Mol Pain
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Dopaminergic fibers originating from area A11 of the hypothalamus project to different levels of the spinal cord and represent the major source of dopamine. In addition, tyrosine hydroxylase, the rate-limiting enzyme for the synthesis of catecholamines, is expressed in 8-10% of dorsal root ganglia (DRG) neurons, suggesting that dopamine may be released in the dorsal root ganglia. Dopamine has been shown to modulate calcium current in DRG neurons, but the effects of dopamine on sodium current and on the firing properties of small DRG neurons are poorly understood. ⋯ We conclude that activation of D1/D5 dopamine receptors inhibits TTX-R sodium current in unmyelinated nociceptive neurons and dampens their intrinsic excitability by reducing the number of action potentials in response to stimulus. Increasing or decreasing levels of dopamine in the dorsal root ganglia may serve to adjust the sensitivity of nociceptors to noxious stimuli.
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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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Pain in masticatory muscles is among the most prominent symptoms of temperomandibular disorders (TMDs) that have diverse and complex etiology. A common complaint of TMD is that unilateral pain of craniofacial muscle can cause a widespread of bilateral pain sensation, although the underlying mechanism remains unknown. To investigate whether unilateral inflammation of masseter muscle can cause a bilateral allodynia, we generated masseter muscle inflammation induced by unilateral injection of complete Freund's adjuvant (CFA) in rats, and measured the bilateral head withdrawal threshold at different time points using a von Frey anesthesiometer. ⋯ Interestingly, central injection of TRPV1 antagonist 5-iodoresiniferatoxin into the hippocampus significantly attenuated the head withdrawal response of both CFA injected and non-CFA injected contralateral masseter muscle. Our findings show that unilateral inflammation of masseter muscle is capable of inducing bilateral allodynia in rats. Upregulation of TRPV1 at the TRG level is due to nociception caused by inflammation, whereas contralateral nocifensive behavior in masticatory muscle nociception is likely mediated by central TRPV1, pointing to the involvement of altered information processing in higher centers.
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Leptin, an adipocytokine produced mainly by white adipose tissue, has a broad role in the regulation of neuronal functions. Accumulating evidence has revealed that leptin plays an important role in influencing neuropathic pain, shown recently by the finding that chronic administration of leptin induced thermal hyperalgesia and mechanical allodynia in naïve rats. Chronic constriction sciatic nerve injury (CCI) is a well characterized model used for studying neuropathic pain. The present study was designed to investigate whether leptin plays a role in neuropathic pain in rats induced by CCI by examining particular pain behaviors. ⋯ Our findings suggest that exogenous leptin can alleviate the chronic neuropathic pain caused by CCI. The leptin effect may be mediated by attenuated expression of IL-6, TNFα, and the P2X2 and P2X3 receptors in the DRG of CCI rats.