STZ, and STD + VEH mice, and developed glucose tolerance and insulin resistance. Skin mechanical sensitivity was detected as early as 12 weeks post-STZ injections and it was significantly attenuated by intraperitoneal acute treatment with amitriptyline, gabapentin, tramadol, duloxetine, or carbamazepine but not by diclofenac. The density of PGP-9.5 nerve fibers was reduced in CAF + STZ mice compared to other groups. This reverse translational study provides a painful DPN mouse model which may help in developing a better understanding of the factors that generate and maintain neuropathic pain and denervation of skin under T2DM and to identify mechanism-based new treatments.
Learn More >Medication overuse headache (MOH)is a disabling problem worldwide with areas of controversy regarding its cause. This article reviews the recent ideas regarding the development of this disorder and its effective management.
Learn More >Our previous study showed the intrinsic ability of descending noradrenergic neurons projecting from the locus coeruleus to the spinal dorsal horn (SDH) to suppress itch-related behaviors. Noradrenaline and α-adrenaline receptor (α-AR) agonist increase inhibitory synaptic inputs onto SDH interneurons expressing gastrin-releasing peptide receptors, which are essential for itch transmission. However, the contribution of α-ARs expressed in SDH inhibitory interneurons to itch-related behavior remains to be determined. In this study, RNAscope in situ hybridization revealed that Adra1a mRNA is expressed in SDH inhibitory interneurons that are positive for Slc32a1 mRNA (known as vesicular GABA transporter). Mice with conditional knock-out of α-ARs in inhibitory interneurons (Vgat-Cre;Adra1a mice) exhibited an increase in scratching behavior when induced by an intradermal injection of chloroquine, but not compound 48/80, which are known as models of histamine-independent and dependent itch, respectively. Furthermore, knockout of inhibitory neuronal α-ARs in the SDH using the CRISPR-Cas9 system also increased the scratching behavior elicited by chloroquine but not compound 48/80. Our findings demonstrated for the first time that α-ARs in SDH inhibitory interneurons contribute to the regulation of itch signaling with preference for histamine-independent itch.
Learn More >Cisplatin plays an essential role in the treatment of various cancers. Cisplatin exhibits high efficacy, but it often leads to severe neurotoxic side effects, such as chemotherapy-induced polyneuropathy (CIPN). The pathophysiology of CIPN is not fully understood. There is increasing evidence for damage to satellite glial cells (SGC) and dorsal root ganglion (DRG) neurons. We investigated the influence of cisplatin on the function of SGCs and the direct influence on DRGs. Satellite glial cells were isolated from DRG and exposed to 0.1, 1, 10, or 100 μM cisplatin for 2 h, 4 h, and 24 h. Using immunocytochemical staining and Western blot analysis, the expression of the glial fibrillary acid protein (GFAP), reactive oxygen species (ROS), and inward rectifier potassium channel 4.1 (K) was determined. An increase in the immune reactivity (IR) and protein levels of GFAP and ROS was measured, and a reduction of IR and protein level of K was detected. A decrease in these channels' current density was observed using the whole-cell patch-clamp recording. The interleukin-6 (IL-6) and tumor necrosis factor α (TNFα) release of SGCs increased after cisplatin exposure as measured using ELISA, and interleukin-1β (IL-1β) decreased. The SGC-secreted factors in the supernatant after cisplatin treatment led to a modulation of cultured DRG neurons' excitability. Taken together, the modulation and function of different SGC proteins could be linked to a direct impact of cisplatin. Further, SGC-secreted factors influenced the excitability of sensory neurons. Overall, SGCs could be a potential target in preventing and treating chemotherapy-induced neuropathic pain.
