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The innate immune regulator STING is a critical sensor of self- and pathogen-derived DNA. DNA sensing by STING leads to the induction of type-I interferons (IFN-I) and other cytokines, which promote immune-cell-mediated eradication of pathogens and neoplastic cells. STING is also a robust driver of antitumour immunity, which has led to the development of STING activators and small-molecule agonists as adjuvants for cancer immunotherapy. Pain, transmitted by peripheral nociceptive sensory neurons (nociceptors), also aids in host defence by alerting organisms to the presence of potentially damaging stimuli, including pathogens and cancer cells. Here we demonstrate that STING is a critical regulator of nociception through IFN-I signalling in peripheral nociceptors. We show that mice lacking STING or IFN-I signalling exhibit hypersensitivity to nociceptive stimuli and heightened nociceptor excitability. Conversely, intrathecal activation of STING produces robust antinociception in mice and non-human primates. STING-mediated antinociception is governed by IFN-Is, which rapidly suppress excitability of mouse, monkey and human nociceptors. Our findings establish the STING-IFN-I signalling axis as a critical regulator of physiological nociception and a promising new target for treating chronic pain.
Learn More >Up to 20% of people worldwide develop gastrointestinal symptoms following a meal, leading to decreased quality of life, substantial morbidity and high medical costs. Although the interest of both the scientific and lay communities in this issue has increased markedly in recent years, with the worldwide introduction of gluten-free and other diets, the underlying mechanisms of food-induced abdominal complaints remain largely unknown. Here we show that a bacterial infection and bacterial toxins can trigger an immune response that leads to the production of dietary-antigen-specific IgE antibodies in mice, which are limited to the intestine. Following subsequent oral ingestion of the respective dietary antigen, an IgE- and mast-cell-dependent mechanism induced increased visceral pain. This aberrant pain signalling resulted from histamine receptor H-mediated sensitization of visceral afferents. Moreover, injection of food antigens (gluten, wheat, soy and milk) into the rectosigmoid mucosa of patients with irritable bowel syndrome induced local oedema and mast cell activation. Our results identify and characterize a peripheral mechanism that underlies food-induced abdominal pain, thereby creating new possibilities for the treatment of irritable bowel syndrome and related abdominal pain disorders.
Learn More >Although placebo effect sizes in clinical trials of chronic pain treatments have been increasing, it remains unknown if characteristics of individuals' thoughts or prior experiences can reliably infer placebo pill responses. Research using language to investigate emotional and cognitive processes has recently gained momentum. Here, we quantified placebo response in chronic low back pain using over 300 semantic and psycholinguistic features derived from patients' language. This speech content was collected in an exit interview as part of a clinical trial investigating placebo analgesia (62 patients, 42 treated; 20 not treated). Utilizing a nested leave-one-out cross-validated approach, we distinguished placebo responders from non-responders with 79% accuracy using language features alone; a subset of these features – semantic distances to identity and stigma and the number of achievement-related words – also explained 46% of the variance in placebo analgesia. Importantly, these language features were not due to generic treatment effects and were associated with patients' specific baseline psychological traits previously shown to be predictive of placebo including awareness and personality characteristics, explaining an additional 31% of the variance in placebo analgesia beyond that of personality. Initial interpretation of the features suggests that placebo responders differed in how they talked about negative emotions and the extent that they expressed awareness to various aspects of their experiences; differences were also seen in time spent talking about leisure activities. These results indicate that patients' language is sufficient to identify placebo response and implies that specific speech features may be predictive of responders prior to treatment.
Learn More >Despite successful research efforts aimed at understanding pain mechanisms, there is still no adequate treatment for many patients suffering from chronic pain. The contribution of neuroinflammation to chronic pain is widely acknowledged. Here, we summarize findings indicating that T cells play a key role in the suppression of pain. An active contribution of the immune system to resolution of pain may explain why immunosuppressive drugs are often not sufficient to control pain. This would also imply that dysregulation of certain immune functions promote transition to chronic pain. Conversely, stimulating the endogenous immune-mediated resolution pathways may provide a potent approach to treat chronic pain.
Learn More >Empathy is an essential component of social communication that involves experiencing others' sensory and emotional states. We observed that a brief social interaction with a mouse experiencing pain or morphine analgesia resulted in the transfer of these experiences to its social partner. Optogenetic manipulations demonstrated that the anterior cingulate cortex (ACC) and its projections to the nucleus accumbens (NAc) were selectively involved in the social transfer of both pain and analgesia. By contrast, the ACC→NAc circuit was not necessary for the social transfer of fear, which instead depended on ACC projections to the basolateral amygdala. These findings reveal that the ACC, a brain area strongly implicated in human empathic responses, mediates distinct forms of empathy in mice by influencing different downstream targets.
Learn More >The objective of this study was to assess whether migraine-related outcomes changed during intelligent lockdown when compared with the prior period.
Learn More >The primary aim of this randomized clinical trial is to investigate the effects of ultrasound guided transversus abdominis plane (TAP) versus ultrasound guided trigger point injections (TPIs) on numerical rating scale (NRS) pain scores at month 3 follow-up in patients with a chronic abdominal wall pain (AWP). The primary outcome measure was the difference in mean numeric rating scale pain scores between the TAP and TPI groups at month 3 in an intent-to-treat (ITT) analysis. A total of 60 patients were randomized 1:1 to receive an ultrasound-guided TAP block (n=30) or an ultrasound-guided TPI (n=30). No significant group differences in baseline demographic or clinical characteristics were observed. The mean baseline pain score for the TAP and TPI groups were 5.5 and 4.7, respectively. In the ITT analysis at month 3, the between group difference in pain scores was 1.7 (95% CI, 0.3 to 3.0) favoring the TPI group. In a secondary per-protocol analysis, the between group difference in pain scores was 1.8 (95% CI, 0.4 to 3.2) favoring the TPI group. For the ITT and per-protocol analyses, the group differences in pain scores were consistent with a medium effect size. The main finding of this randomized clinical trial is that adults with chronic AWP who received a TPI reported significantly lower pain scores at month 3 follow-up compared to patients who received a TAP block.
Learn More >Pain puts patients at risk for developing psychiatric conditions such as anxiety and depression. Pre-clinical mouse models of pain-induced affective behavior vary widely in methodology and results, impairing progress towards improved therapeutics. To systematically investigate the effect of long-term inflammatory pain on exploratory behavior and stress coping strategy, we assessed male C57BL/6J mice in the forced swim test (FST), elevated zero maze (EZM), and open field test (OFT) at four and six weeks post-injection of Complete Freund's Adjuvant (CFA), while controlling for testing order and combination. Inflammatory pain did not induce a passive stress coping strategy in the FST and did not reduce exploratory behavior in the EZM or the OFT. Using systematic correlational analysis and composite behavioral scores, we found no consistent association among measures for mice with or without inflammatory pain. A meta-analysis of similar studies indicated a modest, significant effect of CFA on exploratory behavior, but not immobility in the FST, and high heterogeneity among effect sizes in all three paradigms. Given the urgency for understanding the mechanisms of pain comorbidities and identifying novel therapies, these findings support the reallocation of our limited resources away from such unreliable assays and toward motivated and naturalistic behaviors. Future studies in pain and psychiatric translational research may benefit by considering outcomes beyond binary categorization, quantifying the associations between multiple measured behaviors, and agnostically identifying subtle yet meaningful patterns in behaviors.
Learn More >Adults are more likely to suffer from chronic pain than minors, and its underlying mechanism remains unclear. SIRT1 as important aging-related protein with function of lifespan extension, whether SIRT1 plays a role in the different pain vulnerability of adult and juvenile remains unclear. Here, we found that the expression level of SIRT1 in dorsal root ganglia (DRG) was related to the pain vulnerability. Following nerve injury, the expression of SIRT1 in DRG was decreased in adult rodents while increased in juvenile rodents. Differential manipulation of SIRT1 abolished the different pain vulnerability between adult and juvenile rodents. Furthermore, SIRT1 interacted with ClC-3 channel and mediated ClC-3 membrane trafficking and Cl¯ current in DRG neurons. Differential manipulation of ClC-3 also abolished the difference in pain vulnerability between adult and juvenile rodents. The different anti-inflammatory ability determined the different change trends of SIRT1 and ClC-3 trafficking contributed to the different pain vulnerability in adult and juvenile rodents. In addition, the serum SIRT1 level was negatively correlated with pain score in chronic pain patients. These findings revealed the mechanism of the difference in pain vulnerability between adult and juvenile rodents and provided evidence for age-specific treatment of chronic pain.
Learn More >A cardinal, intractable symptom of neuropathic pain is mechanical allodynia, pain caused by innocuous stimuli via low-threshold mechanoreceptors such as Aβ fibers. However, the mechanism by which Aβ fiber-derived signals are converted to pain remains incompletely understood. Here we identify a subset of inhibitory interneurons in the spinal dorsal horn (SDH) operated by adeno-associated viral vectors incorporating a neuropeptide Y promoter (AAV-NpyP) and show that specific ablation or silencing of AAV-NpyP SDH interneurons converted touch-sensing Aβ fiber-derived signals to morphine-resistant pain-like behavioral responses. AAV-NpyP neurons received excitatory inputs from Aβ fibers and transmitted inhibitory GABA signals to lamina I neurons projecting to the brain. In a model of neuropathic pain developed by peripheral nerve injury, AAV-NpyP neurons exhibited deeper resting membrane potentials, and their excitation by Aβ fibers was impaired. Conversely, chemogenetic activation of AAV-NpyP neurons in nerve-injured rats reversed Aβ fiber-derived neuropathic pain-like behavior that was shown to be morphine-resistant and reduced pathological neuronal activation of superficial SDH including lamina I. These findings suggest that identified inhibitory SDH interneurons that act as a critical brake on conversion of touch-sensing Aβ fiber signals into pain-like behavioral responses. Thus, enhancing activity of these neurons may offer a novel strategy for treating neuropathic allodynia.
Learn More >Anxiety is often comorbid with pain. Delta opioid receptors (DORs) are promising targets for the treatment of pain and mental disorders with little addictive potential. However, their roles in anxiety symptoms at different stages of pain are unclear. In the current study, mice with inflammatory pain at the 4th hour following complete Freund's adjuvant (CFA) injection displayed significant anxiety-like behavior, which disappeared at the 7th day. Combining electrophysiology, optogenetics, and pharmacology, we found that activation of delta opioid receptor 1 (DOR1) in the central nucleus amygdala (CeA) inhibited both the anxiolytic excitatory input from the basolateral amygdala (BLA) and the anxiogenic excitatory input from the parabrachial nucleus (PBN). In contrast, activation of delta opioid receptor 2 (DOR2) did not affect CeA excitatory synaptic transmission in normal and 4-hour CFA mice but inhibited the excitatory projection from the PBN rather than the BLA in 7-day CFA mice. Furthermore, the function of both DOR1 and DOR2 was downregulated to the point of not being detectable in the CeA of mice at the 21st day following CFA injection. Taken together, these results suggest that functional switching of DOR1 and DOR2 is associated with anxiety states at different stages of pain via modulating the activity of specific pathways (BLA-CeA and PBN-CeA).
