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About half of patients with spinal cord injury (SCI) develop debilitating central neuropathic pain (CNP), with no effective treatments. Thus, effective, safe, and novel therapies are needed urgently. Previously, docosahexaenoic acid (DHA) was reported to confer neuroprotection in preclinical SCI models. However, its therapeutic potential on SCI-CNP remains to be elucidated. Here, we demonstrated for the first time that intravenous DHA administrations with 3-day intervals (250 nmol/kg; starting 30 minutes after injury and maintained for 6 weeks) effectively prevented SCI-CNP development in a clinically relevant rat contusion model. SCI-CNP was assessed by a novel sensory profiling approach combining evoked pain measures and pain-related ethologically relevant rodent behaviours (burrowing, thigmotaxis, and place/escape avoidance) to mimic those for measuring human (sensory, affective, cognitive, and spontaneous) pain. Strikingly, already established SCI-CNP could be abolished partially by similar DHA administrations, starting from the beginning of week 4 after injury and maintained for 4 weeks. At spinal (epicenter and L5 dorsal horns) and supraspinal (anterior cingulate cortex) levels, both treatment regimens potently suppressed microglial and astrocyte activation, which underpins SCI-CNP pathogenesis. Spinal microgliosis, a known hallmark associated with neuropathic pain behaviours, was reduced by DHA treatments. Finally, we revealed novel potential roles of peroxisome proliferator-activated and retinoid X receptors and docosahexaenoyl ethanolamide (DHA's metabolite) in mediating DHA's effects on microglial activation. Our findings, coupled with the excellent long-term clinical safety of DHA even in surgical and critically ill patients, suggest that systemic DHA treatment is a translatable, effective, safe, and novel approach for preventing and managing SCI-CNP.
Learn More >Ubrogepant is an oral, small-molecule calcitonin gene-related peptide receptor antagonist for acute migraine treatment.
Learn More >Our tibial fracture orthopaedic injury model in mice recapitulates the major manifestations of complex trauma including nociceptive sensitization, bone fracture, muscle fibrosis and muscle fibre loss. Delayed exercise after complex orthopaedic trauma results in decreased muscle fibrosis and improved pain Losartan, an angiotensin-receptor blocker with antifibrotic abilities, recapitulates the effect of exercise on post-injury recovery and may provide an enhanced recovery option for those who are unable to exercise after injury ABSTRACT: Chronic pain and disability after limb injury are major public health problems. Early mobilization after injury improves functional outcomes for patients but when and how to implement rehabilitation strategies remains a clinical challenge. Additionally, whether the beneficial effects of exercise can be reproduced using pharmacological tools remains unknown and may benefit patients who are unable to exercise due to immobilization. We developed a murine model of orthopaedic trauma combining tibia fracture and pin fixation with muscle damage. Behavioral measures included mechanical nociceptive thresholds and distances run on exercise wheels. Bone healing was quantified using microCT scanning, and muscle fibre size distribution and fibrosis were followed using immunohistochemistry. We found that the model provided robust mechanical allodynia, fibrosis and a shift to smaller average muscle fibre size lasting up to 5 weeks from injury. We also observed that allowing "late" (weeks 1-2) rather than "early" (weeks 0-1) exercise after injury resulted in greater overall running activity and greater reversal of allodynia. In parallel, the late running paradigm was associated with reduced muscle fibrosis, earlier increase in muscle fibre diameter and a short-term benefit in reducing callus volume. Providing the anti-fibrotic angiotensin receptor blocker losartan to mice in drinking water reduced both allodynia and muscle fibrosis. Combining losartan and late exercise provided no additional benefit. We conclude that early healing after orthopaedic trauma must be allowed prior to the initiation of exercise to achieve optimal pain, functional and physiological outcomes and that losartan is a viable candidate for translational studies. This article is protected by copyright. All rights reserved.
Learn More >The transient receptor potential ankyrin 1 (TRPA1) channel functions as an irritant sensor and is a therapeutic target for treating pain, itch, and respiratory diseases. As a ligand-gated channel, TRPA1 can be activated by electrophilic compounds such as allyl isothiocyanate (AITC) through covalent modification or activated by noncovalent agonists through ligand binding. However, how covalent modification leads to channel opening and, importantly, how noncovalent binding activates TRPA1 are not well-understood. Here we report a class of piperidine carboxamides (PIPCs) as potent, noncovalent agonists of human TRPA1. Based on their species-specific effects on human and rat channels, we identified residues critical for channel activation; we then generated binding modes for TRPA1-PIPC interactions using structural modeling, molecular docking, and mutational analysis. We show that PIPCs bind to a hydrophobic site located at the interface of the pore helix 1 (PH1) and S5 and S6 transmembrane segments. Interestingly, this binding site overlaps with that of known allosteric modulators, such as A-967079 and propofol. Similar binding sites, involving π-helix rearrangements on S6, have been recently reported for other TRP channels, suggesting an evolutionarily conserved mechanism. Finally, we show that for PIPC analogs, predictions from computational modeling are consistent with experimental structure-activity studies, thereby suggesting strategies for rational drug design.
Learn More >Despite its prevalence and high disease burden, the pathophysiological mechanisms underlying chronic migraine (CM) are not well understood. As CM is a complex disorder associated with a range of sensory, cognitive, and affective comorbidities, examining structural network disruption may provide additional insights into CM symptomology beyond studies of focal brain regions. Here, we compared structural interconnections in patients with CM (n = 52) and healthy controls (HC) (n = 48) using MRI measures of cortical thickness and subcortical volume combined with graph theoretical network analyses. The analysis focused on both local (nodal) and global measures of topology to examine network integration, efficiency, centrality, and segregation. Our results indicated that patients with CM had altered global network properties that were characterized as less integrated and efficient (lower global and local efficiency) and more highly segregated (higher transitivity). Patients also demonstrated aberrant local network topology that was less integrated (higher path length), less central (lower closeness centrality), less efficient (lower local efficiency) and less segregated (lower clustering). These network differences not only were most prominent in the limbic and insular cortices but also occurred in frontal, temporal, and brainstem regions, and occurred in the absence of group differences in focal brain regions. Taken together, examining structural correlations between brain areas may be a more sensitive means to detect altered brain structure and understand CM symptomology at the network level. These findings contribute to an increased understanding of structural connectivity in CM and provide a novel approach to potentially track and predict the progression of migraine disorders.This study is registered on ClinicalTrials.gov (Identifier: NCT03304886).
Learn More >Chronic itch is a highly debilitating symptom among patients with inflammatory skin diseases. Recent studies have revealed that gastrin-releasing peptide (GRP) and its receptor (gastrin-releasing peptide receptor [GRPR]) in the spinal dorsal horn (SDH) play a central role in itch transmission.
Learn More >The ability to sense visceral pain during appendicitis is diminished with age leading to delay in seeking healthcare and poorer clinical outcomes. To understand the mechanistic basis of this phenomenon, we examined visceral nociception in aged mouse and human tissue. Inflamed and non-inflamed appendix was collected from consenting patients undergoing surgery for the treatment of appendicitis or bowel cancer. Supernatants were generated by incubating samples in buffer and used to stimulate multiunit activity in intestinal preparations, or single unit activity from teased fibres in colonic preparations, of young and old mice. Changes in afferent innervation with age were determined by measuring the density of CGRP positive afferent fibres and by counting dorsal root ganglia back-labelled by injection of tracer dye into the wall of the colon. Finally, the effect of age on nociceptor function was studied in mouse and human colon. Afferent responses to appendicitis supernatants were greatly impaired in old mice. Further investigation revealed this was due to a marked reduction in the afferent innervation of the bowel, and a substantial impairment in the ability of the remaining afferent fibres to transduce noxious stimuli. Translational studies in human tissue demonstrated a significant reduction in the multiunit but not the single unit colonic mesenteric nerve response to capsaicin with age, indicative of a loss of nociceptor innervation. Our data demonstrates that anatomical and functional deficits in nociception occur with age, underpinning the atypical or silent presentation of appendicitis in the elderly.
Learn More >Migraine with brainstem aura is a rare subtype of migraine with aura. Although this entity has been known for many years, its diagnosis and even its existence are still a matter of debate. Previous studies demonstrated that current diagnostic criteria for migraine with brainstem aura are too open and brainstem symptoms may originate within the cortex and not in the brainstem. The aims of the present study were to analyse whether aura from the brainstem exists, how prevalent such a core syndrome is, to analyse if current diagnostic criteria define such a core syndrome and, if necessary, to develop new diagnostic criteria that define only the core syndrome. We analysed all migraine with brainstem aura cases described in detail in the literature, clinical cases from the Danish Headache Center (DHC) and our large sample of telephone interviewed cases with migraine with aura. We selected the 20 most convincing cases from the literature and convincing cases from the DHC. Of 79 migraine with brainstem aura cases described in detail in the literature, 44 fulfilled the diagnostic criteria for migraine with brainstem aura of the International Classification of Headache Disorders, 3rd edition (ICHD-3). In the DHC after face-to-face interview, neurological examination and imaging, four migraine with brainstem aura of 293 cases with migraine with aura (1.37%) were found, corresponding to 0.04% of the general population. The 20 most convincing cases had symptoms that likely originated in the brainstem. Our telephone-interviewed cohort included 1781 subjects with a diagnosis of migraine with aura or probable migraine with aura. Of these, 228 fulfilled the diagnostic criteria for migraine with brainstem aura of the ICHD-3. Thus, using telephone interview diagnosis according to current diagnostic criteria results in too many cases of migraine with brainstem aura being diagnosed. Therefore, we developed stricter diagnostic criteria in an attempt to include only those rare cases that definitely have aura originating from the brainstem. Migraine with brainstem aura does exist, but it is very rare. Existing diagnostic criteria are too unspecific, but it was possible to develop tighter criteria that define a core syndrome probably caused by brainstem dysfunction.