Learn More >Several -derived venom peptides are promising lead compounds for the management of neuropathic pain, with α-conotoxins being of particular interest. Modification of the interlocked disulfide framework of α-conotoxin Vc1.1 has been achieved using on-resin alkyne metathesis. Although introduction of a metabolically stable alkyne motif significantly disrupts backbone topography, the structural modification generates a potent and selective GABA receptor agonist that inhibits Ca2.2 channels and exhibits dose-dependent reversal of mechanical allodynia in a behavioral rat model of neuropathic pain. The findings herein support the hypothesis that analgesia can be achieved via activation of GABARs expressed in dorsal root ganglion (DRG) sensory neurons.
Learn More >To determine the prevalence and breakdown of pain symptoms among patients with coronavirus disease 2019 (COVID-19) infection admitted for nonpain symptoms and the association between the presence of pain and intensive care unit (ICU) admission and death.
Learn More >The COVID-19 pandemic has affected the entire world and catapulted the United States into one of the deepest recessions in history. While this pandemic rages, the opioid crisis worsens. During this period, the pandemic has resulted in the decimation of most conventional medical services, including those of chronic pain management, with the exception of virtual care and telehealth. Many chronic pain patients have been impacted in numerous ways, with increases in cardiovascular disease, mental health problems, cognitive dysfunction, and early death. The epidemic has also resulted in severe economic and physiological consequences for providers. Drug deaths in America, which fell for the first time in 25 years in 2018, rose to record numbers in 2019 and are continuing to climb, worsened by the coronavirus pandemic. The opioid epidemic was already resurfacing with a 5% increase in overall deaths from 2018; however, the preliminary data show that prescription opioid deaths continued to decline, while at the same time deaths due to fentanyl, methamphetamine, and cocaine climbed, with some reductions in heroin deaths. The health tracker data also showed that along with an almost 88% decline in elective surgeries, pain-related prescriptions declined 15.1%. Despite increases in telehealth, outpatient services declined and only began returning towards normal at an extremely slow pace, accompanied by reduced productivity and increased practice costs. This review, therefore, emphasizes the devastating consequences of concurrent epidemics on chronic pain management and the need to develop best practice efforts to preserve access to treatment for chronic pain.
Learn More >Migraineurs experience increased oxidative stress which drives the initiation and maintenance of migraine-related pain in animal models and, by extension, migraine in humans. Oxidative stress augments calcitonin gene-related peptide (CGRP) levels, a mediator of migraine pain. Insulin-like growth factor-1 (IGF-1), a neuroprotective growth factor, reduces susceptibility to spreading depression, a preclinical model of migraine, in cultured brain slices by blocking oxidative stress and neuroinflammation from microglia. Similarly, nasal delivery of IGF-1 inhibits spreading depression in vivo. After recurrent cortical spreading depression, nasal administration of IGF-1 also significantly reduces trigeminal ganglion oxidative stress and CGRP levels as well as trigeminocervical c-Fos activation. Here, we probed for the impact of nasal IGF-1 pretreatment on trigeminal system activation using a second well-established preclinical model of migraine, systemic nitroglycerin injection. Adult male rats were treated with one of three doses of IGF-1 (37.5, 75 or 150 μg) and the optimal dose found in males was subsequently used for treatment of female rats. One day later, animals received an intraperitoneal injection of nitroglycerin. Measurements taken two hours later after nitroglycerin alone showed increased surrogate markers of trigeminal activation – oxidative stress and CGRP in the trigeminal ganglion and c-Fos in the trigeminocervical complex compared to vehicle control. These effects were significantly reduced at all doses of IGF-1 for trigeminal ganglion metrics of oxidative stress and CGRP and only at the lowest dose in both males and females for c-Fos. The latter inverted U-shaped or hormetic response is seen in enzyme-targeting drugs. While the specific mechanisms remain to be explored, our data here supports the ability of IGF-1 to preserve mitochondrial and antioxidant pathway homeostasis as means to prevent nociceptive activation in the trigeminal system produced by an experimental migraine model.
Learn More >Anti-inflammatory and antinociceptive effects of the selective cannabinoid CB receptor agonist ABK5.