Learn More >The protease activated receptor (PAR) family is a group of G-protein coupled receptors (GPCRs) activated by proteolytic cleavage of the extracellular domain. PARs are expressed in a variety of cell types with crucial roles in hemostasis, immune responses, inflammation, and pain. PAR3 is the least researched of the four PARs, with little known about its expression and function. We sought to better understand its potential function in the peripheral sensory nervous system. Mouse single-cell RNA sequencing data demonstrates that PAR3 is widely expressed in dorsal root ganglion (DRG) neurons. Co-expression of PAR3 mRNA with other PARs was identified in various DRG neuron subpopulations, consistent with its proposed role as a coreceptor of other PARs. We developed a lipid tethered PAR3 agonist, C660, that selectively activates PAR3 by eliciting a Ca response in DRG and trigeminal (TG) neurons. In vivo, C660 induces mechanical hypersensitivity and facial grimacing in WT but not PAR3 mice. We characterized other nociceptive phenotypes in PAR3 mice and found a loss of hyperalgesic priming in response to IL-6, carrageenan, and a PAR2 agonist, suggesting that PAR3 contributes to long-lasting nociceptor plasticity in some contexts. To examine the potential role of PAR3 in regulating the activity of other PARs in sensory neurons, we administered PAR1, PAR2, and PAR4 agonists and assessed mechanical and affective pain behaviors in WT and PAR3 mice. We observed that the nociceptive effects of PAR1 agonists were potentiated in the absence of PAR3. Our findings suggest a complex role of PAR3 in the physiology and plasticity of nociceptors. Perspective: We evaluated the role of PAR3, a G-protein coupled receptor, in nociception by developing a selective peptide agonist. Our findings suggest that PAR3 contributes to nociception in various contexts and plays a role in modulating the activity of other PARs.
Learn More >We aimed to investigate the prevalence of dysautonomia in complex regional pain syndrome (CRPS) via the combined autonomic nervous system (ANS) function tests, including the deep breathing test (DBT), orthostatic test (OST) and sympathetic skin response (SSR).
Learn More >The rationale of spinal administration of endothelin-1(ET-1) mediated anti-nociceptive effect has not been elucidated. ET-1 is reported to promote nuclear effluxion of histone deacetylase 5 (HDAC5) in myocytes, and spinal HDAC5 is implicated in modulation of pain processing. In this study, we aimed to investigate whether central ET-1 plays an anti-nociceptive role by facilitating spinal HDAC5 nuclear shuttling under neuropathic pain. Here, we demonstrate that upregulating spinal ET-1 attenuated the nociception induced by partial sciatic nerve ligation (pSNL) surgery and this analgesic effect mediated by ET-1 was attenuated by intrathecal injection of endothelin A receptor (ETAR) selective inhibitor (BQ123) or by blocking the exportation of nuclear HDAC5 by adeno-associated viruses targeting neuronal HDAC5 (AVV-HDAC5 S259/498A Mutant). Notably, ET-1 administration increased spinal glutamate acid decarboxylases (GAD65/67) expression via initiating HDAC5 nuclear exportation and increased the acetylation of histone 3 at lysine 9 (Acetyl-H3K9) in the promotor regions of spinal Gad1 and Gad2 genes. This was reversed by blocking ETAR function or by inhibiting the spinal neuronal nuclear exportation of HDAC5. Therefore, inducing spinal GABAergic neuronal HDAC5 nuclear exportation may be a novel therapeutic approach for managing neuropathic pain. Perspective: Neuropathic pain is intractable in a clinical setting, and epigenetic regulation is considered to contribute to this processing. Characterizing the anti-nociceptive effect of ET-1 and investigating the associated epigenetic mechanisms in animal models may lead to the development of new therapeutic strategies and targets for treating neuropathic pain.
Learn More >Complex regional pain syndrome (CRPS) is a neuropathic pain condition that is difficult to treat. For behavioral interventions, graded motor imagery (GMI) showed relevant effects, but underlying neural substrates in patient groups have not been investigated yet. A previous study investigating differences in the representation of a left/right hand judgment task demonstrated less recruitment of subcortical structures, such as the putamen, in CRPS patients than in healthy controls. In healthy volunteers, the putamen activity increased after a hand judgment task training. In order to test for longitudinal effects of GMI training, we investigated 20 CRPS patients in a wait-list crossover design with 3 evaluation time points. Patients underwent a 6 week GMI treatment and a 6 week waiting period in a randomized group assignment and treatment groups were evaluated by a blinded rater. When compared to healthy matched controls at baseline, CRPS patients showed less functional activation in areas processing visual input, left sensorimotor cortex, and right putamen. Only GMI treatment, but not the waiting period showed an effect on movement pain, hand judgment task performance. Regression analyses revealed positive associations of movement pain with left anterior insula activation at baseline. Right intraparietal sulcus activation change during GMI was associated with a gain in performance of the hand judgment task. The design used here is reliable for investigating the functional representation of the hand judgment task in an intervention study. PERSPECTIVE: 20 chronic CRPS patients underwent a 6 week graded motor imagery (GMI) intervention in a randomized wait-list crossover design. fMRI was tested pre and post for the hand lateralization task which improved over GMI but not over WAITING. Performance gain was positively related to right parietal fMRI activation.
Learn More >Fibromyalgia syndrome (FMS) is a chronic widespread pain condition of unknown aetiology. The role of temperature in FMS pain has not been reviewed systematically. The goal of this study was to review the influences of temperature on pain in FMS, from meteorological and quantitative sensory testing (QST) studies. The review was registered with Prospero: ID-CRD42020167687, and followed PRISMA guidance. Databases interrogated were: MEDLINE (via OVID), EMBASE, PubMed, Web of Science, ScienceDirect, CINAHL and ProQuest (Feb'20). Exclusion criteria were: age <18, animal studies, non-English and non-controlled articles. Thirteen studies pertaining to ambient temperature and FMS pain were identified; 9 of these found no uniform relationship. Thirty-five QST studies were identified, 17 of which assessed cold pain thresholds (CPTs). All studies showed numerically reduced CPTs in patients, ranging from 10.9°C-26.3°C vs. 5.9°C-13.5°C in controls; this was statistically-significant in 14/17. Other thermal thresholds were often abnormal. We conclude that the literature provides consistent evidence for an abnormal sensitisation of FMS patients' temperature-sensation systems. Additional work is required to elucidate the factors that determine why a sub-group of patients perceive low ambient temperatures as painful, and to characterise that group. PERSPECTIVE: Patients often report increased pain with changes in ambient temperature; even disabling, extreme temperature sensitivity in winter. Understanding this phenomenon may help clinicians provide reassurance and advice to patients and may guide research into the everyday impact of such hypersensitivity, whilst directing future work into the pathophysiology of FMS.
Learn More >Pain and depression are episodic conditions that might take a chronic course. They are clearly related, but information on how they influence each other in the process of chronification is limited. Pain catastrophizing is hypothesized to play a role in the development of depression and chronic pain, but few longitudinal studies have investigated their association over a longer-term. In this study, a random cohort from the general population (n = 4764) answered questions about pain, catastrophizing, and depression at five assessments in yearly intervals. Linear mixed models showed that within persons, increases in pain intensity and catastrophizing were independently associated with increases in depressive symptoms (mean change = -1.12, 95% CI [-1.32, -0.91]) and -1.29, 95% CI [-1.52, -1.05], respectively). In prospective analyses restricted to individuals without depression above cut-off at baseline, chronic pain increased the risk of endorsing depression over the following four years (OR =2.01, 95% CI [1.71, 2.37]). Seven percent showed a chronic course of depression, as indicated by scores above cut-off on at least three of five assessments. Number of years lived with chronic pain was associated with a chronic course of depression, with odds ratios increasing from 1.55 (95% CI [0.87, 2.91]) to 14.19 (95% CI [8.99, 22.41]) when reporting chronic pain on two versus five assessments compared to none. The results suggest that when pain intensity or catastrophizing change, depressive symptoms change in the same direction. When pain and catastrophizing become chronic, they appear to be mutually reinforcing determinants for chronic depression.
Learn More >The nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are trophic factors required by distinct population of sensory neurons during development of the nervous system. Neurons that fail to receive appropriate trophic support are lost during this period of naturally occurring cell death. In the last decade, our understanding of the signalling pathways regulating neuronal death following NGF deprivation has advanced substantially. However, the signaling mechanisms promoting BDNF-deprivation induced sensory neuron degeneration are largely unknown. Using a well-established culture model of dorsal root ganglion (DRG), we have examined degeneration mechanisms triggered upon BDNF withdrawal in sensory neurons. Our results indicate differences and similarities between the molecular signalling pathways behind NGF and BDNF deprivation-induced death. For instance, we observed that the inhibition of Trk receptors (K252a), PKC (Gö6976), protein translation (cycloheximide) or caspases (zVAD-fmk) provides protection from NGF deprivation-induced death but not from degeneration evoked by BDNF-withdrawal. Interestingly, degeneration of BDNF-dependent sensory neurons requires BAX and appears to rely on reactive oxygen species generation rather than caspases to induce degeneration. These results highlight the complexity and divergence of mechanisms regulating developmental sensory neuron death. The elimination of neuronal cells generated in excess during embryonic stages characterizes the maturation of the nervous system. Here we address the developmental cell death mechanisms of BDNF-dependent dorsal root ganglion neurons , comparing and contrast them with those deployed in NGF-dependent sensory neurons. We observe several important differences between the molecular signalling pathways behind NGF and BDNF deprivation-induced death. Significantly, degeneration of BDNF-dependent sensory neurons requires BAX but not caspase activation, instead reactive oxygen species generation appears to play a key role in degeneration. This work highlights the complexity of cell death mechanisms in distinct embryonic sensory neuron populations.
Learn More >Seasonal rhythms influence emotion and sociability. The brain μ-opioid receptor (MOR) system modulates a multitude of seasonally varying socioemotional functions, but its seasonal variation remains elusive with no previously reported evidence. Here, we first conducted a cross-sectional study with previously acquired human [C]carfentanil PET imaging data (132 male and 72 female healthy subjects) to test whether there was seasonal difference in MOR availability. We then investigated experimentally whether seasonal variation in daylength causally influences brain MOR availability in rats. Rats (six male and three female rats) underwent daylength cycle simulating seasonal changes; control animals (two male and one female rats) were kept under constant daylength. Animals were scanned repeatedly with [C]carfentanil PET imaging. Seasonally varying daylength had an inverted U-shaped functional relationship with brain MOR availability in humans. Brain regions sensitive to daylength spanned the socio-emotional brain circuits, where MOR availability formed a spring-like peak. In rats, MOR availabilities in the brain neocortex, thalamus and striatum peaked at intermediate daylength. Varying daylength also affected the weight gain and stress hormone. We conclude that the brain MOR availability in humans and rats shows significant seasonal variation, which is predominately associated with seasonal photoperiodic variation. Given the intimate links between MOR signaling and socioemotional behavior, these results suggest that the MOR system might underlie seasonal variation in human mood and social behavior.Seasonal rhythms influence emotion and sociability. The brain's μ-opioid receptor (MOR) system modulates numerous seasonally varying socioemotional functions, but its seasonal variation remains elusive. Here we used positron emission tomography to show that MOR levels in both human and rat brains show daylength-dependent seasonal variation. The highest MOR availability was observed at intermediate daylengths. Given the intimate links between MOR signaling and socioemotional behavior, these results suggest that the MOR system might underlie seasonal variation in human mood and social behavior.
