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bioRxiv · 10.1101/2024.07.13.603393

Induction of long-term hyperexcitability by memory-related cAMP signaling in isolated nociceptor cell bodies

Bavencoffe, A.·Zhu, M. Y.·Neerukonda, S. V.·Johnson, K. N.·Dessauer, C. W.·Walters, E. T.
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Abstract

Persistent hyperactivity of nociceptors is known to contribute significantly to long-lasting sensitization and ongoing pain in many clinical conditions. It is often assumed that nociceptor hyperactivity is mainly driven by continuing stimulation from inflammatory mediators. We have tested an additional possibility: that persistent increases in excitability promoting hyperactivity can be induced by a prototypical cellular signaling pathway long known to induce late-phase long-term potentiation (LTP) of synapses in brain regions involved in memory formation. This cAMP-PKA-CREB-gene transcription-protein synthesis pathway was tested using whole-cell current clamp methods on small dissociated sensory neurons (primarily nociceptors) from dorsal root ganglia (DRGs) excised from previously uninjured ("naive") rats. Six-hour treatment with the specific Gs-coupled 5-HT4 receptor agonist, prucalopride, or with the adenylyl cyclase activator, forskolin, induced long-term hyperexcitability (LTH) in DRG neurons that manifested 12-24 hours later as action potential (AP) discharge (ongoing activity, OA) during artificial depolarization to -45 mV, a membrane potential that is normally subthreshold for AP generation. Prucalopride treatment also induced significant long-lasting depolarization of resting membrane potential (from -69 to -66 mV), enhanced depolarizing spontaneous fluctuations (DSFs) of membrane potential, and indications of reduced AP threshold and rheobase. LTH was prevented by co-treatment of prucalopride with inhibitors of PKA, CREB, gene transcription, and protein synthesis. As in the induction of synaptic memory, many other cellular signals are likely to be involved. However, the discovery that this prototypical memory induction pathway can induce nociceptor LTH, along with reports that cAMP signaling and CREB activity in DRGs can induce hyperalgesic priming, suggest that early, temporary, cAMP-induced transcriptional and translational mechanisms can induce nociceptor LTH that might last for long periods. An interesting possibility is that these mechanisms can also be reactivated by re-exposure to inflammatory mediators such as serotonin during subsequent challenges to bodily integrity, "reconsolidating" the cellular memory and thereby extending the duration of persistent nociceptor hyperexcitability. HighlightsO_LINociceptor long-term hyperexcitability (LTH) can be induced by a 5-HT4R agonist. C_LIO_LI5-HT4R-induced LTH manifests as ongoing activity during modest depolarization. C_LIO_LIEnhanced ongoing activity is associated with long-term potentiation of DSFs. C_LIO_LIInduction of LTH depends upon PKA, CREB, transcription, and protein synthesis. C_LIO_LINociceptor LTH may be triggered by conserved memory-related plasticity mechanisms. C_LI

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Bavencoffe, A., Zhu, M. Y., Neerukonda, S. V., Johnson, K. N., Dessauer, C. W., Walters, E. T.. 2024-07-17. Induction of long-term hyperexcitability by memory-related cAMP signaling in isolated nociceptor cell bodies. https://doi.org/10.1101/2024.07.13.603393

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