Cannabinoid receptors are a potential target for anti-inflammatory and pain therapeutics. There are two subtypes, CB and CB, and Δ-tetrahydrocannabinol activates both of them, providing an analgesic effect but also psychoactive side effects. The psychoactive side effects are considered to be caused by activation of CB, but not CB. ABK5 is a CB subtype selective agonist that has a very different structure from known cannabinoid receptor agonists. Here, we report anti-inflammatory effects of ABK5 using the T-cell line Jurkat cells, and antinociceptive effect in an inflammatory pain model in rats. Production of the cytokines IL-2 and TNF-α was measured in stimulated Jurkat cells and MOLT-4 cells, and CXCL12-mediated chemotaxis of Jurkat cells was evaluated by a transwell migration assay. Anti-inflammatory and antinociceptive effects of ABK5 were also evaluated in a hindpaw CFA model in rats. ABK5 significantly decreased production of IL-2 and TNF-α measured as both mRNA and protein levels, and reduced chemotaxis towards CXCL12. It also attenuated edema and increased mechanical threshold in the hindpaw of CFA-treated rats. These results suggest that ABK5 is a good lead compound for the development of potential anti-inflammatory and analgesic agents.
Learn More >Pain is a major comorbidity of sickle cell disease (SCD). Patients with SCD may suffer from both acute and chronic pain. Acute pain is caused by recurrent and unpredictable episodes of vaso-occlusive crises (VOC), whereas the exact etiology of chronic pain is still unknown. Opioids are the mainstay for pain treatment, but the opioid epidemic has significantly altered access to prescription opioids and has brought concerns over their long-term use into the forefront, which have negatively impacted the treatment of sickle pain. Opioids remain potent analgesics but growing opioid-phobia has led to the realization of an unmet need to develop non-opioid therapies that can provide relief for severe sickle pain. This realization has contributed to the approval of 3 different drugs by the Food and Drug Administration (FDA) for the treatment of SCD, particularly to reduce VOC and/or have an impact on the pathobiology of SCD. In this review, we outline the challenges and need for validation of side-effects of opioids and provide an update on the development of mechanism-based translational therapies, specifically targeting pain in SCD.
Learn More >Acute or chronic stress may trigger or aggravate symptoms of fibromyalgia (FM). We aimed to evaluate the physical and mental health of fibromyalgia patients during the COVID 19 outbreak and identify protective/risk factors.
Learn More >Our objective is to explore whether blood-cerebrospinal fluid (CSF) barrier biomarkers differ in episodic migraine (EM) or chronic migraine (CM) from controls.
Learn More >Pain catastrophizing and pain acceptance are psychological factors that have been shown to be associated with pain-related outcomes and predict multidisciplinary pain treatment outcomes. However, they are rarely examined in the same study. This study aimed to: (a) assess the independent roles of pain catastrophizing and pain acceptance as predictors of pain intensity, pain interference, and depression; and (b) evaluate the potential moderating role of pain acceptance on the association between pain catastrophizing and both pain and function.
Learn More >A scarcity of studies on the role of resilience resources (RRs) and vulnerability risk (VR) in children and adolescents with primary headache hampers the development of a risk-resilience model for pediatric headaches.
Learn More >Cancer is the second leading cause of death globally. Up to 86% of advanced cancer patients experience significant pain, while 10-20% live in chronic pain. Besides, increasing prescription of opioids resulted in 33,000 deaths in the US in 2015. Both reduce patients' functional status and quality of life. While cancer survival rates are increasing, therapeutic options for chronic opioid refractory pain are still limited. Esketamine is the s-enantiomer of ketamine, with superior analgesic effect and less psychotomimetic side effects. Intranasal esketamine was approved by the FDA for treatment-resistant depression. However, its use in chronic cancer pain has never been tested. Therefore, we propose a phase II, randomized, placebo-controlled trial to evaluate the efficacy and safety of intranasal esketamine in chronic opioid refractory cancer pain. We will recruit 120 subjects with chronic opioid refractory pain, defined as pain lasting more than 3 months despite optimal therapy with high dose opioids (>60 mg morphine equivalent dose/day) and optimal adjuvant therapy. Subjects will be randomized into two groups: intranasal esketamine (56mg) and placebo. Treatment will be administered twice a week for four consecutive weeks. The primary outcome is defined as reduction in the Numeric Pain Rating Scale (NPRS) after first application. Secondary outcomes include NPRS reduction after four weeks, the number of daily morphine rescue doses, functional status and satisfaction, and depression. This study may extend therapeutic options in patients with chronic pain, thus improving their quality of life and reducing opioid use. Clinical Trials.gov, NCT04666623. Registered on 14 December 2020.