Learn More >To assess the safety profile of erenumab, galcanezumab and fremanezumab in pregnancy and lactation.
Learn More >Medical outcomes are strongly affected by placebo and nocebo effects. Prediction of who responds to such expectation effects has proven to be challenging. Most recent approaches to prediction have focused on placebo effects in the context of previous treatment experiences and expectancies, or personality traits. However, a recent model has suggested that basic somatosensory characteristics play an important role in expectation responses. Consequently, this study investigated not only the role of psychological variables, but also of basic somatosensory characteristics. In this study, 624 participants underwent a placebo and nocebo heat pain paradigm. Additionally, individual psychological and somatosensory characteristics were assessed. While no associations were identified for placebo responses, nocebo responses were associated with personality traits (e.g. neuroticism) and somatosensory characteristics (e.g. thermal pain threshold). Importantly, the associations between somatosensory characteristics and nocebo responses were among the strongest. This study shows that apart from personality traits, basic somatosensory characteristics play an important role in individual nocebo responses, in agreement with the novel idea that nocebo responses result from the integration of top-down expectation and bottom-up sensory information.
Learn More >Non-painful symptoms in migraine following headache resolution can last up to days. Studying the postdrome is important to appreciate the morbidity associated with migraine.
Learn More >Treatment of chronic pain remains an unmet medical need. The neuronal voltage-gated potassium Kv7/KCNQ/M channel has been implicated as a therapeutic target for chronic pain. However, whether pharmacological activation of Kv7 channel can alleviate pain remains elusive. In this study, we show that selective activation of native M currents by a novel channel opener SCR2682 reduces repetitive firings of dorsal root ganglia (DRG) sensory neurons. Intraperitoneal administration of SCR2682 relieves mechanical allodynia and thermal hyperalgesia in rat models of pain induced by complete Freund's adjuvant (CFA) or spared nerve injury (SNI) in a dose-dependent manner without affecting locomotor activity. The anti-nociceptive efficacy of SCR2682 can be reversed by the channel specific blocker XE991. Furthermore, SCR2682 increases Kv7.2/KCNQ2 mRNA and protein expression in DRG neurons from rats in the SNI model of neuropathic pain. Taken together, pharmacological activation of neuronal Kv7 channels by opener SCR2682 can alleviate pain in rats, thus possessing therapeutic potential for chronic pain or hyperexcitability-related neurological disorders. A novel Kv7 opener SCR2682 inhibits action potential firings in DRG sensory neurons and exhibits an efficacy in antinociception, thus possessing a developmental potential for treatment of chronic pain or epilepsy.
Learn More >The transition from episodic migraine to chronic migraine, migraine chronification, is usually a gradual process, which involves multiple risk factors. To date, studies of the genetic risk factors for chronic migraine have focused primarily on candidate gene approaches using healthy individuals as controls.
Learn More >Spinal cord injury (SCI) is a devastating injury to the central nervous system in which 60 to 80% of patients experience chronic pain. Unfortunately, this pain is notoriously difficult to treat, with few effective options currently available. Patients are also commonly faced with various compounding injuries and medical challenges, often requiring frequent hospitalization and antibiotic treatment. Change in the gut microbiome from the "normal" state to one of imbalance, referred to as gut dysbiosis, has been found in both patients and rodent models following SCI. Similarities exist in the bacterial changes observed after SCI and other diseases with chronic pain as an outcome. These changes cause a shift in the regulation of inflammation, causing immune cell activation and secretion of inflammatory mediators that likely contribute to the generation/maintenance of SCI pain. Therefore, correcting gut dysbiosis may be used as a tool towards providing patients with effective pain management and improved quality of life.
Learn More >The role of gonadal hormones in neural plasticity remains unclear. This study aimed to examine the effects of naturally fluctuating hormone levels over the menstrual cycle in healthy females. Gray matter, functional connectivity (FC) and white matter changes over the cycle were assessed by using functional magnetic resonance imaging (fMRI), resting state fMRI, and structural MRIs, respectively, and associated with serum gonadal hormone levels. Moreover, electrocutaneous sensitivity was evaluated in 14 women in four phases of their menstrual cycle (menstrual, follicular, ovulatory, and luteal). Electrocutaneous sensitivity was greater during follicular compared to menstrual phase. Additionally, pain unpleasantness was lower in follicular phase than other phases while pain intensity ratings did not change over the cycle. Significant variations in cycle phase effects on gray matter volume were found in the left inferior parietal lobule (IPL) using voxel-based morphometry. Subsequent Freesurfer analysis revealed greater thickness of left IPL during the menstrual phase when compared to other phases. Also, white matter volume fluctuated across phases in left IPL. Blood estradiol was positively correlated with white matter volume both in left parietal cortex and whole cortex. Seed-driven FC between left IPL and right secondary visual cortex was enhanced during ovulatory phase. A seed placed in right IPL revealed enhanced FC between left and right IPL during the ovulatory phase. Additionally, we found that somatosensory cortical gray matter was thinner during follicular compared to menstrual phase. We discuss these results in the context of likely evolutionary pressures selecting for enhanced perceptual sensitivity across modalities specifically during ovulation.
Learn More >Vagus nerve stimulation (VNS) is a promising neuromodulation approach used in the treatment of migraine, whose therapeutic mechanism is largely unknown. Previous studies suggest that VNS's anti-nociceptive effects may, in part, involved engaging opioidergic mechanisms. We used a validated preclinical model of head pain, with good translational outcomes in migraine, acute intracranial-dural stimulation, and has responded to invasive VNS. We tested the effects of μ (MOR), δ (DOR) and κ (KOR) opioid receptor agonists in this model, and subsequently the effects of opioid receptor antagonists against VNS-mediated neuronal inhibition. MOR, DOR, and KOR agonists all inhibited dural-evoked trigeminocervical neuronal responses. Both DOR and KOR agonists also inhibited ongoing spontaneous firing of dural responsive neurons. Both DOR and KOR agonists were more efficacious than the MOR agonist in this model. We confirm the inhibitory effect of invasive VNS and demonstrate that this effect was prevented by a broad-spectrum opioid receptor antagonist, and by a highly selective DOR antagonist. Our data confirm the role of MOR in dural-trigeminovascular neurotransmission and additionally provide evidence of a role of both DOR and KOR in dural-nociceptive transmission of trigeminocervical neurons. Further, the results here provide evidence of engagement of opioidergic mechanisms in the therapeutic action of VNS in headache, specifically the DOR. These studies provide further support for the important role of the DOR in headache mechanisms, and as a potential therapeutic target. The data begin to dissect the mode of action of the analgesic effects of VNS in the treatment of primary headache disorders.
Learn More >Cannabis use has been increasing in recent years, particularly among women, and one of the most common uses of cannabis for medical purposes is pain relief. Pain conditions and response to analgesics have been demonstrated to be influenced by sex, and evidence is emerging that this is also true with cannabinoid-mediated analgesia. In this review we evaluate the preclinical evidence supporting sex differences in cannabinoid pharmacology, as well as emerging evidence from human studies, both clinical and observational. Numerous animal studies have reported sex differences in the antinociceptive response to natural and synthetic cannabinoids that may correlate to sex differences in expression, and function, of endocannabinoid system components. Female rodents have generally been found to be more sensitive to the effects of Δ-THC. This finding is likely a function of both pharmacokinetic and pharmacodynamics factors including differences in metabolism, differences in cannabinoid receptor expression, and influence of ovarian hormones including estradiol and progesterone. Preclinical evidence supporting direct interactions between sex hormones and the endocannabinoid system may translate to sex differences in response to cannabis and cannabinoid use in men and women. Further research into the role of sex in endocannabinoid system function is critical as we gain a deeper understanding of the impact of the endocannabinoid system in various disease states, including chronic pain.
Learn More >Prolonged postoperative pain is a major concern and occurs more frequently in women, but mechanisms remain elusive. NR2B-containging N-methyl-d-aspartate (NMDA) receptor is a key component of nociception transduction. Divalent metal transporter 1 (DMT1)-mediated iron overload involves NMDA-induced neurotoxicity in males. Kalirin-7 is vital in synaptic plasticity underlying pathological pain in males. Herein, the requirement for kalirin-7 in NR2B phosphorylation-dependent iron accumulation and spine plasticity in postoperative pain after tibial fracture in female mice has been examined.
Learn More >In Nepal, traditional treatment using medicinal plants is popular. Whereas medication-overuse headache is, by definition, caused by excessive use of acute headache medication, we hypothesized that medicinal plants, being pharmacologically active, were as likely a cause.
Learn More >Paclitaxel, a widely used anti-cancer drug, is frequently associated with prolonged and severe peripheral neuropathies (PIPN), associated with neuroinflammation. Currently, PIPN effective treatments are lacking. Peroxisome Proliferator-Activated Receptor-α (PPAR-⍺) can modulate inflammatory responses. Thus, the use of PPAR-⍺ agonists, such as fibrates (fenofibrate and choline-fenofibrate), currently used in dyslipidemia treatment, could represent an interesting therapeutic approach in PIPN.
Learn More >Headache is an important manifestation during SARS-CoV-2 infection. In this study, we aim to identify factors associated with headache in COVID-19 and headache characteristics.
Learn More >In the midst of the current coronavirus pandemic, the United States continues to struggle with an ongoing opioid epidemic, initially fueled by widespread prescribing of opioid medications during the 1990s. The primary reason for prescribing opioids is to treat pain. Women have more acute and chronic pain and have been prescribed these drugs in significantly greater numbers than men. Comparison of women and men with chronic pain also shows that women receive the majority of prescription opioids, and the use of these prescribed medications became the major pathway to misuse and addiction for women. Yet, recognition of the extent of women's exposure to opioids and the attendant consequences has been limited. Attempts to stem the overall tide of the epidemic focused on reducing the availability of prescription opioids. However, as these medications became more difficult to obtain and treatment opportunities were limited, many turned to other synthetic opioids, such as heroin and fentanyl. Thus, the public health crisis of opioid addiction has endured. This paper highlights the importance of understanding differences among women and men in opioid use and its biological and psychosocial effects to advance the gender-based treatment approaches and effective public health policy.
Learn More >Adolescents who undergo major surgery experience high rates of disabling acute and chronic postsurgical pain (CPSP). However, little is known about the subacute period when acute to chronic pain transition occurs.
Learn More >To describe headache characteristics, medication use, disability, and quality of life in a large patient cohort from the United States who have chronic migraine (CM) and medication overuse headache (MOH).
Learn More >Behavioral pain scales are recommended to assess postoperative pain for children who are too young to use self-report tools. Their main limitation is underestimation of pain in the days following an intervention. Although relevant, facial expression is not used in daily clinical practice. This prospective study aimed to assess the validity and reliability of the Facial Action Summary Score (FASS), a five-item scale, to assess postoperative pain until hospital discharge in children <7 years.
