M2 receptors exert analgesic action on DRG sensory neurons by negatively modulating VR1 activity

Federica De Angelis, Sara Marinelli, Bernard Fioretti, Luigi Catacuzzeno, Fabio Franciolini, Flaminia Pavone, Ada Maria Tata

Research output: Contribution to journalArticle

Abstract

The peripheral application of the M2 cholinergic agonist arecaidine on sensory nerve endings shows anti-nociceptive properties. In this work, we analyze in vitro, the mechanisms downstream M2 receptor activation causing the analgesic effects, and in vivo the effects produced by M2 agonist arecaidine administration on nociceptive responses in a murine model of nerve growth factor (NGF)-induced pain. Cultured DRG neurons treated with arecaidine showed a decreased level of VR1 and SP transcripts. Conversely, we found an increased expression of VR1 and SP transcripts in DRG from M2/M4-/- mice compared to WT and M1-/- mice, confirming the inhibitory effect in particular of M2 receptors on SP and VR1 expression. Patch-clamp experiments in the whole-cell configuration showed that arecaidine treatment caused a reduction of the fraction of capsaicin-responsive cells, without altering the mean capsaicin-activated current in responsive cells. We also demonstrated that arecaidine prevents PKCε{lunate} translocation to the plasma membrane after inflammatory agent stimulation, mainly in medium-small sensory neurons. Finally, in mice, we have observed that intraperitoneal injection of arecaidine reduces VR1 expression blocking hyperalgesia and allodynia caused by NGF intraplantar administration. In conclusion, our data demonstrate that in vivo M2 receptor activation induces desensitization to mechanical and heat stimuli by a down-regulation of VR1 expression and by the inhibition of PKCε{lunate} activity hindering its translocation to the plasma membrane, as suggested by in vitro experiments. J. Cell. Physiol. 229: 783-790, 2014.

Original languageEnglish
Pages (from-to)783-790
Number of pages8
JournalJournal of Cellular Physiology
Volume229
Issue number6
DOIs
Publication statusPublished - 2014

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

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    De Angelis, F., Marinelli, S., Fioretti, B., Catacuzzeno, L., Franciolini, F., Pavone, F., & Tata, A. M. (2014). M2 receptors exert analgesic action on DRG sensory neurons by negatively modulating VR1 activity. Journal of Cellular Physiology, 229(6), 783-790. https://doi.org/10.1002/jcp.24499