Learn More >Acute pancreatitis (AP) and recurring AP are serious health care problems causing excruciating pain and potentially lethal outcomes due to sepsis. The validated caerulein- (CAE) induced mouse model of acute/recurring AP produces secondary persistent hypersensitivity and anxiety-like behavioral changes for study.
Learn More >Emotions are involved in the identification of safety cues in the environment, and are also related to social interaction through recognition of emotional facial expressions. Heart rate variability (HRV) can be an indicator of the adaptive response of the autonomic nervous system to stressful conditions, including pain. This study aimed to investigate the emotional processing in a sample of patients with chronic musculoskeletal by measuring the resting-state HRV and the ability to recognize facial emotion expressions.
Learn More >The present study aimed to determine whether specific cognitive domains part of the Montreal Cognitive Assessment (MoCA) are significantly lower in community-dwelling older adults with chronic pain compared with older adults without pain and whether these domains would be associated with self-reported pain, disability, and somatosensory function.
Learn More >The identification of relevant and valid biomarkers to distinguish patients with non-specific chronic low back pain (NSCLBP) from an asymptomatic population in terms of musculoskeletal factors could contribute to patient follow-up and to evaluate therapeutic strategies. Several parameters related to movement and/or muscular activity impairments have been proposed in the literature in that respect. In this article, we propose a systematic and comprehensive review of these parameters (i.e. potential biomarkers) and related measurement properties. This systematic review (PROSPERO registration number: CRD42020144877) was conducted in Medline, Embase, and Web of Knowledge databases until July 2019. In the included studies, all movements or muscular activity parameters having demonstrated at least a moderate level of construct validity were defined as biomarkers, and their measurement properties were assessed. In total, 92 studies were included. This allowed to identify 121 movement and 150 muscular activity biomarkers. An extensive measurement properties assessment was found in 31 movement and 14 muscular activity biomarkers. On the whole, these biomarkers support the primary biomechanical concepts proposed for low back pain. However, a consensus concerning a robust and standardised biomechanical approach to assess low back pain is needed.
Learn More >Pain, fatigue, and depression commonly co-occur as a symptom cluster in pathological inflammatory states. Psychosocial stressors such as loneliness may lead to similar states through shared mechanisms. We investigated the association of loneliness with pain, fatigue, and depression in older adults. Using Health and Retirement Study data ( = 11,766), we measured cross-sectional prevalence of frequent, moderate to severe pain; severe fatigue; depressive symptoms; and co-occurrence of symptoms surpassing threshold levels (i.e., symptom cluster). Logistic regression models evaluated associations with loneliness. Pain, fatigue, and depression were reported in 19.2%, 20.0%, and 15.3% of the total sample, respectively. The symptom cluster was seen in 4.9% overall; prevalence in lonely individuals was significantly increased (11.6% vs. 2.3%, < .0001). After adjusting for demographic variables, loneliness associated with the symptom cluster (adjusted OR = 3.39, 95% CI = 2.91, 3.95) and each symptom (pain adjusted OR = 1.61, 95% CI = 1.48, 1.76; fatigue adjusted OR = 2.02, 95% CI = 1.85, 2.20; depression adjusted OR = 4.34, 95% CI = 3.93, 4.79). Loneliness strongly associates with the symptom cluster of pain, fatigue, and depression. Further research should examine causal relationships and investigate whether interventions targeting loneliness mitigate pain, fatigue, and depression.