Learn More >Exposure to prenatal maternal stress impacts adult behavioral outcomes and has been suggested as a risk factor for chronic pain. However, the neurobiological mechanisms implicated are not well-characterized. In this study, we analyzed the effect of a prenatal maternal stress on the development of neuropathic pain-related behaviours and gene expression in the frontal cortex and hippocampus in adult offspring following chronic constriction injury of the sciatic nerve in male and female CD1 mice. Nerve injury-induced mechanical hypersensitivity was amplified in both male and female prenatally-stressed offspring, suggesting that prenatal stress exacerbates pain after injury. Analysis of mRNA expression of genes related to epigenetic regulation and stress responses in the frontal cortex and hippocampus, brain structures implicated in chronic pain, showed distinct sex and region-specific patterns of dysregulation. In general, mRNA expression was most frequently altered in the male hippocampus and effects of prenatal stress were more prevalent than effects of nerve injury in both supraspinal areas. These findings demonstrate the impact of prenatal stress on behavioral sensitivity to a painful injury. Changes in the expression of epigenetic- and stress-related genes suggest a possible mechanism by which the early life stress becomes embedded in the central nervous system. Increased understanding of the interactions among early-life stress, sex, and pain may lead to the identification of novel therapeutic targets and epigenetic drugs for the treatment of chronic pain disorders.
Learn More >Neuropathic pain is difficult to treat and remains a major clinical challenge worldwide. While the mechanisms which underlie the development of neuropathic pain are incompletely understood, interferon signaling by the immune system is known to play a role. Here, we demonstrate a role for IFNβ in attenuating mechanical allodynia induced by the spared nerve injury in mice. The results show that intrathecal administration of IFNβ (dosages up to 5000U) produces significant, transient, and dose-dependent attenuation of mechanical allodynia without observable effects on motor activity or feeding behavior, as is common with IFN administration. This analgesic effect is mediated by the ubiquitin-like protein ISG15, which is potently induced within the spinal cord following intrathecal delivery of IFNβ. Both free and conjugated ISG15 are elevated following IFNβ treatment, and this effect is increased in UBP43 mice lacking a key deconjugating enzyme. The IFNβ-mediated analgesia reduces MAPK signaling activation following nerve injury, and this effect requires induction of ISG15. These findings highlight a new role for IFNβ, ISG15 and MAPK signaling in immunomodulation of neuropathic pain and may lead to new therapeutic possibilities. Perspective: Neuropathic pain is frequently intractable in a clinical setting, and new treatment options are needed. Characterizing the anti-nociceptive potential of IFNβ and the associated downstream signaling pathways in preclinical models may lead to the development of new therapeutic options for debilitating neuropathies.
Learn More >Migraine is characterized by sensory hypersensitivity and habituation deficits. Slow brushing over the skin activates C-tactile nerve fibers, which mediate pleasant touch and analgesic effects in healthy subjects. As this function is altered in painful conditions, we aimed to examine whether the C-tactile processing is disrupted in migraines.
Learn More >Avoidance is considered a key contributor to the development and maintenance of chronic pain disability, likely through its excessive generalization. This study investigated whether acquired avoidance behavior generalizes to novel but similar movements. Using a robotic arm, participants moved their arm from a starting to a target location via one of three possible movement trajectories. For the Experimental Group, the shortest, easiest trajectory was always paired with pain (T1 = 100% reinforcement/no resistance and deviation). Pain could be partly or completely avoided by choosing increasingly effortful movements (T2 = 50% reinforcement, moderate resistance/deviation; T3 = 0% reinforcement, strongest resistance/largest deviation). A Yoked Group received the same number of painful stimuli irrespective of their own behavior. Outcomes were self-reported fear of movement-related pain, pain-expectancy, avoidance behavior, (maximal deviation from the shortest trajectory), and trajectory choice behavior. We tested generalization to three novel trajectories (G1-3) positioned next to the acquisition trajectories. Whereas acquired fear of movement-related pain and pain-expectancy generalized in the Experimental Group, avoidance behavior did not, suggesting that threat beliefs and high-cost avoidance may not be directly related. The lack of avoidance generalization may be due to a perceived context-switch in the configurations of the acquisition and the generalization phases.
Learn More >Transcutaneous electrical nerve stimulation (TENS) promotes antinociception by activating the descending pain modulation pathway and consequently releasing endogenous analgesic substances. In addition, recent studies have shown that the endocannabinoid system controls pain. Thus, the present study investigated the involvement of the endocannabinoid system in TENS-induced antinociception of cancer pain using a cancer pain model induced by intraplantar (i.pl.) injections of Ehrlich tumor cells in male Swiss mice. Low- and high-frequency TENS was applied for 20 min to the mice's paws, and to investigate the involvement of the endocannabinoid system were used the N-(peperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pitazole-3-carboixamide (AM251), a cannabinoid CB receptor antagonist and (5Z,8Z,11Z,14Z)-5,8,11,14-eicosatetraenyl-methylester phosphonofluoridic acid (MAFP), an inhibitor of the endocannabinoid metabolizing enzyme fatty acid amide hydrolase, injected by via i.pl., intrathecal (i.t.), and intra-dorsolateral periaqueductal gray matter (i.dl.PAG). Furthermore, liquid chromatography-tandem mass spectrometry, western blot, and immunofluorescence assays were used to evaluate the endocannabinoid anandamide (AEA) levels, cannabinoid CB receptor protein levels, and cannabinoid CB receptor immunoreactivity, respectively. Low- and high-frequency TENS reduced the mechanical allodynia induced by Ehrlich tumor cells and this effect was reversed by AM251 and potentiated by MAFP at the peripheral and central levels. In addition, TENS increased the AEA levels and the cannabinoid CB receptor protein levels and immunoreactivity in the paw, spinal cord, and dorsolateral PAG. These results suggest that low- and high-frequency TENS is effective in controlling cancer pain, and the endocannabinoid system is involved in this effect at both the peripheral and central levels. Perspective: TENS is a non-pharmacological strategy that may be used to control cancer pain. Identification of a new mechanism involved in its analgesic effect could lead to the development of clinical studies as well as an increase in its application, lessening the need for pharmacological treatments.
Learn More >In well-controlled rheumatoid arthritis (RA) without significant joint damage, a substantial proportion of patients complain of persistent pain. Previous studies have identified different pain phenotypes in RA, in which non-nociceptive pain phenotypes are associated with higher concurrent disease activity scores. In this longitudinal study, we explored associations between pain phenotypes and long-term disease activity outcome in RA patients. Secondly, we explored whether pain phenotype is associated with comorbid conditions.
Learn More >Spicy-food intake has been shown to affect various human physiological systems and diseases. This study tested the analgesia effect caused by stimulation of a spicy sensation (spicy stimulation) and explored the effect of spicy-food consumption on human basal pain sensitivity. A total of 60 healthy undergraduates were included in the primary study. Placebo and sweet stimulation were used as reference interventions. Pressure and cold-pain thresholds were measured before and after taste stimulation. The frequency of spicy-food intake was also evaluated. An additional 100 subjects were recruited to validate the results. Compared to placebo stimulation, both pressure and cold-pain thresholds increased during spicy stimulation (P<0.05). The increased thresholds remained, even when the taste stimulation residue was nearly eliminated (P<0.05). The pressure (10.0[2.1]vs.12.7[3.0]kg/cm, P<0.001) and cold-pain (4.4[1.6]vs.6.2[2.7]seconds, P=0.003) thresholds in subjects who consume spicy food ≥ 3 days/week were significantly lower than in those who consume it < 3 days/week. In the validation population, the frequency of spicy-food intake was negatively associated with subjects' pressure (β=-0.218, P=0.013) and cold-pain (β=-0.205, P=0.035) thresholds. Spicy stimulation has an analgesia effect on adults that persists even after the taste stimulation stops. Conversely, a long-term spicy diet can reduce the human basal pain threshold. TRIAL REGISTRATION: The study protocol was approved by the Medical Ethics Committee of the Second Affiliated Hospital of Army Medical University, People's Liberation Army (identification No., 2017-023-01), and it was registered on the Chinese Clinical Trial Registry at www.chictr.org.cn (No. ChiCTR1800015053). PERSPECTIVE: This study directly examined the effects of stimulation of a spicy sensation on adult pain sensitivity and was the first to explore the relationship between long-term spicy-food intake and human pain sensitivity. The results provide evidence for future clinical pain intervention and individualized pain treatment.