Learn More >Functional gastrointestinal disorders (FGIDs), characterized by chronic abdominal complaints without a structural or biochemical cause, are common diseases that are frequently encountered by specialists in internal medicine. Collectively, irritable bowel syndrome (IBS) and functional dyspepsia are estimated to affect up to 22% of the population, and are often associated with additional somatic and pain complaints, all without an obvious structural source [1,2]. An appreciation of the current understanding of the mechanistic basis for these disorders is key to developing treatment goals and optimization of patient management strategies. In recent years, the brain-gut axis increasingly has been recognized as a central factor in the experience of functional abdominal pain disorders, including the most recent Rome IV guidelines which identify FGIDs as disorders of gut-brain interaction [3]. The brain-gut axis (BGA), simply defined, is a complex network of bidirectional communication between the central and enteric nervous systems. This axis broadly includes all the systems involved with communication between the GI tract and central nervous system (CNS), with principle inputs into this network occurring between the CNS, enteric nervous system (ENS), and autonomic nervous systems (ANS), but also includes interfaces with numerous other factors, including endocrine hormones and immune effector cells as well as interactions with the gut microbiota. Perturbances to this system have been found to play a critical role in the development of visceral hypersensitivity, bowel dysregulation, and mood. This review will summarize the principle processes involved in the neurologic and biologic function of the brain-gut axis, our current understanding of its role in functional GI disorders, and potential targets for therapeutic intervention.
Learn More >It is widely agreed that carbamazepine and oxcarbazepine are highly effective in the long-term treatment of trigeminal neuralgia. However, the tolerability of these drugs across the different aetiologies of trigeminal neuralgia is still undetermined.
Learn More >Nociceptor sensitization following nerve injury or inflammation leads to chronic pain. An increase in the nociceptor hyperpolarization-activated current, I, is observed in many models of pathological pain. Pharmacological blockade of I prevents the mechanical and thermal hypersensitivity that occurs during pathological pain. Alterations in the Hyperpolarization-activated Cyclic Nucleotide-gated ion channel 2 (HCN2) mediate I-dependent thermal and mechanical hyperalgesia. Limited knowledge exists regarding the nature of these changes during chronic inflammatory pain. Modifications in HCN2 expression and post-translational SUMOylation have been observed in the Complete Freund's Adjuvant (CFA) model of chronic inflammatory pain. Intra-plantar injection of CFA into the rat hindpaw induces unilateral hyperalgesia that is sustained for up to 14 days following injection. The hindpaw is innervated by primary afferents in lumbar DRG, L4-6. Adjustments in HCN2 expression and SUMOylation have been well-documented for L5 DRG during the first 7 days of CFA-induced inflammation. Here, we examine bilateral L4 and L6 DRG at day 1 and day 3 post-CFA. Using L4 and L6 DRG cryosections, HCN2 expression and SUMOylation were measured with immunohistochemistry and proximity ligation assays, respectively. Our findings indicate that intra-plantar injection of CFA elicited a bilateral increase in HCN2 expression in L4 and L6 DRG at day 1, but not day 3, and enhanced HCN2 SUMOylation in ipsilateral L6 DRG at day 1 and day 3. Changes in HCN2 expression and SUMOylation were transient over this time course. Our study suggests that HCN2 is regulated by multiple mechanisms during CFA-induced inflammation.
Learn More >Prurigo nodularis (PN) is a chronic skin dermatosis with hyperkeratotic and intensely pruritic nodules. Managing PN-associated itch is difficult because its etiology is still unknown. This study aimed to investigate the correlation between itch intensity in PN and the expression of a pruritogenic cytokine interleukin (IL)-31, its receptor complex components IL-31 receptor a (IL31RA) and oncostatin M receptor b (OSMRb), and oncostatin M (OSM), which is a ligand of OSMRb, through immunofluorescence staining examination. Itch intensity in PN was closely correlated with the number of dermal IL-31(+) cells (Spearman's r = 0.551, p < 0.05), dermal IL-31RA(+) cells(r = 0.475, p < 0.05), and dermal OSM(+) cells (r = 0.505, p < 0.05). In addition, the number of dermal OSMRb(+) cells was increased in PN (t-test, p < 0.05), despite not being correlated with itch intensity (Spearman's r = 0.375, p > 0.05). Major cellular sources of dermal IL-31 were T cells (27.0% of total IL-31-expressing cells) and macrophages (35.0%), while those of OSM were mainly T cells (49.8%) and mast cells (26.8%). IL-31RA expressing dermal cells were mostly mast cells (49.3%) and macrophages (36.6%), and OSMRb were mainly expressed by macrophages (51.8%) in the dermis. These findings indicate that IL-31 (mainly from macrophages and T cells) and OSM (principally from T cells and mast cells) stimulate dermal cells expressing IL-31RA and OSMRb (e.g. macrophages), which may further promote itch and inflammation in PN. This complex dermal milieu of cell/cytokine/receptor network can be a therapeutic target for PN-associated itch.
Learn More >Fibromyalgia (FM) is a generalized chronic pain condition whose pathophysiology is poorly understood, and both basic and translational research are needed to advance the field. Here we used the Sluka model to test whether FM-like pain in mice would produce detectable brain modifications using resting-state (rs) functional Magnetic Resonance Imaging (fMRI). Mice received intramuscular acid saline treatment, images were acquired at 7 T 5 days post-treatment, and pain thresholds tested 3 weeks post-scanning. Data-driven Independent Component Analysis revealed significant reduction of functional connectivity (FC) across several component pairs, with major changes for the Retrosplenial cortex (RSP) central to the default mode network, and to a lesser extent the Periaqueductal gray (PAG), a key pain processing area. Seed-to-seed analysis focused on 14 pain-related areas showed strongest FC reduction for RSP with several cortical areas (somatosensory, prefrontal and insular), and for PAG with both cortical (somatosensory) and subcortical (habenula, thalamus, parabrachial nucleus) areas. RSP-PAG FC was also reduced, and this decreased FC tended to be positively correlated with pain levels at individual subject level. Finally, seed-voxelwise analysis focused on PAG confirmed seed-to-seed findings and, also detected reduced PAG FC with the anterior cingulate cortex, increasingly studied in aversive pain effects. In conclusion, FM-like pain triggers FC alterations in the mouse, which are detected by rs-fMRI and are reminiscent of some human findings. The study reveals the causal fingerprint of FM-like pain in rodents, and indicates that both RSP and PAG connectional patterns could be suitable biomarkers, with mechanistic and translational value, for further investigations.
Learn More >T-type calcium channels regulate neuronal excitability and are important contributors of pain processing. CaV3.2 channels are the major isoform expressed in non-peptidergic and peptidergic nociceptive neurons and are emerging as promising targets for pain treatment. Numerous studies have shown that CaV3.2 expression and/or activity are significantly increased in spinal dorsal horn and in dorsal root ganglia neurons in different inflammatory and neuropathic pain models. Pharmacological campaigns to inhibit the functional expression of CaV3.2 for treatment of pain have focused on the development of direct channel blockers, but none have produced have lead candidates. Targeting the proteins that regulate the trafficking or transcription, and the ones that modify the channels via post-translational modifications are alternative means to regulate expression and function of CaV3.2 channels and hence to develop new drugs to control pain. Here we synthesize data supporting a role for CaV3.2 in numerous pain modalities and then discuss emerging opportunities for the indirect targeting of CaV3.2 channels.
Learn More >Pain is a major health problem, affecting over fifty million adults in the US alone, with significant economic cost in medical care and lost productivity. Despite evidence implicating nicotinic acetylcholine receptors (nAChRs) in pathological pain, their specific contribution to pain processing in the spinal cord remains unclear given their presence in both neuronal and non-neuronal cell types. Here we investigated if loss of neuronal-specific TMEM35a (NACHO), a novel chaperone for functional expression of the homomeric α7 and assembly of the heteromeric α3, α4, and α6-containing nAChRs, modulates pain in mice. Mice with tmem35a deletion exhibited thermal hyperalgesia and mechanical allodynia. Intrathecal administration of nicotine and the α7-specific agonist, PHA543613, produced analgesic responses to noxious heat and mechanical stimuli in tmem35a KO mice, respectively, suggesting residual expression of these receptors or off-target effects. Since NACHO is expressed only in neurons, these findings indicate that neuronal α 7 nAChR in the spinal cord contributes to heat nociception. To further determine the molecular basis underlying the pain phenotype, we analyzed the spinal cord transcriptome. Compared to WT control, the spinal cord of tmem35a KO mice exhibited 72 differentially-expressed genes (DEGs). These DEGs were mapped onto functional gene networks using the knowledge-based database, Ingenuity Pathway Analysis, and suggests increased neuroinflammation as a potential contributing factor for the hyperalgesia in tmem35a KO mice. Collectively, these findings implicate a heightened inflammatory response in the absence of neuronal NACHO activity. Additional studies are needed to determine the precise mechanism by which NACHO in the spinal cord modulates pain.
Learn More >Chronic low back pain (CLBP) is a leading cause of disability and is associated with neurodegenerative changes in brain structure. These changes lead to impairments in cognitive function and are consistent with those seen in aging, suggesting an accelerated aging pattern. In this study we assessed this using machine-learning estimated brain age (BA) as a holistic metric of morphometric changes associated with aging. Structural imaging data from 31 non-depressed CLBP patients and 32 healthy controls from the Pain and Interoception Imaging Network were included. Using our previously developed algorithm, we estimated BA per individual based on grey matter density. We then conducted multivariable linear modeling for effects of group, chronological age, and their interaction on BA. We also performed two voxel-wise analyses comparing grey matter density between CLBP and control individuals and the association between gray matter density and BA. There was an interaction between CLBP and greater chronological age on BA such that the discrepancy in BA between healthy and CLBP individuals was greater for older individuals. In CLBP individuals, BA was not associated with sex, current level of pain, duration of CLBP, or mild to moderate depressive symptoms. CLBP individuals had lower cerebellar grey matter density compared to healthy individuals. Brain age was associated with lower gray matter density in numerous brain regions. CLBP was associated with greater BA, which was more profound in later life. BA as a holistic metric was sensitive to differences in gray matter density in numerous regions which eluded direct comparison between groups.
Learn More >Owing to their functional diversity, the Mas-related G-protein-coupled receptor (Mrgpr) family has a role in both itch and pain modulation. While primarily linked to pruritis, Mrgprs were originally characterized in small-diameter nociceptive neurons of dorsal root ganglia (DRG) and trigeminal ganglia. This review will focus on the role Mrgpr's have in pain physiology, discussing recent discoveries as well as how Mrgpr's may provide a new target for the treatment of pathological pain.
Learn More >A novel missense mutation in the CACNA1A gene that encodes the pore forming α subunit of the Ca2.1 voltage-gated calcium channel was identified in a patient with trigeminal neuralgia. This mutation leads to a substitution of proline 2455 by histidine (P2455H) in the distal C-terminus region of the channel. Due to the well characterized role of this channel in neurotransmitter release, our aim was to characterize the biophysical properties of the P2455H variant in heterologously expressed Ca2.1 channels. Whole-cell patch clamp recordings of wild type and mutant Ca2.1 channels expressed in tsA-201 cells reveal that the mutation mediates a depolarizing shift in the voltage-dependence of activation and inactivation. Moreover, the P2455H mutant strongly reduced calcium-dependent inactivation of the channel that is consistent with an overall gain of function. Hence, the P2455H Ca2.1 missense mutation alters the gating properties of the channel, suggesting that associated changes in Ca2.1-dependent synaptic communication in the trigeminal system may contribute to the development of trigeminal neuralgia.