Learn More >Pain is a major and common symptom reported as a top priority in patients with rheumatoid arthritis (RA). Intuitively, RA-related pain is often considered to be a natural consequence of peripheral inflammation, so treatment of RA is expected to manage pain concurrently as part of inflammation control. However, pain in patients with RA can be poorly correlated with objective measures of inflammation, for example, in patients who are otherwise in remission. Joint damage appears to account for only a fraction of this residual pain. Emerging evidence suggests that alteration of peripheral and central pain processing contributes to RA-related pain; this is parallel to, but somewhat independent of, joint inflammation. Interleukin (IL)-6 is a proinflammatory cytokine that contributes to the pathogenesis of RA. It exerts systemic effects via signaling through soluble forms of the IL-6 receptor ("trans-signaling"). Evidence from preclinical studies demonstrates that intra-articular IL-6 can produce long-lasting peripheral sensitization to mechanical stimulation and suggests an important role for IL-6 in central pain sensitization. This may be partly explained by its ability to activate neurons through trans-signaling, affecting nociceptive plasticity and nerve fiber regrowth. Local activity at neuron endings may culminate in altered pain processing in the central nervous system because of persistent signaling from sensitized peripheral neurons. Peripheral and central sensitization can promote the development of chronic pain, which can have a significant impact on patients' health and quality of life. A proportion of pain in RA may be more appropriately managed as an entity separate from inflammation. Both the peripheral and central nervous systems should be recognized as important potential systems targeted by RA. The substantial burden of RA-related chronic pain suggests that pain should be a key focus in RA management and should be assessed and addressed early and separately from the inflammatory component.
Learn More >About a third of patients with multiple sclerosis (MS) suffer from chronic and excruciating central neuropathic pain (CNP). The mechanism underlying CNP in MS is not clear, since previous studies are scarce and their results are inconsistent. Our aim was to determine whether CNP in MS is associated with impairment of the spinothalamic-thalamocortical pathways (STTCs) and/or increased excitability of the pain system.
Learn More >Pruritus is one of the most distressing symptoms in cholestatic patients. Plasma autotaxin (ATX) activity correlates with the severity of pruritus in cholestatic patients, but the pathophysiology is unclear. To study pruritus in mice, we measured scratch activity in cholestatic Atp8b1 mutant mice, a model for Progressive Familial Intrahepatic Cholestasis type 1, and wild type mice (WT) with alpha-naphthylisothiocyanate (ANIT)-induced cholestasis. To induce cholestasis, Atp8b1 mutant mice received a diet containing 0.1% cholic acid (CA) and WT mice were treated with ANIT. In these mice ATX was also overexpressed by transduction with AAV-ATX. Scratch activity was measured using an unbiased, electronic assay. Marked cholestasis was accomplished in both Atp8b1 mutant mice on a CA-supplemented diet and in ANIT-treatment in WT mice, but scratch activity was decreased rather than increased while plasma ATX activity was increased. Plasma ATX activity was further increased up to fivefold with AAV-ATX, but this did not induce scratch activity. In contrast to several reports two cholestatic mouse models did not display increased scratch activity as a measure of itch perception. Increasing plasma ATX activity by overexpression also did not lead to increased scratch activity in mice. This questions whether mice are suitable to study cholestatic itch.
Learn More >Temporal estimation can be influenced by pain, which is a complex psychological and physiological phenomenon. However, the time range in which perception is most sensitive to pain remains unclear.
Learn More >To explore small fiber somatosensory and sympathetic function in PD and MSA.