Learn More >Glial cells in the central nervous system play a key role in neuroinflammation and subsequent central sensitization to pain. They are therefore involved in the development of persistent pain. One of the main sites of interaction of the immune system with persistent pain has been identified as neuro-immune crosstalk at the glial-opioid interface. The present study examined a potential association between the DNA methylation of two key players of glial/opioid intersection and persistent postoperative pain.
Learn More >This is an observational cohort study.
Learn More >Using experimental, yet realistic, headache calendars, this laboratory study evaluated the ability of individuals to identify the degree of association between triggers and headaches.
Learn More >Neutrophils are the first immune cells that enter the skin and cause itch in atopic dermatitis.
Learn More >Peripheral nerve injury can lead to remodeling of brain circuits, and this can cause chronification of pain. We have recently reported that male mice subjected to spared injury of the sciatic nerve undergo changes in the function of the medial prefrontal cortex (mPFC) that culminate in reduced output of layer 5 pyramidal cells. More recently, we have shown that this is mediated by alterations in synaptic inputs from the basolateral amygdala (BLA) into GABAergic interneurons in the mPFC. Optogenetic inhibition of these inputs reversed mechanical allodynia and thermal hyperalgesia in male mice. It is known that the processing of pain signals can exhibit marked sex differences. We therefore tested whether the dysregulation of BLA to mPFC signaling is equally altered in female mice. Injection of AAV-Arch3.0 constructs into the BLA followed by implantation of a fiberoptic cannula into the mPFC in sham and SNI operated female mice was carried out, and pain behavioral responses were measured in response to yellow light mediated activation of this inhibitory opsin. Our data reveal that Arch3.0 activation leads to a marked increase in paw withdrawal thresholds and latencies in response to mechanical and thermal stimuli, respectively. However, we did not observe nerve injury-induced changes in mPFC layer 5 pyramidal cell output in female mice. Hence, the observed light-induced analgesic effects may be due to compensation for dysregulated neuronal circuits downstream of the mPFC.
Learn More >The popular herbal medicine, St. John's wort, is a potent inducer of several cytochrome P450 enzymes, including CYP3A4, which plays a role in the metabolism of fentanyl. St. John's wort may also influence the expression of P-glycoprotein, which can alter the movement of drugs across the blood-brain barrier.
Learn More >Synovitis is one of the possible pain generators in osteoarthritis (OA) and is associated with upregulation of proinflammatory cytokines, which can lead to worsening of the postoperative pain. This exploratory study aimed to investigate the association between perioperative synovitis and self-reported pain 12 months after total knee arthroplasty (TKA) in patients with OA.
Learn More >Limited research suggests commonalities between urological chronic pelvic pain syndromes (UCPPS) and other nonurological chronic overlapping pain conditions (COPCs) including fibromyalgia, chronic fatigue syndrome, and irritable bowel syndrome. The goal of this case-control study was to examine similarities and differences between UCPPS and these other COPCs.
Learn More >Peripheral and central neurons in the pain pathway are well equipped to detect and respond to extracellular stimuli such as pro-inflammatory mediators and neurotransmitters through the cell surface expression of receptors that can mediate rapid intracellular signaling. Following injury or infection, activation of cell surface G protein-coupled receptors (GPCRs) initiates cell signaling processes that lead to the generation of action potentials in neurons or inflammatory responses such as cytokine secretion by immune cells. However, it is now appreciated that cell surface events alone may not be sufficient for all receptors to generate their complete signaling repertoire. Following an initial wave of signaling at the cell surface, active GPCRs can engage with endocytic proteins such as the adaptor protein β-arrestin (βArr) to promote clathrin-mediated internalization. Classically, βArr-mediated internalization of GPCRs was hypothesized to terminate signaling, yet for multiple GPCRs known to contribute to pain, it has been demonstrated that endocytosis can also promote a unique "second wave" of signaling from intracellular membranes, including those of endosomes and the Golgi, that is spatiotemporally distinct from initial cell-surface events. In the context of pain, understanding the cellular and molecular mechanisms that drive spatiotemporal signaling of GPCRs is invaluable for understanding how pain occurs and persists, and how current analgesics achieve efficacy or promote side-effects. This review article discusses the importance of receptor localization for signaling outcomes of pro- and anti-nociceptive GPCRs, and new analgesic opportunities emerging through the development of "location-biased" ligands that favor binding with intracellular GPCR populations.
Learn More >Chronic pain is a major public health problem in the United States costing $635 billion annually. Hospitalizations for chronic pain in childhood have increased almost tenfold in the past decade, without breakthroughs in novel treatment strategies. Findings from brain imaging studies using structural and resting-state fMRI could potentially help personalize treatment to address this costly and prevalent health problem by identifying the underlying brain pathways that contribute, facilitate, and maintain chronic pain. The aim of this review is to synthesize structural and resting-state network pathology identified by recent brain imaging studies in pediatric chronic pain populations and discuss the potential impact of chronic pain on cortical development. Sex differences as well as treatment effects on these cortical alterations associated with symptom changes are also summarized. This area of research is still in its infancy with currently limited evidence available from a small number of studies, some of which suffer from limitations such as small sample size and suboptimal methodology. The identification of brain signatures of chronic pain in children may help to develop new pathways for future research as well as treatment strategies.
Learn More >Disulfide-rich animal venom peptides targeting either the voltage-sensing domain or the pore domain of voltage-gated sodium channel 1.7 (NaV1.7) have been widely studied as drug leads and pharmacological probes for the treatment of chronic pain. However, despite intensive research efforts, the full potential of NaV1.7 as a therapeutic target is yet to be realized. In this study, using evolved sortase A, we enzymatically ligated two known NaV1.7 inhibitors PaurTx3, a spider-derived peptide toxin that modifies the gating mechanism of the channel through interaction with the voltage-sensing domain, and KIIIA, a small cone snail-derived peptide inhibitor of the pore domain with the aim of creating a bivalent inhibitor which could interact simultaneously with two non-competing binding sites. Using electrophysiology, we determined the activity at NaV1.7 and to maximize potency, we systematically evaluated the optimal linker length, which was nine amino acids. Our optimized synthetic bivalent peptide showed improved channel affinity and potency at NaV1.7 compared to either PaurTx3 or KIIIA individually. This work shows that novel and improved NaV1.7 inhibitors can be designed by combining a pore blocker toxin and a gating modifier toxin to confer desired pharmacological properties from both the voltage sensing domain and the pore domain.
Learn More >Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a common chronic pelvic disorder with sensory symptoms of urinary urgency, frequency, and pain, indicating a key role for hypersensitivity of bladder-innervating sensory neurons. The inflammatory mast cell mediator histamine has long been implicated in IC/BPS, yet the direct interactions between histamine and bladder afferents remain unclear. Here we show, using a mouse bladder afferent preparation, that intravesical histamine enhanced the mechanosensitivity of sub-populations of afferents to bladder distension. Histamine also recruited 'silent afferents', which were previously unresponsive to bladder distension. Furthermore, intravesical histamine enhanced activation of dorsal horn neurons within the lumbosacral spinal cord, indicating increased afferent signaling into the central nervous system. qRT-PCR revealed significant expression of histamine receptor subtypes () in mouse lumbosacral dorsal root ganglia (DRG), bladder detrusor smooth muscle, mucosa, and isolated urothelial cells. In DRG, was the most abundantly expressed. Acute histamine exposure evoked calcium influx in select populations of DRG neurons but did not elicit calcium transients in isolated primary urothelial cells. Histamine-induced mechanical hypersensitivity was abolished in the presence of the histamine H receptor (HR) antagonist pyrilamine and was not present in preparations from mice lacking the TRPV1 receptor. Together, these results indicate that histamine enhances the sensitivity of bladder afferents to distension via interactions with HR and TRPV1. This hypersensitivity translates to increased sensory input and activation in the spinal cord, which may underlie the symptoms of bladder hypersensitivity and pain experienced in IC/BPS.
Learn More >Despite the large comorbidity between PTSD and opioid use disorders, as well as the common treatment of physical injuries resulting from trauma with opioids, the ability of opioid treatments to subsequently modify PTSD-related behavior has not been well studied. Using the stress-enhanced fear learning (SEFL) model for PTSD, we characterized the impact of chronic opioid regimens on the sensitization of fear learning seen following traumatic stress in mice. We demonstrate for the first time that chronic opioid pretreatment is able to robustly augment associative fear learning. Highlighting aversive learning as the cognitive process mediating this behavioral outcome, these changes were observed after a considerable period of drug cessation, generalized to learning about multiple aversive stimuli, were not due to changes in stimulus sensitivity or basal anxiety, and correlated with a marker of synaptic plasticity within the basolateral amygdala. Additionally, these changes were not observed when opioids were given after the traumatic event. Moreover, we found that neither reducing the frequency of opioid administration nor bidirectional manipulation of acute withdrawal impacted the subsequent enhancement in fear learning seen. Given the fundamental role of associative fear learning in the generation and progression of PTSD, these findings are of direct translational relevance to the comorbidity between opioid dependence and PTSD, and they are also pertinent to the use of opioids for treating pain resulting from traumas involving physical injuries.