Learn More >TRPV1, a member of the transient receptor potential (TRP) family, is a nonselective calcium permeable ion channel gated by physical and chemical stimuli. In the skin, TRPV1 plays an important role in neurogenic inflammation, pain and pruritus associated to many dermatological diseases. Consequently, TRPV1 modulators could represent pharmacological tools to respond to important patient needs that still represent an unmet medical demand. Previously, we reported the design of capsaicinoid-based molecules that undergo dermal deactivation (soft drugs), thus preventing their long-term dermal accumulation. Here, we investigated the pharmacological properties of the lead antagonist, 2-((4-hydroxy-2-iodo-5-methoxybenzyl) amino)-2-oxoethyl dodecanoate (AG1529), on heterologously expressed human TRPV1 (hTRPV1), on nociceptor excitability and on an in vivo model of acute pruritus. We report that AG1529 competitively blocked capsaicin-evoked activation of hTRPV1 with micromolar potency, moderately affected pH-induced gating, and did not alter voltage- and heat-mediated responses. AG1529 displays modest receptor selectivity as it mildly blocked recombinant hTRPA1 and hTRPM8 channels. In primary cultures of rat dorsal root ganglion (DRG) neurons, AG1529 potently reduced capsaicin-evoked neuronal firing. AG1529 exhibited lower potency on pH-evoked TRPV1 firing, and TRPA1-elicited nociceptor excitability. Furthermore, AG1529 abolished histaminergic and inflammation mediated TRPV1 sensitization in primary cultures of DRG neurons. Noteworthy, dermal wiping of AG1529, either in an acetone-based formulation or in an anhydrous ointment, dose-dependently attenuated acute histaminergic itch in a rodent model. This cutaneous anti-pruritic effect was devoid of the normal nocifensive action evoked by the burning sensation of capsaicin. Taken together, these preclinical results unveil the mode of action of AG1529 on TRPV1 channels and substantiate the tenet that this capsaicinoid-based soft drug is a promising candidate for drug development as a topical anti-pruritic and anti-inflammatory medication.
Learn More >The moment-to-moment variability of resting-state brain activity has been suggested to play an active role in chronic pain. Here, we investigated the regional blood-oxygen-level-dependent signal variability (BOLD) and inter-regional dynamic functional connectivity (dFC) in the interictal phase of migraine and its relationship with the attack severity.
Learn More >Monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway, including the fully humanized monoclonal antibody (IgG2Δa) fremanezumab, have demonstrated safety and efficacy for migraine prevention. Clinical trials include responders and nonresponders; efficacy outcomes describe mean values across both groups and thus provide little insight into the clinical benefit in responders. Clinicians and their patients want to understand the extent of clinical improvement in patients who respond. This post hoc analysis of fremanezumab treatment attempts to answer this question: what is the benefit in subjects who responded to treatment during the two, phase 3 HALO clinical trials?
Learn More >Structural studies with an α subunit fragment of voltage-gated calcium (CaV) channels in complex with the CaVβ subunits revealed a high homology between the various CaVα-β subunits, predicting that targeting of this interface would result in nonselective compounds. Despite this likelihood, my laboratory initiated a rational structure-based screening campaign focusing on "hot spots" on the alpha interacting domain (AID) of the CaVβ2a subunits and identified the small molecule 2-(3,5-dimethylisoxazol-4-yl)-N-((4-((3-phenylpropyl)amino)quinazolin-2-yl)methyl)acetamide ( ) which selectively targeted the interface between the N-type calcium (CaV2.2) channel and CaVβ. (i) specifically bound to CaVβ2a; (ii) inhibited CaVβ2 's interaction with CaV.2-AID; (iii) inhibited CaV2.2 currents in sensory neurons; (iv) inhibited pre-synaptic localization of CaV2.2 ; and (v) inhibited spinal neurotransmission, which resulted in decreased neurotransmitter release. was anti-nociceptive in naïve rats and reversed mechanical allodynia and thermal hyperalgesia in rodent models of acute, neuropathic, and genetic pain. In structure-activity relationship (SAR) studies focused on improving binding affinity of , another compound (BTT-369), a benzoyl-3,4-dihydro-1'H,2 H-3,4'-bipyrazole class of compounds, was reported by Chen and colleagues, based on work conducted in my laboratory beginning in 2008. BTT-369 contains tetraaryldihydrobipyrazole scaffold – a chemotype featuring phenyl groups known to be significantly metabolized, lower the systemic half-life, and increase the potential for toxicity. Furthermore, the benzoylpyrazoline skeleton in BTT-369 is patented across multiple therapeutic indications. Prior to embarking on an extensive optimization campaign of , we performed a head-to-head comparison of the two compounds. We conclude that is superior to BTT-369 for on-target efficacy, setting the stage for SAR studies to improve on for the development of novel pain therapeutics.
Learn More >Low back pain (LBP) is highly prevalent in the general population and is responsible for increased health-care costs, pain, impairment of activity, and if chronic, is associated with a range of comorbidities.
Learn More >Several studies of patients with polyneuropathy failed to show differences between patients with and without pain. In the current study, we aimed to explore the association between neuropathic symptoms, mainly pain, and polyneuropathy characteristics.
Learn More >Undocumented immigration is often accompanied by multiple and complex stressors, which over time may increase the risk for chronic pain.
Learn More >Existing studies on cognitive impairments in chronic pain do not investigate peripheral neuropathic pain (PNP) or compare pain conditions in a satisfactory manner. Here we aimed to compare executive dysfunctions in PNP patients with fibromyalgia (FM) and healthy controls (HC). Patients who self-reported cognitive impairments were assessed according to criteria for PNP or FM. Seventy-three patients met criteria and completed testing on executive functioning and IQ measures. We also included twenty matched healthy controls. Regression models controlling for age, sex and IQ, tested associations between group category (PNP, FM or HC) and outcomes. If a substantial association was detected, we followed up with head-to-head comparisons between PNP and FM. Multivariate regression models then tested associations between executive functioning and pain type, controlling for significant confounders. Results from head-to-head comparison between pain conditions showed significant differences on years lived with pain (FM > PNP), the use of anticonvulsants (PNP > FM) and use of analgesics (PNP > FM). When controlled for all significant differences, PNP patients had significantly lower scores on an attention-demanding cued-recall task compared to FM. Poor performance on attention-demanding cued-recall task was associated with PNP, which translate into problems with retaining fast-pace or advanced information.
Learn More >The response to pain is highly individual and can be influenced by complex emotional perception. This study aims to investigate the status of the pain-related emotional response, and the influence on headache characteristics and disability in migraine. We studied the pain-related emotional response in 145 consecutive migraine patients using the Pain Anxiety Symptoms Scale (PASS), the Pain Catastrophizing Scale (PCS), and the Pain Sensitivity Questionnaire (PSQ) and compared them with 106 healthy controls. We investigated the relationship between emotional factors and migraine characteristics. The effect of pain-related emotion on migraine-related disability assessed with the Headache Impact Test-6 (HIT-6) and the Migraine Disability Assessment (MIDAS). Migraine patients showed significantly higher scores on total PASS (p < 0.001), PCS (p < 0.001) and PSQ (p = 0.002) compared to the healthy controls. The HIT-6 was weakly correlated with PASS (r = 0.390, p < 0.001) and PCS (r = 0.354, p < 0.001). PASS-Total (p = 0.001), headache frequency (p = 0.003), and HADS-Anxiety (p = 0.028) were independent variables associated with HIT-6. Headache frequency (p < 0.001) was an independent variable associated with MIDAS. The structural equation model indicated that headache severity has direct loading on emotion and subsequently influenced migraine-related disability. Disability has a significant effect on the frequency of abortive medication use. Migraine patients have altered emotional responses to pain perception. Pain-related anxiety made an important contribution to headache-related disability. The present results suggest that the management of disability by considering various pain-related emotional factors may be necessary for the therapeutic aspects of migraine.
Learn More >To identify and analyze postmarketing case reports of elevated blood pressure (BP) associated with erenumab use.
Learn More >Lumbar Modic change (MC) can serve as a diagnostic marker as well as an independent source of chronic low back pain (CLBP). This study aimed to test for the existence of serum biomarkers in CLBP patients with MC.
Learn More >To determine the absolute and relative intra-rater within-session test-retest reliability of pressure pain threshold (PPT) and mechanical temporal summation of pain (TSP) at the low back and the forearm in healthy participants and to test the influence of the number and sequence of measurements on reliability metrics.
Learn More >To evaluate the sensitivity and specificity of the 6-item Identify Chronic Migraine screener (ID-CM[6]), designed to improve the detection of chronic migraine (CM).
Learn More >Chronic administration of opioids produces physical dependence and opioid-induced hyperalgesia. Users claim the Thai traditional tea "kratom" and component alkaloid mitragynine ameliorate opioid withdrawal without increased sensitivity to pain. Testing these claims, we assessed the combined kratom alkaloid extract (KAE) and two individual alkaloids, mitragynine (MG) and the analog mitragynine pseudoindoxyl (MP), evaluating their ability to produce physical dependence and induce hyperalgesia after chronic administration, and as treatments for withdrawal in morphine-dependent subjects. C57BL/6J mice (n = 10/drug) were administered repeated saline, or graded, escalating doses of morphine (intraperitoneal; i.p.), kratom alkaloid extract (orally, p.o.), mitragynine (p.o.), or MP (subcutaneously, s.c.) for 5 days. Mice treated chronically with morphine, KAE, or mitragynine demonstrated significant drug-induced hyperalgesia by day 5 in a 48 °C warm-water tail-withdrawal test. Mice were then administered naloxone (10 mg/kg, s.c.) and tested for opioid withdrawal signs. Kratom alkaloid extract and the two individual alkaloids demonstrated significantly fewer naloxone-precipitated withdrawal signs than morphine-treated mice. Additional C57BL/6J mice made physically dependent on morphine were then used to test the therapeutic potential of combined KAE, mitragynine, or MP given twice daily over the next 3 days at either a fixed dose or in graded, tapering descending doses. When administered naloxone, mice treated with KAE, mitragynine, or MP under either regimen demonstrated significantly fewer signs of precipitated withdrawal than control mice that continued to receive morphine. In conclusion, while retaining some liabilities, kratom, mitragynine, and mitragynine pseudoindoxyl produced significantly less physical dependence and ameliorated precipitated withdrawal in morphine-dependent animals, suggesting some clinical value.
Learn More >Persistent posttraumatic headache (PPTH), one of the most common symptoms following mild traumatic brain injury, is often associated with substantial functional disability. The objective of this study was to assess the contribution of demographics, headache characteristics, and psychological symptoms to disability associated with PPTH.
Learn More >Chronic pruritus (CP) is a subjective symptom and it is necessary to assess its intensity with validated patient-reported outcome tools in order to allow determination of the treatment course.