Learn More >Chronic pain is a prevalent and disabling condition. Reboot Online was developed as a multidisciplinary and widely accessible online treatment program for chronic pain. It has been shown to be effective in clinical trials, but the effectiveness of this program in routine care settings remains unknown. This study aimed to examine program adherence and effectiveness in a real-world sample of participants completing Reboot Online in the community.
Learn More >Chronic postsurgical pain (CPSP) is a common complication after surgery; however, the underlying mechanisms of CPSP are poorly understood. As one of the most important inflammatory pathways, the Toll-like receptor 4/nuclear factor-kappa B (TLR4/NF-κB) signaling pathway plays an important role in chronic pain. However, the precise role of the TLR4/NF-κB signaling pathway in CPSP remains unclear. In the present study, we established a rat model of CPSP induced by skin/muscle incision and retraction (SMIR) and verified the effects and mechanisms of central and peripheral TLR4 and NF-κB on hyperalgesia in SMIR rats. The results showed that TLR4 expression was increased in both the spinal dorsal horn and dorsal root ganglia (DRGs) of SMIR rats. However, the TLR4 expression pattern in the spinal cord was different from that in DRGs. In the spinal cord, TLR4 was expressed in both neurons and microglia, whereas it was expressed in neurons but not in satellite glial cells in DRGs. Further results demonstrate that the central and peripheral TLR4/NF-κB signaling pathway is involved in the SMIR-induced CPSP by different mechanisms. In the peripheral nervous system, we revealed that the TLR4/NF-κB signaling pathway induced upregulation of voltage-gated sodium channel 1.7 (Nav1.7) in DRGs, triggering peripheral hyperalgesia in SMIR-induced CPSP. In the central nervous system, the TLR4/NF-κB signaling pathway participated in SMIR-induced CPSP by activating microglia in the spinal cord. Ultimately, our findings demonstrated that activation of the peripheral and central TLR4/NF-κB signaling pathway involved in the development of SMIR-induced CPSP.
Learn More >Little is known about the pain experience of the Mexican American (MA) population. We investigated the associations between language use and generation status with chronic pain prevalence, health insurance coverage, and analgesic medication use. We examined 3373 MA respondents from the National Health and Nutrition Examination Survey. We found higher levels of English use and generation status were associated with higher odds of reporting chronic pain. For respondents reporting chronic pain, higher levels of English use and generation status were associated with higher odds of being covered by health insurance, lower odds of having a period of time last year without health insurance, and higher odds of being prescribed any analgesic medication, especially opioid medications. We found language use and generation status play a role in MAs' experience, access, and treatment of chronic pain. Patient-, provider-, and systems-level interventions may be needed to reduce these disparities.
Learn More >Excessive pain during medical procedures is a pervasive health challenge. This study tested the (additive) analgesic efficacy of combining hypnotic analgesia and virtual reality (VR) pain distraction. A single blind, randomized, and controlled trial was used to study 205 undergraduate volunteers aged 18 to 20. The individual and combined effects of hypnotic analgesia (H) and VR distraction on experimentally induced acute thermal pain were examined using a 2 X 2, between-groups parallel design (4 groups total). Participants in groups that received hypnosis remained hypnotized during the test phase pain stimulus. The main outcome measure was "worst pain" ratings. Hypnosis reduced acute pain even for people who scored low on hypnotizability. As predicted, H+ VR was significantly more effective than VR distraction alone. However, H+ VR was not significantly more effective than hypnotic analgesia alone. Being hypnotized during thermal pain enhanced VR distraction analgesia.
Learn More >Non-Hispanic black (NHB) individuals have increased risk of Alzheimer's disease (AD) relative to non-Hispanic whites (NHW). Ethnicity/race can serve as a proxy sociodemographic variable for a complex representation of sociocultural and environmental factors. Chronic pain is a form of stress with high prevalence and sociodemographic disparities. Chronic pain is linked to lower cognition and accelerated biological aging.
