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The present study aimed to investigate the effects of high-mobility group box-1 (HMGB-1) on mechanical pain hypersensitivity and the underlying mechanism. Mouse primary astrocytes were isolated and treated as specified. A CCK-8 assay was used to determine cytotoxicity and a gap junctional communication assay was performed. Ethidium bromide (EtBr) uptake was used to evaluate the hemichannel activity of primary astrocytes. A mouse model of neuropathic pain was developed and paw withdrawal threshold was used to evaluate hind paw sensitivity. RT-qPCR and Western blot were used to determine mRNA and protein expression of genes, respectively. ELISA was used to measure the release of inflammatory cytokines. Treatment with HMGB-1 increased the expression of both toll-like receptor-4 (TLR-4) and connexin 43 (Cx43)in mouse primary astrocytes. HMGB-1 also promoted gap junctional intercellular communication and hemichannel function. Our results also demonstrated that HMGB-1 regulated Cx43 through the JNK signaling pathway, and Cx43 was involved in HMGB-1-mediated inflammation in astrocytes. In vivo analysis supported the idea that HMGB-1-induced mechanical hypersensitivity was associated with Cx43. We therefore conclude that HMGB-1-induced mechanical pain hypersensitivity occurs through modulating astrocytic Cx43 via the TLR-4/JNK signaling pathway.
Learn More >Chronic non-specific low back pain is a major public health problem. Evidence supports the effectiveness of exercise as an intervention. Due to a paucity of direct comparisons of different exercise categories, medical guidelines were unable to make specific recommendations regarding the type of exercise working best in improving chronic low back pain. This network meta-analysis (NMA) of randomised controlled trials aims to investigate the comparative efficacy of different exercise interventions in patients with chronic non-specific low back pain.
Learn More >When skin afferents are activated, the sensory signals are transmitted to the spinal cord and eventually reach the primary somatosensory cortex (SI), initiating the encoding of the sensory percept in the brain. While subsets of primary afferents mediate specific somatosensory information from an early age, the subcortical pathways that transmit this information undergo striking changes over the first weeks of life, reflected in the gradual emergence of specific sensory behaviours. We therefore hypothesised that this period is associated with differential changes in the encoding of incoming afferent volleys in SI. To test this, we compared SI responses to A fibre skin afferent stimulation and A+C skin afferent fibre stimulation in lightly anaesthetised male rats at postnatal day (P) 7, 14, 21 and 30. Differences in SI activity following A and A+C fibre stimulation changed dramatically over this period. At P30, A+C fibre stimulation evoked significantly larger gamma, beta and alpha energy increases compared to A fibre stimulation alone. At younger ages, the changes in S1 oscillatory activity evoked by the two afferent volleys were not significantly different. Silencing TRPV1+ C fibres with QX-314 significantly reduced the gamma and beta SI oscillatory energy increases evoked by A+C fibres, at P30 and P21, but not at younger ages. Thus, C fibres differentially modulate SI oscillatory activity only from the third postnatal week, well after the functional maturation of the somatosensory cortex. This age-related change in afferent evoked S1 oscillatory activity may underpin the maturation of sensory discrimination in the developing brain. Behavioural responses to sensory stimulation of the skin undergo major developmental changes over the first postnatal weeks. Here we show that this is accompanied by a shift in the differential frequency encoding of sensory A fibre and C fibre afferent inputs into the developing rat somatosensory cortex. The results demonstrate major postnatal changes in the ability of the cortex to differentiate between afferent sensory inputs arriving in the mammalian brain.
Learn More >Chronic pain is common following stroke, however there is little known about the treatments for pain that are being accessed by stroke survivors, nor their perceived effectiveness.
Learn More >To document the prevalence of new headaches in patients with Covid-19 infection and the potential association with other neuro-sensorial symptoms (anosmia and ageusia). The persistence of these symptoms 1 month after recovery was also documented.
Learn More >To examine the peripheral nervous system (PNS) in spinal cord injured (SCI) patients using two novel methods: (1) MScanFit MUNE; a motor unit number estimation method detecting motor unit loss and (2) muscle velocity recovery cycles (MVRCs) measuring muscle membrane properties which has previously shown depolarization of the muscle membrane in denervated muscles.
Learn More >Peripheral nerve field stimulation (PNFS) is an effective alternative treatment for patients with chronic low back pain. Transcutaneous electrical nerve stimulation (TENS) is frequently used in pain therapy. Aim of this prospective study was to examine the predictive value of TENS for later PNFS treatment.