Learn More >Evaluate changes from baseline in health-related quality of life (QoL) in Japanese patients with episodic migraine receiving preventive treatment with galcanezumab (GMB).
Learn More >Pain in response to various types of acute injury can be a protective stimulus to prevent the organism from using the injured part and allow tissue repair and healing. On the other hand, neuropathic pain, defined as 'pain caused by a lesion or disease of the somatosensory nervous system', is a debilitating pathology. The TRPA1 neurons in the Dorsal Root Ganglion (DRG) respond to reactive oxygen species (ROS) and induce pain. In acute nerve injury and inflammation, macrophages infiltrating the site of injury undergo an oxidative burst, and generate ROS that promote tissue repair and induce pain via TRPA1. The latter discourages using the injured limb, with a lack of movement helping wound healing. In chronic inflammation caused by diabetes, cancer etc., ROS levels increase systemically and modulate TRPA1 neuronal functions and cause debilitating neuropathic pain. It is important to distinguish between drug targets that elicit protective vs. debilitating pain when developing effective drugs for neuropathic pain. In this context, the connection of the Angiotensin type 2 receptor (ATR) to neuropathic pain presents an interesting dilemma. Several lines of evidence show that ATR activation promotes anti-inflammatory and anti-nociceptive signaling, tissue repair, and suppresses ROS in chronic inflammatory models. Conversely, some studies suggest that ATR antagonists are anti-nociceptive and therefore ATR is a drug target for neuropathic pain. However, ATR expression in nociceptive neurons is lacking, indicating that neuronal ATR is not involved in neuropathic pain. It is also important to consider that Novartis terminated their phase II clinical trial (EMPHENE) to validate that ATR antagonist EMA401 mitigates post-herpetic neuralgia. This trial, conducted in Australia, United Kingdom, and a number of European and Asian countries in 2019, was discontinued due to pre-clinical drug toxicity data. Moreover, early data from the trial did not show statistically significant positive outcomes. These facts suggest that may ATR not be the proper drug target for neuropathic pain in humans and its inhibition can be harmful.
Learn More >Effective prevention of chronic postoperative pain is an important clinical goal, informed by a growing body of studies. Peri-operative regional anaesthesia remains one of the most important tools in the multimodal analgesic toolbox, blocking injury-induced activation and sensitisation of both the peripheral and central nervous system. We review the definition and taxonomy of chronic postoperative pain, its mechanistic basis and the most recent evidence for the preventative potential of multimodal analgesia, with a special focus on regional anaesthesia. While regional anaesthesia targets several important aspects of the mechanistic pathway leading to chronic postoperative pain, evidence for its efficacy is still mixed, possibly owing to the heterogeneity of risk profiles within the surgical patient, but also to variation in techniques and medications reported in the literature.
Learn More >The calcitonin gene-related peptide (CGRP) is a new therapeutic target in migraine-a common disorder resulting in reduced quality of life. The aim of this study was to compare the clinical efficacy of five oral CGRP antagonists with that of a placebo and triptans against acute migraine via meta-analysis.
Learn More >Native Americans (NAs) experience higher rates of chronic pain. To examine the mechanisms for this pain inequity, we have previously shown that NAs report higher levels of pain-related anxiety and pain catastrophizing, which are in turn related to pronociceptive (pain-promoting) processes. But, it is currently unclear why NAs would report greater pain-related anxiety and catastrophizing. Given that NAs are also more likely to experience adverse life events (ALEs) and associated psychological distress, it was hypothesized that higher anxiety/catastrophizing in NAs would be partially explained by higher rates of ALEs and psychological distress. Structural equation modeling was used to analyze these pathways (NA ethnicity ➔ ALEs ➔ psychological distress ➔ pain anxiety/catastrophizing) in 305 healthy, pain-free adults (N = 155 NAs, N = 150 non-Hispanic Whites [NHWs]). Pain-related anxiety and situational pain catastrophizing were assessed in response to a variety of painful tasks. The Life Events Checklist was used to assess cumulative exposure to ALEs that directly happened to each participant. A latent psychological distress variable was modeled from self-reported perceived stress and psychological symptoms. Results found that NAs experienced more ALEs and greater psychological distress which was associated with higher rates of pain-related anxiety and pain catastrophizing. Notably, NAs did not report greater psychological distress when controlling for ALE exposure. This suggests that a higher risk of chronic pain in NAs may be due, in part, to psychological distress, pain-related anxiety, and pain catastrophizing that are promoted by exposure to ALEs. These results highlight several targets for intervention to decrease NA pain risk.
Learn More >The CGRP antagonists offer a novel therapeutic approach in migraine. Their utility in patients with severe forms of chronic migraine is a subject of particular interest. We present outcomes of 9 months of erenumab treatment in a cohort of patients with difficult-to-control chronic migraine, all of whom had prior unsatisfactory response to onabotulinumtoxinA.
Learn More >Many epigenetic regulators are involved in pain-associated spinal plasticity. Coactivator-associated arginine methyltransferase 1 (CARM1), an epigenetic regulator of histone arginine methylation, is a highly interesting target in neuroplasticity. However, its potential contribution to spinal plasticity-associated neuropathic pain development remains poorly explored. Here, we report that nerve injury decreased the expression of spinal CARM1 and induced allodynia. Moreover, decreasing spinal CARM1 expression by Fbxo3-mediated CARM1 ubiquitination promoted H3R17me2 decrement at the K channel promoter, thereby causing K channel epigenetic silencing and the development of neuropathic pain. Remarkably, in naïve rats, decreasing spinal CARM1 using CARM1 siRNA or a CARM1 inhibitor resulted in similar epigenetic signaling and allodynia. Furthermore, intrathecal administration of BC-1215 (a novel Fbxo3 inhibitor) prevented CARM1 ubiquitination to block K channel gene silencing and ameliorate allodynia after nerve injury. Collectively, the results reveal that this newly identified spinal Fbxo3-CARM1-K channel gene functional axis promotes neuropathic pain. These findings provide essential insights that will aid in the development of more efficient and specific therapies against neuropathic pain.
Learn More >Thirty-three US states and Washington, D.C., have enacted medical cannabis laws allowing patients with chronic non-cancer pain to use cannabis, when recommended by a physician, to manage their condition. However, clinical guidelines do not recommend cannabis for treatment of chronic non-cancer pain due to limited and mixed evidence of effectiveness. How state medical cannabis laws affect delivery of evidence-based treatment for chronic non-cancer pain is unclear. These laws could lead to substitution of cannabis in place of clinical guideline-discordant opioid prescribing, reducing risk of opioid use disorder and overdose. Conversely, state medical cannabis laws could lead to substitution of cannabis in place of guideline-concordant treatments such as topical analgesics or physical therapy. This protocol describes a mixed-methods study examining the implementation and effects of state medical cannabis laws on treatment of chronic non-cancer pain. A key contribution of the study is the examination of how variation in state medical cannabis laws' policy implementation rules affects receipt of chronic non-cancer pain treatments.
Learn More >Monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP) pathway have been shown to be effective in migraine prevention. Eptinezumab, erenumab, fremanezumab, and galcanezumb have shown efficacy in clinical trials along with favorable safety and tolerability profiles. Although erenumab is a human mAb and the others have been humanized to varying degrees, they all have the capacity to provoke immune reactions. The present review article aims to discuss the current relationship between mAbs targeting the CGRP pathway (CGRP mAbs) and immunogenicity and their potential clinical implications.
Learn More >This review surveys our current understanding of the impact of parental migraine on children. Understanding the impact of migraine on others in a family unit is critical to describing the full burden of migraine and to developing psychosocial supportive interventions for patients and their families.
Learn More >We aimed to determine the burden of opioid consumption in a cohort of patients with functional gastrointestinal disorders. All patients diagnosed with functional gastrointestinal disorders and referred to our university hospital were evaluated from 2013 to the beginning of 2019. Irritable bowel syndrome and functional dyspepsia diagnoses were determined according to Rome criteria and severity according to irritable bowel syndrome severity scoring system. Vomiting was quantified using a 5-point Likert scale, and constipation severity was measured using the Knowles-Eccersley-Scott-Symptom questionnaires. Quality of life was quantified by the GastroIntestinal Quality of Life Index. Patients were categorized as being treated on a chronic basis with either tramadol, step II opioids, step III opioids or as being opioid-free. 2933 consecutive patients were included. In our cohort, 12.5% had only irritable bowel syndrome, 39.3% had only functional dyspepsia, 24.9% had a combination of both, and 23.4% had other functional gastrointestinal disorders. Among them, the consumption of tramadol, step II (tramadol excluded) and step III opioids was 1.8, 1.3 and 0.3 % respectively in 2013 and 4.3, 3.4 and 1.9% in 2018 ( < 0.03). Opioid consumption was associated with increased vomiting ( = 0.0168), constipation ( < 0.0001), symptom severity ( < 0.001), more altered quality of life ( < 0.0001) and higher depression score ( = 0.0045). In functional gastrointestinal disorders, opioid consumption has increased in the last years and is associated with more GI symptoms (vomiting, constipation and GI severity), higher depression and more altered quality of life.
Learn More >Patients frequently report chronic postsurgical pain (CPSP) after breast cancer surgery (BCS). The paravertebral block (PVB) is an effective technique to reduce acute postoperative pain after BCS, but its efficacy in preventing CPSP is unclear. This meta-analysis evaluates the efficacy of PVB in preventing CPSP after BCS. We searched Medline, Embase, CENTRAL, Database of Abstracts of Reviews of Effects, ClinicalTrials.gov, and WHO International Clinical Trials Registry Platform for studies comparing PVB with control for CPSP prevention after BCS, from inception to April 2020. The primary outcome was CPSP at 6 months, and the secondary outcomes were CPSP at 3 and 12 months, chronic postsurgical neuropathic pain (CPSNP) at 6 months, and PVB-related complications. Data were pooled and analyzed with a random-effects model, and the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) system was used to evaluate the certainty of evidence. A total of 12 studies were included in the study; data for the 6-month time point from 7 studies (2161 patients) were analyzed, and no difference was found between PVB and control in terms of efficacy in preventing CPSP after BCS (risk ratio (RR) 0.82 (95% CI 0.62 to 1.08)), with a moderate quality of evidence according to the GRADE system. Similar results were obtained at 3 and 12 months (RR 0.78 (95% CI 0.57 to 1.06), RR 0.45 (95% CI 0.14 to 1.41), respectively). Data for the 12-month time point from seven studies (2087 patients) were analyzed and showed that PVB protected against CPSNP, with low quality of evidence (RR 0.51 (95% CI 0.31 to 0.85)). In conclusion, CPSP was not found significantly prevented by PVB after BCS despite the limits in the included studies; nevertheless, PVB could prevent CPSNP by impacting the transition from acute to chronic pain.
Learn More >There is interest in whether supplements, including vitamin D and marine omega-3 (n-3) fatty acids, may be effective migraine prophylaxis. However, few studies have evaluated whether vitamin D or n-3 fatty acid supplementation may reduce migraine frequency or severity.
Learn More >To identify the prevalence and characteristics of neuropathic pain (NP) in patients with spinal cord injury (SCI) and to investigate associations between NP and demographic or disease-related variables.
