Articles: neuropathic-pain.
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Background Paclitaxel is commonly used as a cancer chemotherapy drug that frequently causes peripheral neuropathic pain. Inflammasome is a multiprotein complex consisting of Nod-like receptor proteins (NLRPs), apoptosis-associated speck-like protein, and caspase-1, which functions to switch on the inflammatory process and the release of interleukin-1β. Growing evidences have supported that peripheral interleukin-1β is critical in enhancing paclitaxel-induced neuropathic pain. ⋯ The administration of a non-specific reactive oxygen species scavenger, phenyl-N-tert-butylnitrone, markedly alleviated mechanical allodynia and inhibited the activation of NLRP3 inflammasome in L4-6 dorsal root ganglia and sciatic nerve of the paclitaxel-induced neuropathic pain model. Conclusions Paclitaxel induced mechanical allodynia and activation of NLRP3 inflammasome in infiltrated macrophages of L4-6 dorsal root ganglia and sciatic nerve. Paclitaxel elicited mitochondria damage and reactive oxygen species production may result in activation of NLRP3 inflammasome in peripheral nerve, which contributes to paclitaxel-induced neuropathic pain.
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Background Accumulating evidence on the causal role of spinal cord microglia activation in the development of neuropathic pain after peripheral nerve injury suggests that microglial activation inhibitors might be useful analgesics for neuropathic pain. Studies also have shown that polyamidoamine dendrimer may function as a drug delivery vehicle to microglia in the central nervous system. In this regard, we developed polyamidoamine dendrimer-conjugated triamcinolone acetonide, a previously identified microglial activation inhibitor, and tested its analgesic efficacy in a mouse peripheral nerve injury model. ⋯ Dendrimer-conjugated triamcinolone acetonide administration right after nerve injury almost completely reversed peripheral nerve injury-induced mechanical allodynia for up to three days. Meanwhile, dendrimer-conjugated triamcinolone acetonide administration 1.5 days post injury significantly attenuated mechanical allodynia. Conclusion Our data demonstrate that dendrimer-conjugated triamcinolone acetonide inhibits spinal cord microglia activation and attenuates neuropathic pain after peripheral nerve injury, which has therapeutic implications for the treatment of neuropathic pain.
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The efficacy of opioids in patients with chronic neuropathic pain remains controversial. Although activation of δ-opioid receptors (DORs) in the brainstem reduces inflammation-induced persistent hyperalgesia, it is not effective under persistent neuropathic pain conditions and these clinical problems remain largely unknown. In this study, by using a chronic constriction injury (CCI) of the sciatic nerve in rats, we found that in the brainstem nucleus raphe magnus (NRM), DORs emerged on the surface membrane of central synaptic terminals on day 3 after CCI surgery and disappeared on day 14. ⋯ NGF was infused into the NRM or incubated CCI rat slices drove DORs to the surface membrane of synaptic terminals. Taken together, epigenetic upregulation of NGF activity by HDAC inhibitors in the NRM promotes the trafficking of DORs to pain-modulating neuronal synapses under neuropathic pain conditions, leading to δ-opioid analgesia. These findings indicate that therapeutic use of DOR agonists combined with HDAC inhibitors might be effective in chronic neuropathic pain managements.
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The mechanism underlying neuropathic pain (NP) is complex and has not been fully elucidated. The TWIK-related spinal cord K+ (TRESK) is the major background potassium current in dorsal root ganglia (DRG), we found that mitogen-activated protein kinase (MAPK) signal pathway were activated in spinal cord accompanied by TRESK down regulation in response to NP. Therefore, we investigated whether TRESK mediates inflammation and apoptosis by MAPK pathway in the spinal cord of NP rats. ⋯ Phosphorylated ERK and p38 were increased in the spinal cord. Intrathecal injection of an ERK antagonist (PD98059) and p38 antagonist (SB203580) prevented ERK and p38 activation in the spinal cord and mechanical allodynia induced by TRESK shRNA lentivirus. In conclusion, our study clearly demonstrated an important role for TRESK in NP and that TRESK regulation contributes to pain sensitivity mediates inflammation and apoptosis by ERK and p38 MAPK signaling in the spinal cord.