Learn More >Fibromyalgia (FM) is a chronic painful condition partly due to alterations in pain modulation by the central nervous system. Multicomponent therapy (MT) and repetitive transcranial magnetic stimulation (rTMS) had both been reported as pain modulators in FM patients. The aim of this study was to compare the effects of rTMS on pain with a combination of MT and rTMS versus MT.
Learn More >Breast cancer is one of the most commonly diagnosed cancers among women, and since the prognosis of breast cancer has substantially improved in past decades, complications of management are becoming increasingly apparent. Persistent pain lasting greater than 3 months after breast cancer surgery is unfortunately a common complication affecting approximately 30% of patients after tumour resection. Persistent breast cancer pain has neuropathic features and is typically mild-to-moderate in intensity, with approximately 10% suffering from severe pain. There is an increasing need to prevent persistent pain through the use of transitional pain programmes and perioperative interventions, and to identify novel treatment modalities to reduce suffering in those who unfortunately develop persistent pain. This review serves to provide an overview on persistent pain after breast cancer surgery, its pathophysiology, and current management strategies.
Learn More >Pain ratings are almost ubiquitous in pain assessment, but their variability is high. Low correlations of continuous/numerical rating scales with categorical scales suggest that individuals associate different sensations with the same number on a scale, jeopardizing the interpretation of statistical results. We analyzed individual conceptions of rating scales and whether these conceptions can be utilized in the analysis of ratings of experimental stimuli in pain-free healthy individuals and people with reoccurring/persistent pain.
Learn More >Low back pain is one of the leading causes of disability worldwide. Exercise therapy is widely recommended to treat persistent non-specific low back pain. While evidence suggests exercise is, on average, moderately effective, there remains uncertainty about which individuals might benefit the most from exercise.
Learn More >Fabry disease (FD) is an X-linked lysosomal storage disorder that leads to cellular globotriaosylceramide (Gb3) accumulation due to mutations in the gene encoding α-galactosidase A. Trigger-induced acral burning pain is an early FD symptom of unknown pathophysiology. We aimed at investigating the potential role of skin fibroblasts in nociceptor sensitization.
Learn More >Long non-coding RNAs (lncRNAs) are a group of non-coding RNAs that act as regulators of gene expression; they are implicated in various human diseases and have been reported to be involved in the modulation of pain. We aimed to study whether: 1) lncRNAs modifications could be found in an experimental model of pain and 2) there was a correlation between lncRNA changes and laser evoked potential (LEP) amplitude/laser-pain rating. LEPs were recorded from 11 healthy subjects to both left hand and perioral region stimulation. Three consecutive averages were calculated for each stimulation site in order to investigate the LEP amplitude habituation. Blood samples were obtained immediately before LEP recording (pre-pain) and 30-min after the recording of the last LEP average (post-pain). Eighty-four lncRNAs, involved in autoimmunity and human inflammatory response, were screened. The criteria used for lncRNAs analysis were fold change > 2 and p < .05. By Real-Time PCR, we identified 2 lncRNAs up-regulated at the post-pain time, as compared to thepre-pain time: RP11-819C21.1 (fold change = 8.2; p = .038) and ZNRD1 antisense RNA 1 non-protein coding (ZNRD1-AS) (fold change = 6.3; p = .037). The ZNRD1-AS up-regulation was directly correlated with the N1 amplitude, while the RP11-819C21.1 increase after pain showed a correlation with the reduced N2/P2 amplitude and laser-pain habituation. This is the first study showing lncRNA changes in a human experimental phasic pain model. The correlation between lncRNA changes and LEP amplitude and habituation suggests that RP11-819C21.1 and ZNRD1-AS could be involved in the pathophysiology of painful diseases characterized by abnormal excitability of the cerebral cortex.
Learn More >Children of parents with chronic pain are a high-risk group to develop own chronic pain. There is evidence that parental responses such as catastrophizing and solicitousness play an important role in the familial transmission of chronic pain. However, little is known about factors that modulate these responses. Based on the literature, we assumed that top-down processes, such as parent chronic pain and anxiety, would be associated with increased catastrophizing and solicitousness. Bottom-up processes, such as child chronic pain and anxiety, were assumed to moderate this association. N = 118 parents (mean age: 43 years, 80.5% females) with chronic pain and/or anxiety symptoms with N = 190 children (mean age: 11 years, 49% females) were recruited in specialized hospitals and via online panels. Parents reported chronic pain, anxiety, catastrophizing, and solicitousness by use of validated questionnaires. Child pain and anxiety were assessed via parent report. Multilevel model results showed that top-down processes, rather than bottom-up processes, predicted parental responses to child's pain. Specifically, parents with more severe chronic pain reported less catastrophizing. Parent anxiety was positively associated with parental catastrophizing and solicitousness. While child chronic pain and anxiety did not exert an impact on parental responses, the parents' and child's age emerged as additional modulating factors for parental solicitousness. Findings support the assumption that top-down processes, particularly parent anxiety, rather than bottom-up processes, exert an impact on parental responses. Specific interventions to decrease parent anxiety in the context of chronic pain and effects of adult treatment on parental responses to child's pain warrant further investigation.
Learn More >We have examined the regulation of mutually exclusive Cav2.2 exon 37a and b variants by the mouse μ-opioid receptor (mMOR) C-terminal splice variants 1, 1C and 1O in tsA-201 cells. Electrophysiological analyses revealed that both channel isoforms exhibit DAMGO-induced voltage-dependent (Gβγ-mediated) inhibition and its recovery by voltage pre-pulses, as well as a voltage-independent component. However, the two channel isoforms differ in their relative extent of voltage-dependent and independent inhibition, with Cav2.2-37b showing significantly more voltage-dependent inhibition upon activation of the three mMOR receptors studied. In addition, coexpression of either mMOR1 or mMOR1C results in an agonist-independent reduction in the peak current density of Cav2.2-37a channels, whereas the peak current density of Cav2.2-37b does not appear to be affected. Interestingly, this decrease is not due to an effect on channel expression at the plasma membrane, as demonstrated by biotinylation experiments. We further examined the mechanism underlying the agonist-independent modulation of Cav2.2-37a by mMOR1C. Incubation of cells with pertussis toxin did not affect the mMOR1C mediated inhibition of Cav2.2-37a currents, indicating a lack of involvement of Gi/o signaling. However, when a Src tyrosine kinase inhibitor was applied, the effect of mMOR1C was lost. Moreover, when we recorded currents using a Cav2.2-37a mutant in which tyrosine 1747 was replaced with phenylalanine (Y1747F), the agonist independent effects of mMOR1C were abolished. Altogether our findings show that Cav2.2-37a and Cav2.2-37b isoforms are subject to differential regulation by C-terminal splice variants of mMORs, and that constitutive mMOR1C activity and downstream tyrosine kinase activity exert a selective inhibition of the Cav2.2-37a splice variant, an N-type channel isoform that is highly enriched in nociceptors. Our study provides new insights into the roles of the MOR full-length C-terminal variants in modulating Cav2.2 channel isoform activities.
Learn More >The determinants and mechanisms contributing to diabetic sensorimotor polyneuropathy (DSPN) remain unclear. Since neuroinflammation and altered nerve regeneration have been implicated in the pathogenesis of both DSPN and neuropathic pain, we hypothesized that the corresponding biomarkers could be associated with DSPN in general and could have the potential to discriminate between the painful and painless DSPN entities.
Learn More >Fibromyalgia (FM) is a chronic widespread pain disorder characterized by negative affect, sleep disturbance, and fatigue. This uncontrolled pilot study investigated the efficacy of daily yoga-based exercise to improve FM symptoms and explored baseline phenotypic characteristics associated with the greatest benefit.
Learn More >We investigated the influence of sleeplessness and number of insomnia symptoms on the probability of recovery from chronic low back pain (LBP), and the possible interplay between sleeplessness and co-occurring musculoskeletal pain on this association.
Learn More >Compression of myofascial trigger points (MTrPs) in muscles is reported to reduce chronic musculoskeletal pain. Although the prefrontal cortex (PFC) is implicated in development of chronic pain, the mechanisms of how MTrP compression at low back regions affects PFC activity remain under debate. In this study, we investigated effects of MTrP compression on brain hemodynamics and EEG oscillation in subjects with chronic low back pain.
Learn More >Pain is a common complaint presented in healthcare, but most epidemiological pain research has focused either on single pain conditions or on the adult population. The aim of this study was to investigate the 2017 consultation prevalence of a wide range of pain conditions in the general population of young people.