Learn More >Alzheimer's disease and related dementias (ADRD), pain and chronic complex conditions (CCC) often co-occur leading to polypharmacy and with potential inappropriate medications (PIMs) use, are important risk factors for adverse drug reactions and hospitalizations in older adults. Many US veterans are at high risk for persistent pain due to age, injury or medical illness. Concerns about inadequate treatment of pain-accompanied by evidence about the analgesic efficacy of opioids-has led to an increase in the use of opioid medications to treat chronic pain in the Veterans Health Administration (VHA) and other healthcare systems. This study aims to investigate the relationship between receipt of pain medications and centrally (CNS) acting PIMs among veterans diagnosed with dementia, pain intensity, and CCC 90-days prior to hospitalization. The final analytic sample included 96,224 (81.7%) eligible older veterans from outpatient visits between October 2012-30 September 2013. We hypothesized that veterans with ADRD, and severe pain intensity may receive inappropriate pain management and CNS-acting PIMs. Seventy percent of the veterans, and especially people with ADRD, reported severe pain intensity. One in three veterans with ADRD and severe pain intensity have an increased likelihood for CNS-acting PIMs, and/or opioids. Regular assessment and re-assessment of pain among older persons with CCC, patient-centered tapering or discontinuation of opioids, alternatives to CNS-acting PIMs, and use of non-pharmacological approaches should be considered.
Learn More >Pharmacological treatment of osteoarthritis is still inadequate due to the low efficacy of the drugs used. Dexmedetomidine via the intra-articular (i.a.) route might be an option for the treatment of osteoarthritis-associated pain. The present study assessed the analgesic and anti-inflammatory effects of dexmedetomidine administered via the i.a. route in different doses in an experimental model of rat knee osteoarthritis induced with monosodium iodoacetate. Rats were allocated to four groups with 24 animals in each group. The OA (osteoarthritis), DEX-1 (dexmedetomidine in dose of 1μg/kg) and DEX-3 (dexmedetomidine in dose of 3μg/kg) groups were subjected to induction of osteoarthritis through injection of monosodium iodoacetate (MIA) via the i.a. route on the right knee; the control group was not subjected to osteoarthritis induction. Clinical assessment was performed on day 0 (before osteoarthritis induction) and then on days 5, 10, 14, 21 and 28 after induction. Treatment was performed on day 7 via the i.a. route, consisting of dexmedetomidine in doses of 1 and 3 μg/kg, while group OA received 0.9% normal saline. The animals were euthanized on days 7, 14, 21 and 28. Samples of the synovial membrane were collected for histopathological analysis, and the popliteal lymph nodes were collected for measurement of cytokines (interleukin [IL] IL-6, tumor necrosis factor alpha [TNF-α]). Dexmedetomidine (1 and 3 μg/kg) significantly reduced the animals' weight distribution deficit during the chronic-degenerative stage of osteoarthritis and improved the pain threshold throughout the entire experiment. Histological analysis showed that dexmedetomidine did not cause any additional damage to the synovial membrane. The TNF-α levels decreased significantly in the DEX-3 group on day 28 compared with the OA group. Dexmedetomidine reduced pain, as evidenced by clinical parameters of osteoarthritis in rats, but did not have an anti-inflammatory effect on histological evaluation.
Learn More >Many national guidelines recommend the use of patient provider agreements (PPAs) when prescribing opioids for chronic pain. There are no standards for PPA content, readability, or administration processes.
Learn More >Migraine is a cyclic disorder but also a chronic pain condition. Left-right recognition tasks have been shown to be impaired in patients with chronic pain.
Learn More >Local anesthetics are still incompletely understood, and none of the currently available drugs are optimal. The primary target of local anesthetics is the voltage-gated sodium channel (VGSC), where they lead to a temporary interruption of nerve conduction. Unfortunately, local anesthetics are neither specific at blocking a specific VGSC isoform, nor a specific cell type. We realize now that the old classification of A and C fibers according to myelin thickness is outdated, that next to differing myelin configuration, cells differ also by their molecular biology, and that there are close to 20 different neuronal subgroups when function is concerned. The ideal local anesthetic would only block sensory impulses, or even only painful impulses. In the search for that drug, several research avenues have been followed. First, efforts have been undertaken to extend duration of local anesthetics, by additives or extended-release formulation. Second, blockade of specific pain fibers has been attempted by targeting permanently charged anesthetics specifically into nociceptors. Third, blockade of specific isoforms using antibodies, and adaptation of naturally occurring neurotoxins has shown promise. Lastly, combination of local anesthetics with other analgesics may improve their duration of action.
Learn More >The Headache Impact Test-6™ is a widely recommended questionnaire to evaluate the impact of headaches. However, its measurement properties were never evaluated in both primary and secondary headaches, and the Brazilian Portuguese version of the questionnaire was never assessed at all.
Learn More >Among opioid-treated chronic pain patients, response inhibition deficits in emotional contexts may contribute to opioid misuse.
Learn More >Limited evidence exists exploring perceptions of which aspects of a pain management program are perceived as valuable and impactful. The aim of this study was to explore patient beliefs about which aspects of a pain management program were valued and/or had perceived impact. One-on-one structured interviews were conducted with 11 adults three months after their completion of the Spark Pain Program at Westmead Hospital, Sydney, Australia. Concepts in the transcripts were inductively identified and explored, utilizing thematic analysis to better understand their relevance to the study aim. : Four themes emerged: (1) "The program overall was positive, but…"; (2) "I valued my improved knowledge and understanding of pain, but…"; (3) "I valued the stretching/relaxation/pacing/activity monitoring"; and (4) "I valued being part of a supportive and understanding group". Participants reported that they liked being treated as an individual within the group. A lack of perceived personal relevance of key messages was identified in some participants; it appears that patients in pain programs must determine that changes in knowledge, beliefs, and attitudes are personally relevant in order for the changes to have a significant impact on them. This study provides new insights into aspects of a pain management program that were perceived as valuable and impactful, areas that "missed the mark", and hypotheses to guide the implementation of service delivery and program redesign.
Learn More >Chronic tear deficiency enhances the excitability of corneal cold-sensitive nerves that detect ocular dryness, which can lead to discomfort in patients with dry eye disease (DED). However, changes in corneal nerve excitations through the polymodal nociceptor "transient receptor potential vanilloid 1" (TRPV1) and the potential link between this receptor and symptoms of DED remain unclear. In this study, we examined the firing properties of corneal cold-sensitive nerves expressing TRPV1 and possible contributions of chronic tear deficiency to corneal nerve excitability by TRPV1 activation. The bilateral excision of lacrimal glands in guinea pigs decreased the tear volume and increased the frequency of spontaneous eyeblinks 1-4 weeks after surgery. An analysis of the firing properties of the cold-sensitive nerves was performed by single-unit recordings of corneal preparations 4 weeks after surgery in both the sham-operated and gland-excised groups. Perfusion of the TRPV1 agonist, capsaicin (1 μM), transiently increased the firing frequency in approximately 46-48% of the cold-sensitive nerves characterized by low-background activity and high threshold (LB-HT) cold thermoreceptors in both groups. Gland excision significantly decreased the latency of capsaicin-induced firing in cold-sensitive nerves; however, its magnitude was unchanged. Calcium imaging of cultured trigeminal ganglion neurons from both groups showed that intracellular calcium elevation of corneal neurons induced by a low concentration of capsaicin (0.03 μM) was significantly larger in the gland excision group, regardless of responsiveness to cold. An immunohistochemical study of the trigeminal ganglion revealed that gland excision significantly increased the proportion of corneal neurons enclosed by glial fibrillary acidic protein (GFAP)-immunopositive satellite glial cells. Topical application of the TRPV1 antagonist, A784168 (30 μM), on the ocular surface attenuated eye-blink frequency after gland excision. Furthermore, gland excision enhanced blink behavior induced by a low concentration of capsaicin (0.1 μM). These results suggest that chronic tear deficiency sensitizes the TRPV1-mediated response in the corneal LB-HT cold thermoreceptors and cold-insensitive polymodal nociceptors, which may be linked to dry eye discomfort and hyperalgesia resulting from nociceptive stimuli in aqueous-deficient dry eyes.
Learn More >Fibromyalgia (FM), a disease of unknown etiology characterized by chronic generalized pain, is partly recapitulated in an animal model induced by repeated acid saline injections into the gastrocnemius muscle. Here, we attempted to investigate the sex difference in pain hypersensitivity (mechanical allodynia and hypersensitivity to electrical stimulation) in the repeated acid saline-induced FM-like generalized pain (AcGP) model. The first unilateral acid injection into gastrocnemius muscle at day 0/D0 and second injection at D5 (post day 0, P0) induced transient and long-lasting mechanical allodynia, respectively, on both sides of male and female mice. The pretreatment with gonadectomy did not affect the first injection-induced allodynia in both sexes, but gradually reversed the second injection-induced allodynia in male but not female mice. Moreover, the AcGP in male mice was abolished by intracerebroventricular minocycline treatments during D4-P4 or P5-P11, but not by early treatments during D0-D5 in male but not female mice, suggesting that brain microglia are required for AcGP in late-onset and sex-dependent manners. We also found that the intravenous treatments of splenocytes derived from male but not female mice treated with AcGP caused allodynia in naive mice. In addition, the purified CD4 T cells derived from splenocytes of acid-treated male mice retained the ability to cause allodynia in naive mice. These findings suggest that FM-like AcGP has multiple sexual dimorphic mechanisms.
Learn More >Peripheral nerve injuries produce a variety of negative structural and functional changes in the central terminal sites of damaged axons, as well as the injured primary afferents. Such changes have been shown to be involved in the development of neuropathic pain, which includes abnormal pain sensations such as allodynia and hyperalgesia. Since the spinal dorsal horn is the first central site where signals from peripheral sensory nerves are transmitted and shows a variety of changes after peripheral nerve injury or chronic inflammation of peripheral tissues, it is one of the most important sites contributing to the mechanisms underlying the development of neuropathic pain. The functional disruption of inhibitory interneurons and glial activation in the spinal dorsal horn after peripheral nerve injury cause reorganization of neuronal circuits and changes in the excitability of second-order neurons. These events are involved in the development or maintenance of neuropathic pain. Here, we describe the interactions of primary afferents, interneurons, and glial cells that may cause reorganization of synaptic inputs to spinal dorsal horn neurons after peripheral nerve injury.
Learn More >Diabetes is an increasingly prevalent disorder affecting nearly 1-in-5 adults, of which half will experience diabetic peripheral neuropathy (DPN) and a quarter will suffer from diabetic peripheral nerve pain (DPNP), severely impacting quality of life. The currently approved treatment options are typically centrally acting agents whose use is limited by systemic effects and drug interactions. The capsaicin 8% dermal patch was recently approved by the U.S. FDA for the treatment of DPNP.
