Mol Pain
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Voltage-gated sodium channel Nav1.7 is a key molecule in nociception, and its dysfunction has been associated with various pain disorders. Here, we investigated the regulation of Nav1.7 biophysical properties by Fyn, an Src family tyrosine kinase. Nav1.7 was coexpressed with either constitutively active (FynCA) or dominant negative (FynDN) variants of Fyn kinase. ⋯ Our study demonstrates that Nav1.7 is a substrate for Fyn kinase, and the effect of the channel phosphorylation depends on the cell background. Fyn-mediated modulation of Nav1.7 may regulate DRG neuron excitability and contribute to pain perception. Whether this interaction could serve as a target for developing new pain therapeutics requires future study.
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Nociceptive signals originating in the periphery are conveyed to the brain through specific afferent and ascending pathways. The spino-(trigemino-)parabrachio-amygdaloid pathway is one of the principal pathways mediating signals from nociception-specific ascending neurons to the central amygdala, a limbic structure involved in aversive signal-associated emotional responses, including the emotional aspects of pain. Recent studies suggest that the right and left central amygdala play distinct roles in the regulation of nociceptive responses. ⋯ Although the single-sided formalin injection caused a significant bilateral increase in c-Fos-expressing neurons in the lateral parabrachial nucleus with slight projection-side dependence, the increase in the amplitude of postsynaptic excitatory currents and the number of c-Fos-expressing neurons in the central amygdala occurred predominantly on the right side regardless of the side of the inflammation. Although there was no significant correlation in the number of c-Fos-expressing neurons between the lateral parabrachial nucleus and central amygdala in the formalin-injected animals, these numbers were significantly correlated between the basolateral amygdala and central amygdala. It is thus concluded that the lateral parabrachial nucleus-central amygdala synaptic potentiation reported in various pain models is not a simple Hebbian plasticity in which raised inputs from the lateral parabrachial nucleus cause lateral parabrachial nucleus-central amygdala potentiation but rather an integrative and adaptive response involving specific mechanisms in the right central amygdala.
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Back pain is common and costly. Although lumbar disc degeneration has long been regarded as a major contributor to back pain, how disc degeneration leads to back pain remains unclear. Recent studies observed microglia activation in the spinal cord after disc degeneration, suggesting activated microglia may be involved in discogenic back pain. ⋯ Immunofluorescence demonstrated colony-stimulating factor 1, a cytokine that promotes microglia repopulation, was significantly increased in L3 dorsal root ganglions, whereas its receptor colony-stimulating factor 1 receptor was upregulated on microglia in the disc-injured mice. In summary, lumbar disc puncture caused progressive disc degeneration which induced microglia activation and back pain in mice. Increased colony-stimulating factor 1/colony-stimulating factor 1 receptor signaling is involved in the disc degeneration-induced microglia activation and back pain.
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Painful burn injuries are among the most debilitating form of trauma, globally ranking in the top 15 leading causes of chronic disease burden. Despite its prevalence, however, chronic pain after burn injury is under-studied. We previously demonstrated the contribution of the Rac1-signaling pathway in several models of neuropathic pain, including burn injury. ⋯ Treatment with romidepsin decreased dendritic spine dysgenesis, reduced c-fos expression, and rescued pain thresholds. Drug discontinuation resulted in a relapse of cellular correlates of pain and in lower pain thresholds in behavioral tests. Taken together, our findings identify Pak1 signaling as a potential molecular target for therapeutic intervention in traumatic burn-induced neuropathic pain.
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Vortioxetine is a multimodal antidepressant that potently antagonizes 5-HT3 serotonin receptors, inhibits the high-affinity serotonin transporter, activates 5-HT1A and 5-HT1B receptors, and antagonizes 5-HT1D and 5-HT7 receptors. 5-HT3 receptors largely mediate the hyperalgesic activity of serotonin that occurs in response to nerve injury. Activation of 5-HT3 receptors contributes to explain why selective serotonin reuptake inhibitors, such as fluoxetine, are not indicated in the treatment of neuropathic pain. Here, we studied the analgesic action of vortioxetine in the chronic constriction injury model of neuropathic pain in mice. ⋯ Vortioxetine enhanced mechanical pain thresholds in chronic constriction injury mice without changing motor activity, as assessed by the open-field and horizontal bar tests. None of the three antidepressants caused analgesia in the complete Freund's adjuvant model of chronic inflammatory pain. These findings raise the attractive possibility that vortioxetine can be effective in the treatment of neuropathic pain, particularly in patients with comorbid depression and cognitive dysfunction.