Mol Pain
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Chronic low back pain is a major cause of disability and health care costs. Current treatments are inadequate for many patients. A number of preclinical models have been developed that attempt to mimic aspects of clinical conditions that contribute to low back pain. ⋯ Although the glucocorticoid receptor is the target of anti-inflammatory steroids, many clinically used steroids activate both receptors. This could be one explanation for the limited effects of epidural steroids in some patients. Additional preclinical research is needed to address other possible reasons for limited efficacy of steroids, such as central sensitization or presence of an ongoing inflammatory stimulus in some forms of low back pain.
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Inhibitory interneurons in the superficial dorsal horn play important roles in modulating sensory transmission, and these roles are thought to be performed by distinct functional populations. We have identified 4 non-overlapping classes among the inhibitory interneurons in the rat, defined by the presence of galanin, neuropeptide Y, neuronal nitric oxide synthase (nNOS) and parvalbumin. The somatostatin receptor sst2A is expressed by ~50% of the inhibitory interneurons in this region, and is particularly associated with nNOS- and galanin-expressing cells. The main aim of the present study was to test whether a genetically-defined population of inhibitory interneurons, those expressing green fluorescent protein (GFP) in the PrP-GFP mouse, belonged to one or more of the neurochemical classes identified in the rat. ⋯ These findings support the view that neurochemistry provides a valuable way of classifying inhibitory interneurons in the superficial laminae. Together with previous evidence that the PrP-GFP cells form a relatively homogeneous population in terms of their physiological properties, they suggest that these neurons have specific roles in processing sensory information in the dorsal horn.
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There is considerable interest in inducing RNA interference (RNAi) in neurons to study gene function and identify new targets for disease intervention. Although short interfering RNAs (siRNAs) have been used to silence genes in neurons, in vivo delivery of RNAi remains a major challenge, especially by systemic administration. We have developed a highly efficient method for in vivo gene silencing in dorsal root ganglia (DRG) by using short hairpin RNA-expressing single-stranded adeno-associated virus 9 (ssAAV9-shRNA). ⋯ Although we previously showed substantial inhibition of target gene expression in DRG via intrathecal ssAAV9-shRNA administration, here we succeeded in inhibiting target gene expression in DRG neurons via intraperitoneal injection of ssAAV9-shRNA. AAV9-mediated delivery of shRNA will pave the way for creating animal models for investigating the molecular biology of the mechanisms of pain and sensory ganglionopathies.
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The G(q/11)-protein signaling mechanism is essential throughout the nervous system, but little is known about the contribution of the individual G-protein GPCR signaling branches towards nociceptor activation and their specific role on nociceptor sensitization. We aimed to unravel the contribution of the G(q/11)-signaling pathway towards nociceptor activation via a variety of classical inflammatory mediators signalling via different G-protein GPCRs and investigated the specific contribution of the individual G(q) and G(11) G-Proteins in nociceptors. ⋯ Our results demonstrate that the G(q/11) signaling branch plays a primary role in nociceptor sensitization upon stimulation with classical GPCR ligands, contributing primarily towards the development of mechanically allodynia. Moreover, the deletion of the individual G-proteins led to the finding that the G(q)-protein dominates the signalling machinery of the G(q/11) family of G-proteins in nociceptive neurons.
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Electroacupuncture (EA) is effective in relieving pain in patients with postherpetic neuralgia (PHN). However, the mechanism underlying the therapeutic effect of EA in PHN is still unclear. Systemic injection of resiniferatoxin (RTX), an ultrapotent analog of TRPV1 agonist, in adult rats can reproduce the clinical symptoms of PHN by ablating TRPV1-expressing sensory neurons. In this study, we determined the beneficial effect of EA and the potential mechanisms in this rat model of PHN. ⋯ EA treatment improves thermal perception by recovering TRPV1-positive sensory neurons and nerve terminals damaged by RTX. EA Also reduces RTX-induced tactile allodynia by attenuating the damage of myelinated afferent nerves and their abnormal sprouting into the spinal lamina II. Our study provides new information about the mechanisms of the therapeutic actions of EA in the treatment of PHN.