Learn More >Vincristine (VCR) is commonly used to treat a variety of hematological malignancies and solid tumors in pediatric and adult patients. However, peripheral neuropathy is a dose-limiting side effect that leaves some patients with functional disability and long-term pain. Oxytocin (OT) has demonstrated analgesic and anti-inflammatory properties, but there is no evidence regarding its effects on VCR-induced neurotoxicity. Therefore, we evaluated the potential protective effects of OT on VCR-induced neurotoxicity. In vitro, VCR (0.005 ∼ 0.1 µmol/l) and OT (10 ∼ 10 mol/l) were added into cultured primary dorsal root ganglion (DRG) neurons of mice. The length of neurites was counted by using immunofluorescence. In vivo, neurotoxicity was induced in mice by administration of VCR (0.1 mg/kg, intraperitoneal injection for 14 days) with or without pretreatment of OT (0.1 mg/kg or 1 mg/kg). Atosiban, an OT receptor (OTR) antagonist and OTR knockout (KO) mice were used for evaluating effects of OTR. Mechanical hyperalgesia was measured by using von Frey filaments. Histology of plantar skin, sciatic nerve and DRG was observed by using transmission electron microscopy (TEM) and hematoxylin-eosin (HE) staining. Results indicated that OT alleviated VCR-induced neurite damage in cultured primary DRG neurons in vitro. In vivo, OT ameliorated VCR-induced hyperalgesia. Histologically, OT attenuated the VCR-induced damages of nerve endings, myelin sheaths and Schwann cells in sciatic nerve and DRG. These effects were antagonized by atosiban. In addition, OTR knockout mice exhibited more severe hyperalgesia than wild-type mice. Globally, these results indicated that OT may have neuroprotective effects on vincristine-induced neurotoxicity in mice.
Learn More >Patient beliefs about pain and opioids have been reported from qualitative data. To overcome limitations of unstructured assessments and small sample sizes, we determined if pain and pain medication beliefs varied by chronic pain status and opioid analgesic use (OAU) duration in primary care patients.
Learn More >Peripheral neuropathy in patients with rheumatoid arthritis is associated with a maladaptive autoimmune response that may cause chronic pain and disability. Nerve conduction studies are the routine method performed when rheumatologists presume its presence. However, this approach is invasive, may not reveal subtle malfunctions in the early stages of the disease, and does not expose abnormalities in structures surrounding the nerves and muscles, limiting the possibility of a timely diagnosis. This work aims to present a narrative review of new technologies for the clinical assessment of peripheral neuropathy in Rheumatoid Arthritis. Through a bibliographic search carried out in five repositories, from 1990 to 2020, we identified three technologies that could detect peripheral nerve lesions and perform quantitative evaluations: (1) magnetic resonance neurography, (2) functional magnetic resonance imaging, and (3) high-resolution ultrasonography of peripheral nerves. We found these tools can overcome the main constraints imposed by the previous electrophysiologic methods, enabling early diagnosis.
Learn More >Diurnal variations in pain hypersensitivity are common in chronic pain disorders. Temporal exacerbation of neuropathic pain hypersensitivity is dependent on diurnal variations in glucocorticoid secretion from the adrenal glands. We previously demonstrated that spinal expression of serum- and glucocorticoid-inducible kinase-1 (SGK-1) is associated with glucocorticoid- induced exacerbation of pain hypersensitivity, but there are no available strategies to inhibit SGK-1 in the spinal cord. By screening a clinically approved drug library (more than 1,200 drugs), we found that sulfasalazine (SSZ) has inhibitory effects on SGK-1. SSZ is a prodrug composed of 5-aminosalicylic acid and sulfapyridine linked by N=N bond, which is therapeutically effective for inflammatory bowel diseases. However, the N=N bond in SSZ was necessary for its inhibitory action against SGK-1. Although intrathecal injection of SSZ to nerve-injured mice significantly alleviated mechanical pain hypersensitivity, no significant anti- neuropathic pain effects of SSZ were detected after oral administration due to its low bioavailability and limited spinal distribution, which were associated with efflux by the xenobiotic transporter breast cancer resistance protein (BCRP). Concomitant oral administration of SSZ with febuxostat (FBX), which is an approved drug to inhibit BCRP, improved the distribution of SSZ to the spinal cord. The concomitant oral administration with FBX also increased the anti-neuropathic pain effects of SSZ. Our study revealed a previously unrecognized pharmacological effect of SSZ to alleviate SGK-1-induced painful peripheral neuropathy, and concomitant oral administration of SSZ with FBX may also be a preventative option for diurnal exacerbation of neuropathic pain hypersensitivity.
Learn More >To date, treatment options (i.e. psychotherapy, antidepressant medications) for patients with posttraumatic stress disorder (PTSD), are relatively few, and considering their limited efficacy, novel therapies have gained interest among researchers and treatment providers alike. Among patients with chronic pain (CP) about one third experience comorbid PTSD, which further complicates their already challenging pharmacological regimens. Low dose ketamine infusion has shown promise in PTSD, and in treatment of CP, however they have not been studied in comorbid population and under rigorous control conditions.
Learn More >Spinal inflammation is a pathophysiological state of neuropathic pain (NP). The subsequent microglial activation and neuroinflammatory response are contributing factors for long-lasting behavioral hypersensitivity. Valproic acid (VPA), a histone deacetylase inhibitor, has promising anti-inflammatory and neuroprotective properties for clinical use in the treatment of neurological disorders. However, the underlying mechanisms of its effects on NP have not been determined. This study aimed to clarify the possible mechanisms by which VPA alleviates NP in rat models induced by spinal nerve ligation (SNL). Intraperitoneal injection of VPA (300 mg/kg) efficiently attenuated mechanical allodynia in rats with NP. VPA exerted anti-inflammatory effects by downregulating proinflammatory cytokines (tumor necrosis factor-α, cytokines interleukin-1β, cytokines interleukin-6; TNF-α, IL-1β, and IL-6) and upregulating anti-inflammatory cytokines (transforming growth factor-β, cytokines interleukin-10, cytokines interleukin-4; TGF-β, IL-10 and IL-4). Additionally, VPA suppressed spinal microgliosis and promoted the polarization of microglia towards the M2 phenotype to further ameliorate spinal neuroinflammation. VPA also exerted neuroprotective effects by decreasing spinal cell apoptosis. The anti-inflammatory and neuroprotective effects may have depended on changes in nuclear histone deacetylase 3 (HDAC3) expression following VPA treatment. Moreover, VPA treatment inhibited nuclear factor-κB (NF-κB) p65 nuclear expression and upregulated acetylated the signal transducer and activator of transcription 1 (STAT1). In addition, VPA suppressed SNL-induced phosphorylation of Janus Kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3). Taken together, our results demonstrate that VPA is a promising anti-inflammatory agent suitable for NP therapy that regulates microglial function and suppresses spinal neuroinflammation via the STAT1/NF-κB and JAK2/STAT3 signaling pathways.
Learn More >A few modes of perioperative local analgesia have been studied in order to reduce postoperative pain after laparoscopy, including preemptive local anesthetics in the trocar sites and intraperitoneal anesthetics administration at the end of the surgery. However, the evidence regarding their efficacy are conflicting. In addition, the combination of both aforementioned methods has been rarely studied. Our aim was to evaluate whether subcutaneous trocar site and/or intraperitoneal analgesia reduce pain after gynecologic operative laparoscopy. This was a single-centered, randomized, controlled, double-blinded trial. The patients were randomly assigned to one of four equally sized groups: group 1-subcutaneous and intraperitoneal analgesia; group 2-subcutaneous analgesia and intraperitoneal placebo; group 3-subcutaneous placebo and intraperitoneal analgesia; Group 4-subcutaneous and intraperitoneal placebo. The patients, the surgeons, and the pain evaluators were all blinded to the patient's allocation. Included were patients who underwent elective operative laparoscopy. Exclusion criteria were: active infection, pregnancy, known sensitivity to Bupivacaine-Hydrochloride, chronic pelvic pain, surgeries with additional vaginal procedures, conversion to laparotomy, and malignancy. A total of 9 ml of Bupivacaine-Hydrochloride (Marcaine) 0.5%, or Sodium-Chloride 0.9%, as a placebo, were injected subcutaneously to the trocar sites (3 ml to each trocar site), prior to skin incision. In addition, 10 ml of Bupivacaine-Hydrochloride 0.5%, diluted with 40 ml of Sodium-Chloride 0.9% (a total of 50 ml solution), or 50 ml of Sodium-Chloride 0.9%, as a placebo, were injected intraperitoneally at the end of the surgery. By utilizing the 10 cm Visual-analogue-scale (VAS) we assessed post-operative pain at rest at 3, 8, and 24 h, and during ambulation at 8 and 24 h. The study was approved by the local Institutional Review Board and has been registered at clinicaltrials.gov. We conformed to the CONSORT recommendations. Between December 2016 and July 2019, a total of 119 patients were included in the study. Demographic and interventional characteristics were similar among the groups. The level of postoperative pain, either at rest or with change of position, was not significantly different between the groups, at all-time points. Application of subcutaneous and/or intraperitoneal analgesia is not effective in reducing pain after gynecologic operative laparoscopy.Clinical trial identification number: NCT02976571. Date of trial registration 11/29/2016. URL of the registration site: https://clinicaltrials.gov .
Learn More >The aim of the present study was to investigate the effects of microRNA (miR)‑142‑3p on neuropathic pain caused by sciatic nerve injury in chronic compression injury (CCI) rats, and further investigate its mechanism. Rat experiments were divided into four parts in the study. In the first part, the rats were divided into the Sham and CCI groups. The expression of miR‑142‑3p, AC9 and cAMP were detected. In the second part, the rats were divided into the Sham, CCI, miR‑142‑3p mimic, mimic‑negative control (NC), miR‑142‑3p small interfering RNA (siRNA) and siRNA‑NC groups. The expression of cAMP and the levels of AMPK pathway‑related proteins were detected. In the third part, the rats were randomly divided into Sham, CCI, AC9 mimic, mi‑NC, AC9 siRNA and si‑NC groups. Double luciferase reporter assay was used to analyse the targeting relationship between miR‑142‑3p and AC9. In the fourth part, the rats were divided into the Sham, CCI, miR‑142‑3p siRNA, AC9 mimic, miR‑142‑3p siRNA + AC9 siRNA, cAMP activator (Forskolin) and miR‑142‑3p siRNA + cAMP inhibitor groups. The expression of miR‑142‑3p was significantly increased while AC9 and cAMP expression significantly decreased in CCI rats. However, AC9 overexpression significantly increased the levels of cAMP protein. Luciferase reporter assay also proved that AC9 is the target gene of miR‑142‑3p. Moreover, miR‑142‑3p silencing was found to reduce neuropathic pain in CCI rats by upregulating the expression of AC9. It was also found that cAMP activation can relieve neuropathic pain and promote the expression of AMPK‑related proteins in CCI rats. Silencing miR‑142‑3p can target AC9 to reduce the expression of inflammatory factors and neuropathic pain in CCI rats by increasing the expression of cAMP/AMPK pathway‑related proteins.
Learn More >The use of exercise is a potential treatment option to modulate pain (exercise-induced hypoalgesia). The pain threshold (PT) response is a measure of pain sensitivity that may be a useful marker to assess the effect of physical exercise on pain modulation.
Learn More >The increasing trends in opioid prescribing and opioid-related deaths in England are concerning. A greater understanding of the association of deprivation with opioid prescribing is needed to guide policy responses and interventions.
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