Learn More >Chronic pain patients often suffer from insomnia or impaired sleep which has been associated with increased pain sensitivity, but a limited amount of studies have investigated the effects of total sleep deprivation on central pain mechanisms. Therefore, the aim of this study was to determine the effects of total sleep deprivation on temporal summation, conditioned pain modulation, thermal and pressure pain sensitivity in healthy participants. Twenty-four healthy participants took part in this two-session trial. The measurements were conducted after a night of habitual sleep (baseline) and following 24 hours of total sleep deprivation. Detection thresholds for cold and warmth and pain thresholds for cold and heat were assessed. Cuff induced pressure pain detection and tolerance thresholds, temporal summation and conditioned pain modulation were assessed with user-independent, computer-controlled cuff algometry. Conditioned pain modulation was significantly impaired, temporal summation was significantly facilitated and pain sensitivity to pressure and cold pain were significantly increased at follow-up compared with baseline. In conclusion, this study found that one night of total sleep deprivation impaired descending pain pathways, facilitated spinal excitability and sensitized peripheral pathways to cold and pressure pain. Future studies are encouraged to investigate if sleep therapy might normalize pain sensitivity in sleep-deprived chronic pain patients.
Learn More >Whiplash injury is a common consequence of motor vehicle crashes (MVC), yet it is also one of the most poorly understood. While more than 50% of those injured should expect to rapidly recover, others are not as fortunate with approximately 25% of those exposed to and injured in an MVC transitioning from acute to chronic pain and disability. The purpose of this prospective study was to determine if the severity and direction of collisions involving participants enrolled in a longitudinal study of recovery from whiplash are able to differentiate between different recovery groups based on the neck disability index (NDI) percentage scores at 3-months, and if these crash specific parameters are associated with known risk factors for recovery. Here, we examined objective collision data, repair invoices, and characteristics of the crash for 37 acutely injured participants consented and enrolled at their emergency department visit and further assessed at three time points; < 1 week, 2-weeks, and 3-months post MVC. Collision data were used to reconstruct and estimate the severity of the crash and determine if they aligned with the heterogeneity of whiplash injury recovery. Wilcoxon rank sum tests were used to determine if % scores on the Neck Disability Index (NDI) at 3-months post MVC were associated with the following variables: sex, head turned at time of impact, seatbelt use, whether or not airbags deployed, if the vehicle was struck while stopped or while turning, or the principle direction of force (PDOF). Spearman's correlation coefficients were used to determine if NDI at 3-months post MVC was associated with age, Body Mass Index, pain-related disability at baseline, signs of post-traumatic distress, intrusion/hyperarousal, negative affect, pain intensity, estimated speed change from the impact, and damage estimates (in US$). There was a significant positive association between self-reported neck disability at 3-months post MVC, post-traumatic distress, negative affect and uncontrolled pain. There was no direct effect of participant characteristics, arousal, intrusion/hyperarousal sub-score, damage, PDOF, speed change, or other crash characteristics. Established crash parameters were not associated with the heterogeneity of whiplash injury recovery in a small sample of injured participants.
Learn More >Chronic back pain (CBP) is a leading cause of disability and results in considerable socio-economic burdens worldwide. Although CBP patients are commonly diagnosed and treated with a focus on the "end organ dysfunction" (i.e., peripheral nerve injuries or diseases), the evaluation of CBP remains flawed and problematic with great challenges. Given that the peripheral nerve injuries or diseases are insufficient to define the etiology of CBP in some cases, the evaluation of alterations in the central nervous system becomes particularly necessary and important. With the development of advanced neuroimaging techniques, extensive studies have been carried out to identify the cortical abnormalities in CBP patients. Here, we provide a comprehensive overview on a series of novel findings from these neuroimaging studies to improve our understanding of the cortical abnormalities originated in the disease. First, CBP patients normally exhibit central sensitization to external painful stimuli, which is indexed by increased pain sensitivity and brain activations in pain-related brain regions. Second, long-term suffering from chronic pain leads to emotional disorders, cognitive impairments, and the abnormalities of the relevant brain networks among CBP patients. Third, CBP is associated with massive cortical reorganization, including structural, functional, and metabolic brain changes. Overall, a deep insight into the neural mechanisms underlying the development and outcome of CBP through more sophisticated neuroimaging investigations could not only improve our current understanding of the etiology of CBP but also facilitate the diagnosis and treatment of CBP based on precision medicine.
Learn More >Neuroplastic changes in the neuronal networks involving the trigeminal ganglion (TG), trigeminal spinal subnucleus caudalis (Vc), and upper cervical spinal cord (C1/C2) are considered the mechanisms underlying the ectopic orofacial hypersensitivity associated with trigeminal nerve injury or orofacial inflammation. It has been reported that peripheral nerve injury causes injury discharges in the TG neurons, and a barrage of action potentials is generated in TG neurons and conveyed to the Vc and C1/C2 after trigeminal nerve injury. Long after trigeminal nerve injury, various molecules are produced in the TG neurons, and these molecules are released from the soma of TG neurons and are transported to the central and peripheral terminals of TG neurons. These changes within the TG cause neuroplastic changes in TG neurons and they become sensitized. The neuronal activity of TG neurons is further accelerated, and Vc and C1/C2 neurons are also sensitized. In addition to this cascade, non-neuronal glial cells are also involved in the enhancement of the neuronal activity of TG, Vc, and C1/C2 neurons. Satellite glial cells and macrophages are activated in the TG after trigeminal nerve injury and orofacial inflammation. Microglial cells and astrocytes are also activated in the Vc and C1/C2 regions. It is considered that functional interaction between non-neuronal cells and neurons in the TG, Vc, and C1/C2 regions is a key mechanism involved in the enhancement of neuronal excitability after nerve injury or inflammation. In this article, the detailed mechanisms underlying ectopic orofacial hyperalgesia associated with trigeminal nerve injury and orofacial inflammation are addressed.
Learn More >To review the published findings relevant to migraine and driving performance, with an intent to encourage discussion on research which may broaden understanding in this area and help educate healthcare providers and their patients.
Learn More >The aim of this study was to investigate the effects of aquaporin 1 (AQP1) knockdown on allodynia in rats with chronic compression of the dorsal root ganglia (DRG) and the role of TRPV4 in these effects.
Learn More >Effectively treating chronic pain remains a therapeutic challenge in the clinic. Recent evidence has shown the inhibition of the soluble epoxide hydrolase (sEH) to be an effective strategy to limit chronic pain in preclinical models, horses and companion animals. Determining the safety ofsEH inhibition in addition to this demonstrated efficacy is a critical step to the further development ofsEH inhibitors (sEHI) as analgesics. Here we describe a comparison of thesEHI TPPU with other first in class analgesics for human chronic pain. We assess the development of tolerance to the analgesia mediated by TPPU with extended use. We also assess for CNS effects by measuring changes in motor control and functioning. ThesEHI are multimodal analgesics that have demonstrated potent efficacy against chronic pain. They have previously been tested and show no reward potential using operant methods. The results of the current experiments show that they lack motor function effects and also lack the development of tolerance with extended dosing.
Learn More >Neuropathic pain (NP) is a complex chronic pain state with a prevalence of almost 10% in the general population. Pharmacological options for NP are limited and slightly effective, so there is a need of developing more efficacious NP attenuating drugs. Activation of the type 1 lysophosphatidic acid (LPA1) receptor is a crucial factor in the initiation of NP. Hence, it is conceivable that a functional antagonism strategy could lead to NP mitigation. Here we describe a new series of LPA1 agonists among which derivative (S)-17 (UCM-05194) stands out as the most potent and selective LPA1 receptor agonist described so far (Emax=118%, EC50=0.24 µM, KD=19.6 nM; inactive at autotaxin and LPA2-6 receptors). This compound induces characteristic LPA1-mediated cellular effects and prompts the internalization of the receptor leading to its functional inactivation in primary sensory neurons and to an efficacious attenuation of the pain perception in an in vivo model of NP.
Learn More >Because nitric oxide could play an important role in the pathogenesis of migraine (suggested by experimental, neuropathological, biochemical, and pharmacological data), and a recent meta-analysis showed an association between the single-nucleotide polymorphism (SNP) rs2070744 in the endothelial nitric oxide synthase (eNOS or NOS3) gene (chromosome 7q36.1) and the risk for migraine in Caucasians, we attempted to replicate the possible association between this SNP and the and the risk for migraine in the Caucasian Spanish population. The frequencies for the NOS3 rs2070744 genotypes and allelic variants were assessed in 283 migraine patients and 287 healthy controls with a TaqMan-based qPCR Assay. The putative influence on genotype frequency of age at onset of migraine attacks, gender, family history of migraine, absence or presence of aura, and triggering of migraine attacks by ethanol, were also analyzed. The frequencies of NOS3 rs2070744 genotypes and allelic variants were not associated with the risk for migraine (OR [95%] CI for the minor allele = 0.91 [0.72-1.15]) and were not influenced by age at onset of migraine, gender, presence of aura, or triggering of migraine attacks by ethanol. NOS3 rs2070744CC genotypes were significantly more frequent in patients with a family history of migraine. NOS3 rs2070744 SNP is not associated with the risk for migraine in Caucasian Spanish people although it might be related to family history.
Learn More >Pain is the primary symptom of chronic pancreatitis (CP), but methods for sensory testing and pain characterization have not previously been validated for clinical use. We present a clinically feasible method for the assessment and characterization of pain mechanisms in patients with CP based on quantitative sensory testing (QST).
