Pain
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A strong link between histone deacetylases (HDACs) and nociceptive hypersensitivity has been indicated in different pain models. However, the underlying molecular and cellular mechanisms remain elusive. Here, we discovered that partial sciatic nerve ligation-induced mechanical allodynia and thermal hyperalgesia in mice were associated with increased mRNA and protein expressions of HDAC5 (a member of class IIa HDACs) and SRY-related HMG-box 10 (SOX10) in the ipsilateral lumbar dorsal horn. ⋯ Chromatin-immunoprecipitation assay further confirmed a novel nonhistone modulation function of HDACs on SOX10 expression, that is, HDAC5 regulates SOX10 by binding to the promoter region of Sox10 gene. In conclusion, this study for the first time demonstrates that HDAC5 regulates spinal neuronal sensitization in neuropathic pain by upregulating modulating SOX10 expression. Thus, interventions that reduce HDAC5/SOX10 expression may represent promising avenues in the treatment of neuropathic pain.
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The sodium channel NaV1.7 contributes to action potential (AP) generation and propagation. Loss-of-function mutations in patients lead to congenital indifference to pain, though it remains unclear where on the way from sensory terminals to central nervous system the signalling is disrupted. We confirm that conditional deletion of NaV1.7 in advillin-expressing sensory neurons leads to impaired heat and mechanical nociception in behavioural tests. ⋯ On prolonged electrical stimulation at 2 Hz, (7) activity-dependent slowing of nerve fiber conduction was markedly less, and (8) was less likely to result in conduction failure of the mutant single fibers. Finally, recording of compound APs from the whole saphenous nerve confirmed slower conduction and less activity-dependent slowing as well as the functional absence of a large subpopulation of C-fibers (9) in conditional NaV1.7 knockouts. In conclusion, the clear deficits in somatic primary afferent functions shown in our study may be complemented by previously reported synaptic dysfunction and opioidergic inhibition, together accounting for the complete insensitivity to pain in the human mutants lacking NaV1.7.
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Research shows that chronic pain is related to cortical alterations that can be reflected in reduced tactile acuity, but whether acute pain perception influences tactile acuity has not been tested. Considering the biological role of nociception, it was hypothesized that nociceptive pain will lead to a rapid improvement in tactile acuity and that this effect is correlated with pain intensity and pain distribution. In this randomised double-blind controlled experiment (trial no. ⋯ Other tests, point-to-point test and two-point estimation task, changed with a similar trend but did not reach significance. We concluded that acute, nociceptive pain does not improve but deteriorates tactile acuity linearly. The biological role of the observed phenomenon is unknown, and therefore, future studies should address this question.