Learn More >Inhibition of the pituitary adenylate cyclase 1 receptor (PAC1R) is a novel mechanism that could be used for abortive treatment of acute migraine. Our research began with comparative analysis of known PAC1R ligand scaffolds, PACAP38 and Maxadilan, which resulted in the selection of des(24-42) Maxadilan, , as a starting point. C-terminal modifications of improved the peptide metabolic stability and . SAR investigations identified synergistic combinations of amino acid replacements that significantly increased the PAC1R inhibitory activity of the analogs to the pM IC range. Our modifications further enabled deletion of up to six residues without impacting potency, thus improving peptide ligand binding efficiency. Analogs and exhibited robust efficacy in the rat Maxadilan-induced increase in blood flow (MIIBF) pharmacodynamic model at 0.3 mg/kg subcutaneous dosing. The first cocrystal structure of a PAC1R antagonist peptide () with PAC1R extracellular domain is reported.
Learn More >Low back pain (LBP) is a common reason for adults to seek medical care and is associated with important functional limitation and patient burden. Yet, heterogeneity in the causes and presentation of LBP and a lack of standardization in its management impede effective prevention and treatment.
Learn More >To assess whether body pain was associated with different trauma histories (physical injury vs. interpersonal injury [IPI]) within Australian women, along with body pain and trauma history associations with biological and psychological (biopsycho) confounders.
Learn More >Itch is a complex symptom that is both common and burdensome in atopic dermatitis (AD). Yet, little is known about the longitudinal course of itch in AD. A prospective, dermatology practice-based study was performed of adults with AD (n = 463). Patients were assessed at baseline and approximately 6, 12, 18 and 24 months. Itch was assessed using Numeric Rating Scale (NRS) average and worst-itch scores, and frequency of itch in the past week. Repeated-measures regression models were constructed to examine itch over time. Overall, 31.5% and 22.5% had moderate (4-6) or severe (7-10) NRS average-itch scores; 27.4% and 36.4% had moderate (4-6) or severe (7-10) NRS worst-itch scores; 12.7% and 62.0% had itch from eczema 3-4 and ≥ 5 days in the past week; 27.4% and 45.1% reported sometimes and often/almost always having itch, respectively. Among patients with baseline moderate (4-6) or severe (7-10) NRS average-itch scores, 21.2% and 16.3% continued to have moderate or severe scores at ≥ 1 follow-up visits. In repeated-measures regression models, persistent NRS average-itch scores were associated with baseline NRS average-itch [adjusted β (95% CI): 0.75 (0.68, 0.82)] and food allergy [- 0.45 (- 0.84, – 0.07)]. Persistent NRS worst-itch was associated with baseline worst-itch NRS [0.73 (0.66, 0.80)] and Medicaid insurance [1.06 (0.17, 1.94)]. AD patients had a heterogeneous longitudinal course with fluctuating and complex overlapping patterns of average- and worst-itch intensity, and frequency.
Learn More >Increased evidence indicates that pain location affects central sensitization (CS)-related symptoms. In addition, pain location and pain duration may be intricately related to CS-related symptoms. However, these factors have been investigated separately. This study aimed to investigate the association between CS-related symptoms and pain location and/or pain duration in patients with musculoskeletal disorders.
Learn More >Ketamine, an N-methyl-D-aspartate receptor antagonist, is widely known as a dissociative anesthetic and phencyclidine derivative. Due to an undesirable adverse event profile when used as an anesthetic it had widely fallen out of human use in favor of more modern agents. However, it has recently been explored for several other indications such as treatment resistant depression and chronic pain. Several recent studies and case reports compiled here show that ketamine is an effective analgesic in chronic pain conditions including cancer-related neuropathic pain. Of special interest is ketamine's opioid sparing ability by counteracting the central nervous system sensitization seen in opioid induced hyperalgesia. Furthermore, at the sub-anesthetic concentrations used for analgesia ketamine's safety and adverse event profiles are much improved. In this article, we review both the basic science and clinical evidence regarding ketamine's utility in chronic pain conditions as well as potential adverse events.
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