Learn More >It is expected that the number of surgical procedures to diagnose, treat, and palliate cancers will increase in the near future. While many of those interventions can be performed with minimally invasive techniques, others require surgical large incisions and in some instances, they involve multiple areas of the body (i.e., tumor resections with flap reconstructions). Pain after major oncological procedures can be severe and many times difficult to treat as patients can present to the operating room with several conditions including preoperative pain (i.e., rapidly growing tumors and painful neuropathies), opioid tolerance, and contraindications to nonopioid analgesics or regional anesthesia. Inadequately treated postoperative pain is associated with activation of the sympathetic system, postoperative complications, large perioperative opioid use, and an increased risk of developing postoperative persistent pain. Furthermore, it has been theorized that poorly treated pain is associated with cancer recurrence and a reduced survival. Lastly, recent research questions the oncological safety of robotic surgery in gynecological procedures and indicates the need of open surgeries, which will be associated with an increased risk in moderate-to-severe postoperative pain. In conclusion, the management of acute postoperative pain in patients with cancer can be challenging.
Learn More >In the midst of an epidemic of opioid abuse and overdose-related morbidity and mortality, the use of opioids remains the most common means of providing analgesia in the perioperative period. In this article, we review the risks and benefits of opioid use in preoperative, intraoperative and post-operative phases of care. Furthermore, we describe the role that surgeons and anaesthesiologists can play in reducing perioperative opioid use and mitigate their adverse effects, from both an individual and a population health perspective.
Learn More >More than 300 million patients undergo surgery worldwide each year. Pain associated with these procedures is associated with short- and long-term negative sequelae for patients, healthcare providers, and healthcare systems. The following chapter is a review of the reality of postoperative pain management in everyday clinical routine based on survey- and registry-derived data with a focus on care in adults. Between 30% and up to 80% of patients report moderate to severe pain in the days after surgery. Structures, processes, and outcomes vary widely between hospitals and indicate gaps between evidence-based findings and practice. Pain assessment is not effectively implemented in many hospitals and should consider cultural differences. Few data exist on the situation of pain management in low- and middle-income countries, indicating lack of resources and available medication in many of these areas. Certain types of surgery as well as demographic and clinical factors are associated with increased risk of severe postoperative pain.
Learn More >17β-estradiol plays a role in pain sensitivity, analgesic drug efficacy, and neuropathic pain prevalence, but the underlying mechanisms remain unclear. Here, we investigated whether voltage-gated chloride channel-3 (ClC-3) impacts the effects of 17β-estradiol (E2) on spared nerve injury (SNI)-induced neuropathic pain in ovariectomized (OVX) female Sprague Dawley rats that were divided into OVX, OVX + SNI, OVX + SNI + E2, OVX + SNI + E2 + DMSO (vehicle, dimethyl sulfoxide), or OVX + SNI + E2+Cltx (ClC-3-blocker chlorotoxin) groups. Changes in ClC-3 protein expression were monitored by western blot analysis. Behavioral testing used the paw withdrawal threshold to acetone irritation and paw withdrawal thermal latency (PWTL) to thermal stimulation. Immunofluorescence indicated the localization and protein expression levels of ClC-3. OVX + SNI + E2 rats were subcutaneously injected with 17β-estradiol once daily for 7 days; a sheathed tube was implanted, and chlorotoxin was injected for 4 days. Intrathecal Cltx to OVX and OVX + SNI rats was administered for 4 consecutive days (days 7-10 after SNI) to further determine the contribution of ClC-3 to neuropathic pain. Patch clamp technology in current clamp mode was used to measure the current threshold (rheobase) dorsal root ganglion (DRG) neurons and the minimal current that evoked action potentials (APs) as excitability parameters. The mean number of APs at double-strength rheobase verified neuronal excitability. There was no difference in behaviors and ClC-3 expression after OVX. Compared with OVX + SNI rats, OVX + SNI + E2 rats showed a lower paw withdrawal threshold to the acetone stimulus, but the PWTL was not significantly different, indicating increased sensitivity to cold but not to thermal pain. Co-immunofluorescent data revealed that ClC-3 was mainly distributed in A- and C-type nociceptive neurons, especially in medium/small-sized neurons. 17β-estradiol administration was associated with increased expression of ClC-3. 17β-estradiol-induced increase in ClC-3 expression was blocked by co-administration of Cltx. Cltx causes hyperalgesia and decreased expression of ClC-3 in OVX rats. Patch clamp results suggested that 17β-estradiol attenuated the excitability of neurons induced by SNI by up-regulating the expression of ClC-3 in the DRG of OVX rats. 17β-estradiol administration significantly improved cold allodynia thresholds in OVX rats with SNI. The mechanism for this decreased sensitivity may be related to the upregulation of ClC-3 expression in the DRG.
Learn More >Opioids and NSAIDs are commonly used for pain relief in AP. Opioids carry risk of sphincter of oddi constriction. Although diclofenac prevents post ERCP pancreatitis, few reports of diclofenac associated AP is also present. Although, both tramadol and diclofenac are commonly used for pain relief in AP, no study has evaluated their comparative efficacy and safety.
Learn More >Background and aims The purpose of this study was to (a) develop and (b) conduct exploratory factor analysis on a novel self-report instrument for symptoms associated with altered central pain processing. Methods We first developed a 25-item questionnaire based on previous literature identifying symptoms and behaviours that may reflect altered spinal and supraspinal pain processing. We then administered this questionnaire to 183 people with chronic pain (n = 99) and healthy individuals (n = 84). Exploratory factor analysis was conducted to identify the factor structure of the questionnaire. Results Our results support a two-factor solution for the 25-item questionnaire that accounted for 57.2% of the total variance of responses in people with and without chronic pain. Factor one (11 items) included items related to alterations in sensation of pain, while factor two (seven items) included items associated with emotional and fatigue symptoms. Seven items showed weak factor loadings and were eliminated. Reliability was excellent, while both factors showed strong correlations with previously-validated self-report Instruments: (pain catastrophising, mood, vigilance, pain self-efficacy) and conditioned pain modulation, providing evidence for their validity. Conclusions We have developed a questionnaire containing two factors that appear to be related to two different symptom clusters, one of which is specifically related to pain and one of which contains other health-related symptoms related to mood and fatigue. These factors show excellent internal consistency and validity. This questionnaire may be a quick, easy and reliable instrument to assess central pain processing in clinical settings.
Learn More >The pathogenesis of fibromyalgia is still unknown. Core symptoms include pain, depression and sleep disturbances with high comorbidity, suggesting alterations in the monoaminergic system as a common origin of this disease. The reserpine-induced myalgia model (RIM) lowers pain thresholds and produces depressive-like symptoms. The present work aims to evaluate temporal dynamics in the oscillatory profiles and motor activity during sleep in this model and to evaluate if the model mimics the sleep disorders that occur in fibromyalgia patients. Hippocampal and EMG activity were recorded in chronically implanted rats. Following 3 days of basal recordings, reserpine was administered on 3 consecutive days to achieve the RIM. Post-reserpine recordings were taken on alternate days for 21 days. Reserpine induced changes in the sleep architecture with more transitions between states, and a different pattern between the administration period and post-reserpine weeks. Administration days were characterized by a larger amount of REM sleep with dominant theta waves without atonia. Following the reserpinization, theta oscillations were always more fragmented and with lower frequency. On the post-reserpine days, sleep was dominated by slow-wave sleep with fast intrusions and reduced hierarchical coupling with spindles and ripples. Simultaneous electromyography recordings also showed muscle twitches during sleep and the dissociation of theta activity and muscle atonia. Abnormally high slow waves, alpha/delta intrusions, frequent transitions and muscle twitches are common traits in fibromyalgia. Therefore, our analyses support the validity of the reserpine-induced myalgia model to study sleep disorders in fibromyalgia, and provide new insights into the research of oscillographic biomarkers. This article is protected by copyright. All rights reserved.
Learn More >Mechanical injury is the most important risk factor in osteoarthritis (OA) development. Although once considered a passive disease of mechanical attrition, injury drives active mechanosensitive intracellular signalling which affects the structural and symptomatic course of disease. Mechanosensitive signalling in cartilage has been elucidated over the years and two principal responses emerge: those that cause the release of growth factors from the matrix and which stimulate repair, and those that drive inflammatory signalling, a process that we have termed "mechanoflammation". The up-stream activator of mechanoflammation remains unknown, but it results in rapid activation of NFkB and the inflammatory mitogen activated protein (MAP) kinases and this controls the bioavailability of aggrecanase and regulation of nerve growth factor (NGF), causing pain. The precise relationship between mechanoflammation and cartilage repair is currently unclear but it is likely that chronic mechanoflammation will contribute to disease by also suppressing intrinisic tissue repair.
Learn More >To develop and test the feasibility and preliminary efficacy of a cognitive behavioral therapy-based, internet-delivered self-management program for chronic low back pain (cLBP) in veterans.
Learn More >Up to 30% of patients experience persistent pain and functional limitations following total knee replacement (TKR). Rapid symptom relief in the early postoperative period may be linked to longer-term outcome improvements. We sought to identify early improvement trajectories and to identify risk factors for suboptimal outcomes.
