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Our previous findings indicate that HCN2 contributes to oxaliplatin-induced neuropathic pain, but the mechanisms underlying the development of neuropathic pain are still unclear. Here, we found that the rat HCN2 levels significantly increased after high-frequency stimulation-induced long-term potentiation (LTP). Spinal local application of ZD7288 (a cyclic-nucleotide-gated-channel-specific inhibitor) prevented LTP induction after intraperitoneal injection of oxaliplatin. In addition, oxaliplatin administration induced spinal LTP via activation of the CaMKII-CREB cascade in the rat spinal dorsal horn. Moreover, we found that administration of oxaliplatin significantly increased the amplitude of excitatory postsynaptic currents and the number of action potentials, but these effects were attenuated by pretreatment with either CaMKII inhibitor KN-93 or NR2B antagonist Ro 25-6981. An increase in the phosphorylation of spinal N-methyl-d-aspartate (NMDA) receptor subunit 1 (NR1) after oxaliplatin administration was weakened by ZD7288 pretreatment. Administration of noncompetitive NMDA receptor antagonist MK-801 blocked oxaliplatin-evoked CaMKII-CREB cascade activation and prevented HCN2-mediated spinal-LTP induction in vitro and suppressed neuropathic-pain behaviors of rats. All these data suggest that HCN2 contributes to the development of neuropathic pain by inducing spinal LTP via activation of NMDA receptor-mediated CaMKII signaling.
Learn More >The scarcity and limited risk/benefit ratio of painkillers available on the market, in addition to the opioid crisis, warrant reflection on new innovation strategies. The pharmacopoeia of analgesics is based on products that are often old and derived from clinical empiricism, with limited efficacy or spectrum of action, or resulting in an unsatisfactory tolerability profile. Although they are reference analgesics for nociceptive pain, opioids are subject to the same criticism. The use of opium as an analgesic is historical. Morphine was synthesized at the beginning of the 19th century. The efficacy of opioids is limited in certain painful contexts and these drugs can induce potentially serious and fatal adverse effects. The current North American opioid crisis, with an ever-rising number of deaths by opioid overdose, is a tragic illustration of this. It is therefore legitimate to develop research into molecules likely to maintain or increase opioid efficacy while improving their tolerability. Several avenues are being explored including targeting of the mu opioid receptor (MOR) splice variants, developing biased agonists or targeting of other receptors such as heteromers with MOR. Ion channels acting as MOR effectors, are also targeted in order to offer compounds without MOR-dependent adverse effects. Another route is to develop opioid analgesics with peripheral action or limited central nervous system (CNS) access. Finally, endogenous opioids used as drugs or compounds that modify the metabolism of endogenous opioids (Dual ENKephalinase Inhibitors) are being developed. The aim of the present review is to present these various targets/strategies with reference to current indications for opioids, concerns about their widespread use, particularly in chronic non-cancer pains, and ways of limiting the risk of opioid abuse and misuse.
Learn More >The gastrointestinal tract is the only internal organ to have evolved with its own independent nervous system, known as the enteric nervous system (ENS). This Review provides an update on advances that have been made in our understanding of how neurons within the ENS coordinate sensory and motor functions. Understanding this function is critical for determining how deficits in neurogenic motor patterns arise. Knowledge of how distension or chemical stimulation of the bowel evokes sensory responses in the ENS and central nervous system have progressed, including critical elements that underlie the mechanotransduction of distension-evoked colonic peristalsis. Contrary to original thought, evidence suggests that mucosal serotonin is not required for peristalsis or colonic migrating motor complexes, although it can modulate their characteristics. Chemosensory stimuli applied to the lumen can release substances from enteroendocrine cells, which could subsequently modulate ENS activity. Advances have been made in optogenetic technologies, such that specific neurochemical classes of enteric neurons can be stimulated. A major focus of this Review will be the latest advances in our understanding of how intrinsic sensory neurons in the ENS detect and respond to sensory stimuli and how these mechanisms differ from extrinsic sensory nerve endings in the gut that underlie the gut-brain axis.
Learn More >Because intractable itch reduces quality of life, understanding the fundamental mechanisms of itch is required to develop antipruritic treatments. Itch is mediated by peripheral sensory neurons, which originate from the neural crest (NC) during development. Itch-associated signaling molecules have been detected in genetically engineered animals and in cultures of peripheral neurons from dorsal root ganglia (DRG). Ethical difficulties collecting peripheral neurons from human DRG have limited analysis of itch in humans. This study describes a method of differentiating peripheral neurons from human induced pluripotent stem cells (hiPSCs) for physiological study of itch. This method resulted in the robust induction of p75 and HNK1 double-positive NC cells from hiPSCs. The expression of NC markers TFAP2A, SOX10 and SNAI1 increased during NC induction. The induction efficiency was nearly 90%, and human peripheral neurons expressing peripherin were efficiently differentiated from hiPSC-derived NC cells. Moreover, induced peripheral neurons expressed the sensory neuronal marker BRN3A and the itch-related receptors HRH1, MRGPRX1, IL31R and IL-4R. Calcium imaging analyses indicated that these peripheral neurons included sensory neurons responsive to itch-related stimuli such as histamine, BAM8-22, IL-31 and IL-4. These findings may enable detailed analyses of human DRG neurons and may result in new therapies for intractable itch.
