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Persistent hyperexcitability of primary nociceptors is a major contributor to diverse forms of chronic pain. While much is known about mechanisms that maintain persistent hyperexcitability, little is known about induction mechanisms. Interesting parallels have been noted between processes that can induce long-lasting nociceptor hyperexcitability and mechanisms involved in memory formation (e.g., Weragoda et al., 2004; J Neurosci 24:10393; Price et al., 2015, Prog Mol Biol Transl Sci, 131:409). We have developed an in vitro model to test the hypothesis that cellular processes important for the induction of late long-term synaptic potentiation (L-LTP) and memory in the hippocampus can also induce long-term hyperexcitability (LTH) of dissociated rat nociceptor somata. We have begun by testing whether nociceptor LTH can be induced by cAMP signaling involving PKA activity, CREB activity, gene transcription, and protein synthesis. Rat DRG neurons were dissociated and cultured overnight. Beginning 1 h after dissociation, neurons were incubated for 6 h with the adenylyl cyclase activator, forskolin, or a Gs-coupled serotonin receptor (5-HT4R) agonist, prucalopride. Other neurons received co-treatment with either a PKA inhibitor, H89; a CREB inhibitor, 666-15; a transcription inhibitor, actinomycin D; or a translation inhibitor, cycloheximide, at concentrations known to block the induction of hippocampal L-LTP. Whole-cell patch recordings under current-clamp were made 12-24 h after washout. The early treatment with forskolin or prucalopride induced LTH manifested as depolarization of resting membrane potential and increased action potential generation when neurons were further depolarized artificially to -45 mV for 30 s. Co-treatment during induction by prucalopride with H89, 666-15, actinomycin D, or cycloheximide significantly reduced LTH. These results support the hypothesis that conserved, memory-related mechanisms can induce nociceptor alterations known to promote persistent pain. This preparation enables efficient, detailed examination of numerous potential induction mechanisms, and might reveal new pharmacological targets for preventing the transition to chronic pain. Grant support from NIH grants NS091759 and NS111521.
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