Learn More >Long-term neuropathic pain can lead to anxiety, depression, and other issues, which seriously affect patients' quality of life. For this reason, it is important to find effective treatments. Studies have shown that glial cell-derived neurotrophic factor (GDNF) can relieve neuropathic pain. However, its mechanism of action is unknown. Our previous study of GDNF suggested that the N-cadherin-β-catenin transmembrane signaling system might play a role in GDNF transmembrane signaling. Based on this, the current study aimed to produce a neuropathic pain model to confirm the activation of the N-cadherin-β-catenin signaling system in the spinal dorsal horn under pain conditions and to study the impact of GDNF intrathecal injection on central sensitization of dorsal horn neurons. The results showed that N-cadherin expression, as well as the expression of membrane-associated β-catenin, was reduced in the dorsal horn of the spinal cord in the chronic pain model. Intrathecal injection of GDNF could reactivate the N-cadherin-β-catenin system, improve central sensitization, and relieve pain. Knockdown of N-cadherin or β-catenin could significantly reduce the analgesic effect of GDNF. These results provide clear experimental evidence that the N-cadherin-β-catenin signaling system participates in the analgesic effect of GDNF in neuropathic pain and help identify transmembrane and intracellular signal transduction mechanisms associated with GDNF's analgesic effects.
Learn More >The cost of US health care continues to increase, with treatments related to low back and neck pain and other musculoskeletal disorders accounting for the third highest amount of various disease categories. Interventional techniques for managing pain apart from conservative modalities and surgical interventions, have generally been thought to be growing rapidly. However, a recent analysis of utilization of interventional techniques from 2000 to 2016 has shown a modest decline from 2009 to 2016, compared to 2000 to 2009.
Learn More >The traditional analgesics used to treat neuropathic pain such as anticonvulsants, opioids, and nonsteroidal anti-inflammatory drugs (NSAIDs) lack efficacy and/or carry unpleasant side effects. The present study aimed to investigate the synergistic antinociceptive effects of co-administered low doses of ibuprofen and dexamethasone in rats with trigeminal neuropathic pain.
Learn More >Dealing with the high prevalence of pain among the oldest-old (+75) is becoming a major health issue. Therefore, the aim of the study was to uncover health-related lifestyle behaviors (HLB) and age-related comorbidities which may predict, influence and prevent pain in old age.
Learn More >Hyperglycemia is considered a key risk factor for development of diabetic complications including neuropathy. There is strong scientific evidence showing a primary role of aldose reductase, the first enzyme of the polyol pathway, in the cascade of metabolic imbalances responsible for the detrimental effects of hyperglycemia. Aldose reductase is thus considered a significant drug target. We investigated the effects of cemtirestat, a novel aldose reductase inhibitor, in the streptozotocin-induced rat model of uncontrolled type 1 diabetes in a 4-month experiment. Markedly increased sorbitol levels were recorded in the erythrocytes and the sciatic nerve of diabetic animals. Osmotic fragility of red blood cells was increased in diabetic animals. Indices of thermal hypoalgesia were significantly increased in diabetic rats. Tactile allodynia, recorded in diabetic animals in the early stages, turned to mechanical hypoalgesia by the end of the experiment. Treatment of diabetic animals with cemtirestat (i) reduced plasma triglycerides and TBAR levels; (ii) did not affect the values of HbA1c and body weights; (iii) reversed erythrocyte sorbitol accumulation to near control values, while sorbitol in the sciatic nerve was not affected; (iv) ameliorated indices of the erythrocyte osmotic fragility; and (v) attenuated the symptoms of peripheral neuropathy more significantly in the middle of the experiment than at the end of the treatment. Taking into account the lipid metabolism as an interesting molecular target for prevention or treatment of diabetic peripheral neuropathy, the triglyceride-lowering effect of cemtirestat should be considered in future studies. The most feasible mechanisms of triglyceride-lowering action of cemtirestat were suggested.
Learn More >Post-traumatic stress disorder (PTSD) and chronic pain often co-occur. Understanding the shared mechanisms, signs to identify PTSD, and treatment options is integral in allowing providers to better serve their patients.
Learn More >The aim of this cross-sectional study was to investigate the cortical metabolite concentrations in patients suffering from migraine with aura (MWA). We hypothesized that occipital γ-aminobutyric acid (GABA) levels are lower in MWA patients.
Learn More >Pulsed radiofrequency stimulation at the dorsal root ganglion is used for treatment of radicular pain; however, its mechanism for neuropathic pain treatment has not been fully elucidated. Here, we investigated whether pulsed radiofrequency stimulation affects the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, which play a critical role in synaptic plasticity.
Learn More >Dexmedetomidine, a highly selective alpha-2 adrenergic receptor agonist and novel sedative drug with minimal respiratory suppression, have shown anti-nociceptive activity in various pain models by poorly understood mechanisms. Because alpha-2 adrenergic receptor is co-localized with TRPV1 polymodal nociceptive receptor in dorsal root ganglion neurons and up-regulated in neuropathic pain animal models, the analgesic activity might be mediated through inhibition of TRPV1 in the peripheral nervous system. In an effort to elucidate whether modulatory effect of dexmedetomidine on TRPV1 activity could be the potential peripheral mechanism underlying the antinociceptive effect of dexmedetomidine, intracellular calcium concentration after capsaicin application was investigated in mice dorsal root ganglion (DRG) neurons, with and without pretreatment of dexmedetomidine. Dexmedetomidine (10 μM) reduced capsaicin-induced calcium responses by 29.7 ± 7.39% (n = 34, p < 0.0001), in dose-dependent manner. Higher level of inhibition was observed with increased dose of dexmedetomidine (50 μM, 45.1 ± 8.58%, n = 15, p = 0.0002), and lower inhibition by decreased dose (1 μM, 18.8 ± 1.48%, n = 148, p = 0.004). RT-PCR analysis revealed expression of TRPV1 and alpha-2A, alpha-2B and alpha-2C subtypes of adrenergic receptor in mice DRG neurons, and immunocytochemical analysis revealed co-expression of TRPV1 and alpha-2A receptors in primary cultured DRG neurons. In summary, these results suggested the inhibition of TRPV1 expressed in the primary sensory neurons as a potential mechanism that contributes to the anti-nociceptive action of dexmedetomidine.
Learn More >Our aim was to assess gender differences in variables associated with the emotional and physical burdens of tension-type headache (TTH). Participants with TTH diagnosed according to the ICHD-III were recruited from three university-based hospitals (in Spain, Italy, Denmark) between January 2015 and June 2017. The physical/emotional headache burden was assessed with the Headache Disability Inventory (HDI-P/HDI-E, respectively). Headache features were collected with a four-week diary. Sleep quality was assessed with Pittsburgh Sleep Quality Index. The Hospital Anxiety and Depression Scale evaluated anxiety and depressive symptom levels. Trait and state anxiety levels were evaluated with the State-Trait Anxiety Inventory. Two hundred and twelve (28% men) participants (aged 41-48 years old) participated. Multiple regression models revealed that sleep quality explained 36.7% of the variance of HDI-E and 31.1% of the variance of HDI-P in men, whereas headache intensity, depressive levels, and younger age explained 37.5% of the variance of HDI-E and 32.8% of the variance of HDI-P in women (all < .001). This study observed gender differences in variables associated with headache burden in TTH. Management of men with TTH should focus on interventions targeting sleep quality, whereas the management of women with TTH should combine psychological approaches and interventions targeting pain mechanisms.
Learn More >The present study examined the roles of 5-HT2A, 5-HT2B and 5-HT2C receptor subtypes in mediating the ventrolateral orbital cortex (VLO)-induced antiallodynia in a rat model of neuropathic pain induced by spared nerve injury (SNI). Change of mechanical paw withdrawal threshold (PWT) was measured using von-Frey filaments. Microinjection of preferential or selective 5-HT2A/C, 5-HT2B and 5-HT2C receptor agonists, (±)-1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), α-methyl-5-(2-thienylmethoxy)-1H-Indole-3-ethanamine hydrochloride (BW723C86) and 1-(3-Chlorophenyl)-piperazine hydrochloride (m-CPP) into the VLO significantly depressed allodynia induced by SNI, and the inhibitory effect of DOI was blocked or attenuated by selective 5-HT2A/C receptor antagonists ketanserin (+)-tartrate salt (ketanserin) and 5-HT2A receptor antagonist R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol (M100907); the effects of BW723C86 and m-CPP were antagonized by 5-HT2B receptor antagonists N-(1-Methyl-1H-5-indolyl)-N'-(3-methyl-5-isothiazolyl)urea (SB204741) and 5-HT2C receptor antagonist RS102221 hydrochloride hydrate (RS-102221), respectively. These results suggest that 5-HT2A, 5-HT2B, 5-HT2C receptor subtypes are involved in mediating the VLO-induced antiallodynia in the neuropathic pain state.