Learn More >Abdominal pain in childhood is extremely common and presents frequently to both primary and secondary care, with many children having recurrent pain which impacts on daily functioning. Despite this most children have no discernible underlying pathology. We discuss the underlying mechanism for functional abdominal pain (visceral hypersensitivity), the evidence base linking parental anxiety and patient symptoms, and how parents can be supported in managing their children's symptoms by addressing questions commonly asked by children and families. We look at the evidence for a one-stop rational approach to investigation including a coeliac screen, inflammatory markers and consideration of stool faecal calprotectin, in the absence of red flags. We evaluate commonly used treatments for functional abdominal pain, within a context of managing family expectations. Given the limitations in pharmacological treatment options, trials of probiotics, peppermint oil, mebeverine and (for short-term use only) hyoscine butylbromide may be appropriate. Psychological interventions including cognitive-behavioural therapy, distraction techniques and hypnotherapy have a better evidence base. There is also some evidence for other complementary therapies in children, including yoga and neurostimulation. Outcome is generally good providing there is child and family acceptance of the multiple factors implicated in the aetiology of the pain.
Learn More >Women who develop bladder pain syndrome (BPS), irritable bowel syndrome, or dyspareunia frequently have an antecedent history of dysmenorrhea. Despite the high prevalence of menstrual pain, its role in chronic pelvic pain emergence remains understudied. We systematically characterized bladder, body, and vaginal mechanical sensitivity with quantitative sensory testing in women with dysmenorrhea (DYS, n = 147), healthy controls (HCs) (n = 37), and women with BPS (n = 25). Previously, we have shown that a noninvasive, bladder-filling task identified a subset of women with both dysmenorrhea and silent bladder pain hypersensitivity, and we repeated this to subtype dysmenorrhea sufferers in this study (DYSB; n = 49). DYS, DYSB, and BPS participants had lower vaginal mechanical thresholds and reported more pain to a cold stimulus during a conditioned pain modulation task and greater pelvic examination after-pain than HCs (P's < 0.05). DYSB participants also had reduced body mechanical thresholds and less conditioned pain modulation compared to HCs and DYS participants (P's < 0.05). Comparing quantitative sensory testing results among the DYS and HC groups only, provoked bladder pain was the only significant predictor of self-reported menstrual pain (r = 0.26), bladder pain (r = 0.57), dyspareunia (r = 0.39), and bowel pain (r = 0.45). Our findings of widespread sensory sensitivity in women with dysmenorrhea and provoked bladder pain, much like that observed in chronic pain, suggest a need to study the trajectory of altered mechanisms of pain processing in preclinical silent visceral pain phenotypes to understand which features convey inexorable vs modifiable risk.
Learn More >A relevant subsample of patients with chronic low back pain (CLBP) have manifested augmented central pain processing, central sensitisation (CS). Patients with CLBP have limited functioning and participation. Theoretically, physical functioning in patients with CLBP can plausibly be linked to CS; however, evidence to explain such association is scarce. Moreover, there is no gold standard for CS diagnosis. The objectives of the study are: (1) to analyse the association between instruments assessing reference symptoms and signs attributed to CS; (2) to analyse whether reference symptoms and signs attributed to CS are associated with functioning measurement outcomes; and (3) to analyse whether changes (between baseline and discharge) in reference symptoms and signs attributed to CS are related to changes in each of the functioning measurement outcomes.
Learn More >Switching microglial polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype represents a novel therapeutic strategy for diabetic neuropathic pain (DNP). This study aims to determine the role and mechanism of interleukin (IL)-35 in regulating microglial M1/M2 polarization in DNP. A rat model of DNP was induced by a single streptozocin injection and recombinant IL-35 (rIL-35) was then intrathecally administered to the rats for 14 days. The mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were measured to assess the therapeutic effect of IL-35. Highly aggressive proliferating immortalized (HAPI), a rat microglia cell line, was treated with lipopolysaccharide (LPS) for M1 polarization or IL-4 for M2 polarization. The M1 markers (CD68, iNOS, TNF-α, IL-6) and M2 markers (CD206, Arg-1, IL-10) were examined. rIL-35 administration in DNP model rats elevated MWT and TWL, induced microglial polarization toward the M2 phenotype, suppressed JNK signaling and activated JAK2/STAT6 signaling. In vitro assay confirmed that rIL-35 induced microglial M2 polarization in HAPI cells through inhibiting JNK signaling and activating JAK2/STAT6 signaling. Collectively, the mechanism underlying therapeutic effect of IL-35 on DNP may relate to its promotion of microglial M2 polarization by regulating JNK signaling and JAK2/STAT6 signaling.
Learn More >An important challenge in pain assessment is the inability of an evaluator to corroborate, using objective signs or indicators, the subjective pain report of a patient. In this scenario, the Electronic von Frey (EVF) anaesthesiometer rises as a valuable Quantitative Sensory Testing modality for pain evaluation. Although EVF showed good reproducibility when applied to healthy areas in humans, its use for evaluation of burn-related pain threshold has not yet been validated. The present study demonstrated the concurrent validity of EVF by determining its correlation with the traditionally used Visual Analog Scale (VAS). EVF was compared to VAS through pain measurements obtained from 44 patients with superficial partial thickness burns treated with silver sulfadiazine. A very good and significant positive correlation between both methods was detected. Baseline clinical and demographic parameters did not significantly affect the association between EVF and VAS. Additionally, EVF had significant and moderate positive correlation with the amount of analgesic used and with the Burns Specific Pain Anxiety Scale scores. Regular pain assessment is essential for the establishment of an appropriate treatment plan; thus, it is critical that we continue to refine our pain assessment skills to avoid chronic pain and psychological trauma in burn patients.
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