Learn More >The chronification of pain can be attributed to changes in membrane receptors and channels underlying neuronal plasticity and signal transduction largely within nociceptive neurons that initiate and maintain pathological pain states. These proteins are subject to dynamic modification by post-translational modifications (PTM), creating a code that controls protein function in time and space. Phosphorylation is an important PTM that affects ∼30% of proteins in vivo. Increased phosphorylation of various nociceptive ion channels and of their modulators underlies sensitization of different pain states. Cyclin-dependent kinases are proline-directed serine/threonine kinases that impact various biological and cellular systems. Cdk5, one member of this kinase family, and its activators p35 and p39 are expressed in spinal nerves, dorsal root ganglia and in the dorsal horn of the spinal cord. In neuropathic pain conditions expression and/or activity of Cdk5 is increased, implicating Cdk5 in nociception. Experimental evidence suggests that Cdk5 is regulated via its own phosphorylation, through increasing p35's interaction with Cdk5, and via cleavage of p35 into p25. This narrative review discusses the molecular mechanisms of Cdk5-mediated regulation of target proteins involved in neuropathic pain. We focus on Cdk5-substrates that have been linked to nociceptive pathways, including channels (e.g., transient receptor potential cation channel, voltage-gated calcium channel), proteins involved in neurotransmitter release (e.g., synaptophysin, collapsin response mediator protein 2), and receptors (e.g., glutamate, purinergic, and opioid). By altering the phosphoregulatory "set-point" of proteins involved in pain signaling, Cdk5 thus appears to be an attractive target for treating neuropathic pain conditions.
Learn More >Descending facilitatory circuitry that involves the rostroventromedial medulla (RVM) exerts a significant role in the development of antinociceptive tolerance and hyperalgesia following chronic morphine treatment. The role of the RVM in the development of antinociceptive tolerance to oxycodone, another clinically used strong opioid, is not yet known. Ketamine, an NMDA receptor antagonist, attenuates opioid antinociceptive tolerance, but its effect on RVM cell discharge in opioid tolerant animals is not known. Here, we compared chronic effects of morphine and oxycodone on the discharge properties of RVM cells and attempted to attenuate chronic treatment-induced changes with ketamine. Parallel recordings of RVM cell discharge and limb withdrawal response were performed under light pentobarbital anesthesia in male rats following sustained systemic treatment with morphine or oxycodone at equianalgesic doses. Ongoing activity and the response to noxious heat and pinch were determined in pronociceptive RVM ON-cells and antinociceptive OFF-cells on the sixth treatment day. Proportions of RVM cell types were not changed. Chronic oxycodone induced antinociceptive tolerance both in limb withdrawal and RVM cell activity. Chronic morphine induced antinociceptive tolerance in limb withdrawal that was accompanied by pronociceptive heat response changes in RVM ON- and OFF-cells. A behaviorally subantinociceptive dose of acute ketamine reversed antinociceptive tolerance both to morphine and oxycodone in limb withdrawal and reversed the chronic morphine-induced pronociceptive discharge changes in RVM cells. The results indicate that an NMDA receptor-dependent descending pronociceptive circuitry involving the RVM has an important role in behavioral antinociceptive tolerance to morphine but not oxycodone.
Learn More >Fibromyalgia is a common and challenging chronic pain disorder with few, if any, highly effective and well tolerated treatments. Alpha-lipoic acid (ALA) is a non-sedating antioxidant with evidence of efficacy in the treatment of symptomatic diabetic neuropathy that has not been evaluated in the setting of fibromyalgia treatment. Thus, we conducted a single-centre, proof-of-concept, randomized, placebo-controlled, crossover trial of ALA for the treatment of fibromyalgia. Twenty-seven participants were recruited and 24 participants completed both treatment periods of the trial. The median maximal tolerated dose of ALA in this trial was 1,663 mg/day. Treatment-emergent adverse events with ALA were infrequent and not statistically different from placebo. For the primary outcome of pain intensity, and for several other validated secondary outcomes, there were no statistically significant differences between placebo and ALA. A post hoc exploratory subgroup analysis showed a significant interaction between gender and treatment with a significant favourable placebo-ALA difference in pain for males, but not for females. Overall, the results of this trial do not provide any evidence to suggest promise for ALA as an effective treatment for fibromyalgia, which is predominantly prevalent in females. This negative clinical trial represents an important step in a collective strategy to identify new, better tolerated and more effective treatments for fibromyalgia.
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