Learn More >Sickle cell disease (SCD) is an inherited red blood cell disorder affecting millions worldwide, and it results in many potential medical complications throughout the life course. The hallmark of SCD is pain. Many patients experience daily chronic pain as well as intermittent, unpredictable acute vaso-occlusive painful episodes called pain crises. These pain crises often require acute medical care through the day hospital or emergency department. Following presentation, a number of these patients are subsequently admitted with continued efforts of treatment focused on palliative pain control and hydration for management. Mitigating pain crises is challenging for both the patients and their providers, given the perceived unpredictability and subjective nature of pain.
Learn More >Breast carcinoma causes severe pain, which decreases the quality of life of patients. Current treatments produce adverse effects and have limited efficacy. Transient potential receptor ankyrin 1 (TRPA1) is related to the onset of cancer and neuropathic pain. The aim of this study was to evaluate the involvement of TRPA1 in a model of breast carcinoma. We injected 4T1 cells in the fourth caudal mammary fat pad of female BALB/c mice, and after 20 days we observed mechanical and cold allodynia and spontaneous nociception behavior (mouse grimace scale detection, MGS). TRPA1 selective antagonist (HC-030031 or A-967079) administration or intrathecal administration of TRPA1 antisense (AS) oligonucleotide was performed. The activity of NADPH oxidase, superoxide dismutase (SOD) and hydrogen peroxide (HO) levels were evaluated. The chemical hyperalgesia produced by a TRPA1 agonist (allyl isothiocyanate, AITC) was also detected. The administration of TRPA1 antagonists, TRPA1 AS, or antioxidant, transiently attenuated MGS, or mechanical and cold allodynia. Intraplantar injection of AITC also caused nociception. NADPH oxidase or SOD activity and HO levels were increased in the sciatic nerve and hind paw skin samples. The 4T1 cells did not express TRPA1, and the use of HC-030031 or α-lipoic acid did not reduce the cytotoxic effect of a chemotherapeutic drug (paclitaxel). Thus, TRPA1 could be investigated as a target for breast carcinoma pain treatment.
Learn More >To clarify whether photoreception of intrinsically photosensitive retinal ganglion cells (ipRGCs) is related to migraine, we investigated the relationship between hemodynamic responses related to neural activity and visual stimulation of ipRGCs. It has been established that photoreception in ipRGCs is associated with photophobia in migraine. However, the relationship between visual stimulation of ipRGCs and hemodynamic responses in the visual cortex has not been clarified. Hemodynamic responses in the visual cortex were measured using functional near-infrared spectroscopy (fNIRS) as signals reflecting changes in oxygenated and deoxygenated hemoglobin concentrations. Different types of visual stimulation generated by a metamerism method were applied to the peripheral field of the eye of patients with migraine (N = 20) and healthy participants (N = 21). The stimulation intensity on the retina was controlled using an artificial pupil. In the primary visual cortex of patients with migraine, statistically significant changes in fNIRS signals dependent on visual stimulation intensity applied to ipRGCs were observed (p < 0.01), while no such changes were observed in healthy participants. These results reveal that visual stimulation of ipRGCs projecting to the primary visual cortex is involved in hemodynamic responses in patients with migraine, suggesting that ipRGCs, in addition to photometric values related to cones, are associated with migraine.
Learn More >Trigeminal neuropathic pain (TNP) remains a tremendous clinical challenge due to its elusive mechanisms. Previous studies showed that peripheral nerve injury facilitated a selective GABAergic neuronal apoptosis in the superficial dorsal horn and contributed to the development and maintenance of neuropathic pain. It has also demonstrated that downregulation of the anaphase-promoting complex/cyclosome(APC/C) and its coactivator Cdh1 contribute to neuronal apoptosis in diverse neurodegenerative diseases. However, whether APC/C-Cdh1 downregulation could induce GABAergic neuronal apoptosis in trigeminal caudalis nucleus (Vc), and then contribute to the development and maintenance of TNP remains unknown. In this study, we aimed to investigate the role of APC/C-Cdh1 in a TNP rat model and its underlying mechanisms. Our results showed that Cdh1 was primarily distributed in superficial laminae of Vc and significantly downregulated in Vc at day 14 post trigeminal nerve injury. Furthermore, trigerminal nerve injury leads to neuronal apoptosis, especially GABAergic interneurons in the superficial of Vc. Upregulating Cdh1 in Vc ameliorated mechanical allodynia and inhibited GABAergic neuronal apoptosis induced by chronic constriction injury of trigeminal infraorbital nerve (CCI-ION).
Learn More >Preoperative pain and impaired endogenous analgesia are risk factors of chronic postsurgical persistent pain (CPSP). A Chronic neuropathic pain model induced by spinal nerve ligation (SNL6W) shows impaired endogenous analgesia and delayed recovery from incisional pain. Repeated amitriptyline treatment can restore the endogenous analgesia, but its effects on delayed recovery are not clear.
Learn More >Accidental contact with caterpillar bristles causes local symptoms such as severe pain, intense heat, edema, erythema, and pruritus. However, there is little functional evidence to indicate a potential mechanism. In this study, we analyzed the biological characteristics of the crude venom from the larval stage of living in South-West China. Intraplantar injection of the venom into the hind paws of mice induced severe acute pain behaviors in wild type (WT) mice; the responses were much reduced in TRPV1-deficit (TRPV1 KO) mice. The TRPV1-specific inhibitor, capsazepine, significantly attenuated the pain behaviors. Furthermore, the crude venom evoked strong calcium signals in the dorsal root ganglion (DRG) neurons of WT mice but not those of TRPV1 KO mice. Among the pain-related ion channels we tested, the crude venom only activated the TRPV1 channel. To better understand the venom components, we analyzed the transcriptome of the sebaceous gland region. Our study suggests that TRPV1 serves as a primary nociceptor in caterpillar-induced pain and forms the foundation for elucidating the pain-producing mechanism.
Learn More >Vesicular glutamate transporter 2 (VGLUT2)-which uptakes glutamate into presynaptic vesicles-is a fundamental component of the glutamate neurotransmitter system. Although several lines of evidence from genetically modified mice suggest a possible association of VGLUT2 with neuropathic pain, the specific role of VGLUT2 in the spinal cord during neuropathic pain, and its regulatory mechanism remain elusive. In this study, we report that spared nerve injury induced an upregulation of VGLUT2 in the spinal cord, and intrathecal administration of small hairpin RNAs (shRNA) against VGLUT2 before or after surgery attenuated mechanical allodynia, and pathologically-enhanced glutamate release. Meanwhile, nerve injury activated the Wnt1/β-catenin signaling pathway in a quick-onset and sustained manner, and blocking the Wnt1 signaling with a Wnt1 targeting antibody attenuated neuropathic pain. In naïve mice, administration of a Wnt agonist or Wnt1 increased spinal VGLUT2 protein levels. Moreover, intrathecal administration of the Wnt/β-catenin inhibitor, XAV939 attenuated mechanical allodynia, and this effect was concurrent with that of VGLUT2 downregulation. Pretreatment with VGLUT2 shRNAs abolished the allodynia induced by the Wnt agonist or Wnt1. These findings reveal a novel mechanism wherein there is Wnt1/β-catenin-dependent VGLUT2 upregulation in neuropathic pain, thus potentiating the development of new therapeutic strategies in pain management.
Learn More >Variants in the SCN1A gene are associated with a wide range of disorders including genetic epilepsy with febrile seizures plus (GEFS+), familial hemiplegic migraine (FHM), and the severe childhood epilepsy Dravet syndrome (DS). Predicting disease outcomes based on variant type remains challenging. Despite thousands of SCN1A variants being reported, only a minority has been functionally assessed. We review the functional SCN1A work performed to date, critically appraise electrophysiological measurements, compare this to in silico predictions, and relate our findings to the clinical phenotype. Our results show, regardless of the underlying phenotype, that conventional in silico software correctly predicted benign from pathogenic variants in nearly 90%, however was unable to differentiate within the disease spectrum (DS vs. GEFS+ vs. FHM). In contrast, patch-clamp data from mammalian expression systems revealed functional differences among missense variants allowing discrimination between disease severities. Those presenting with milder phenotypes retained a degree of channel function measured as residual whole-cell current, whereas those without any whole-cell current were often associated with DS (p = .024). These findings demonstrate that electrophysiological data from mammalian expression systems can serve as useful disease biomarker when evaluating SCN1A variants, particularly in view of new and emerging treatment options in DS.
Learn More >Previous studies suggest higher mindfulness may be associated with better sleep quality in people with chronic pain conditions. However, the relationship between mindfulness and sleep in fibromyalgia patients, who commonly suffer from sleep problems, remains unstudied. We examined the relationship between mindfulness and sleep, and how this relationship may be mediated by depression, anxiety, and pain interference in fibromyalgia patients.
Learn More >Thalamic pain is a neuropathic pain syndrome that occurs as a result of thalamic damage. It is difficult to develop therapeutic interventions for thalamic pain because its mechanism is unclear. To better understand the pathophysiological basis of thalamic pain, we developed and characterized a new rat model of thalamic pain using a technique of microinjecting cobra venom into the ventral posterolateral nucleus (VPL) of the thalamus.
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