Mol Pain
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Voltage-gated potassium (Kv) channels are critical in controlling neuronal excitability and are involved in the induction of neuropathic pain. Therefore, Kv channels might be potential targets for prevention and/or treatment of this disorder. We reported here that a majority of dorsal root ganglion (DRG) neurons were positive for Kv channel alpha subunit Kv1.2. ⋯ Rescuing nerve injury-induced reduction of Kv1.2 in the injured L5 DRG attenuated the development and maintenance of SNL-induced pain hypersensitivity without affecting acute pain and locomotor function. This effect might be attributed to the prevention of SNL-induced upregulation of endogenous Kv1.2 antisense RNA, in addition to the increase in Kv1.2 protein expression, in the injured DRG. Our findings suggest that Kv1.2 may be a novel potential target for preventing and/or treating neuropathic pain.
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Lamina I projection neurons respond to painful stimuli, and some are also activated by touch or hair movement. Neuropathic pain resulting from peripheral nerve damage is often associated with tactile allodynia (touch-evoked pain), and this may result from increased responsiveness of lamina I projection neurons to non-noxious mechanical stimuli. It is thought that polysynaptic pathways involving excitatory interneurons can transmit tactile inputs to lamina I projection neurons, but that these are normally suppressed by inhibitory interneurons. Vertical cells in lamina II provide a potential route through which tactile stimuli can activate lamina I projection neurons, since their dendrites extend into the region where tactile afferents terminate, while their axons can innervate the projection cells. The aim of this study was to determine whether vertical cell dendrites were contacted by the central terminals of low-threshold mechanoreceptive primary afferents. ⋯ These results show that vertical cell dendritic spines are frequently contacted by the central terminals of myelinated low-threshold mechanoreceptive afferents. Since dendritic spines are associated with excitatory synapses, it is likely that most of these contacts were synaptic. Vertical cells in lamina II are therefore a potential route through which tactile afferents can activate lamina I projection neurons, and this pathway could play a role in tactile allodynia.
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The phylogenetically highly conserved CK1 protein kinases consisting of at least seven isoforms form a distinct family within the eukaryotic protein kinases. CK1 family members play crucial roles in a wide range of signaling activities. However, the functional role of CK1 in somatosensory pain signaling has not yet been fully understood. The aim of this study was to clarify the role of CK1 in the regulation of inflammatory pain in mouse carrageenan and complete Freund's adjuvant (CFA) models. ⋯ These results suggest that CK1 plays an important pathophysiological role in spinal inflammatory pain transmission, and that inhibition of the CK1 activity may provide a novel strategy for the treatment of inflammatory pain.
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Histone deacetylases (HDACs) and histone acetyltransferases (HATs) are key players in epigenetic regulation of gene expression. Analgesic activity by HDAC inhibitors has been reported in different pain models including inflammatory and neuropathic pain. These drugs interfere with gene expression through different mechanisms including chromatin remodeling and/or activation of transcription factors. Among other targets, HDAC inhibitors regulate metabotropic glutamate receptors type 2 (mGlu2) expression in central and peripheral central nervous system. However whether inhibition of HAT activity also regulates mGlu2 expression has not been reported. ⋯ Our results demonstrate that systemically injected CUR is able to inhibit H3 and H4 acetylation in the DRG and to down-regulate mGlu2 receptors in the spinal cord. We also demonstrate that long term modification of the mGlu2 expression affects the analgesic properties of the orthosteric mGlu2/3 agonist, LY379268. These data open up the possibility that epigenetic modulators might be given in combination with "traditional" drugs in a context of a multi target approach for a better analgesic efficacy.
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The P2X7 receptor is a member of the P2X family of adenosine 5'-triphosphate-gated cation channels. Several recent studies have demonstrated that this receptor is involved in mechanisms related to pain and inflammation. However, unknown is whether polymorphisms of the P2RX7 gene that encodes the human P2X7 receptor influence pain sensitivity and analgesic effects of opioids. The P2RX7 gene is known to be highly polymorphic. Thus, the present study examined associations between fentanyl sensitivity and polymorphisms in the P2RX7 gene in 355 Japanese patients who underwent painful orofacial cosmetic surgery. ⋯ Cold pain sensitivity and analgesic effects of fentanyl were related to the SNP and haplotypes of the P2RX7 gene. The patients with the rs1718125 G>A SNP tended to show higher VAS24 scores. Moreover, the combination of polymorphisms from the 5'-flanking region to exon 5 recessively affected cold pain sensitivity and analgesic effects of opioids for acute cold pain. The present findings shed light on the involvement of P2RX7 gene polymorphisms in naive cold pain sensitivity and analgesic effects of fentanyl.