A Female-Specific Role for Calcitonin Gene-Related Peptide (CGRP) in Rodent Pain Models

Candler Paige, Isabel Plasencia-Fernandez, Moeno Kume, Melina Papalampropoulou-Tsiridou, Louis Etienne Lorenzo, Eric T. David, Lucy He, Galo L. Mejia, Christopher Driskill, Francesco Ferrini, Andrew L. Feldhaus, Leon F. Garcia-Martinez, Armen N. Akopian, Yves De Koninck, Gregory Dussor, Theodore J. Price

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

We aimed to investigate a sexually dimorphic role of calcitonin gene-related peptide (CGRP) in rodent models of pain. Based on findings in migraine where CGRP has a preferential pain-promoting effect in female rodents, we hypothesized that CGRP antagonists and antibodies would attenuate pain sensitization more efficaciously in female than male mice and rats. In hyperalgesic priming induced by activation of interleukin 6 signaling, CGRP receptor antagonists olcegepant and CGRP8-37 both given intrathecally, blocked, and reversed hyperalgesic priming only in females. A monoclonal antibody against CGRP, given systemically, blocked priming specifically in female rodents but failed to reverse it. In the spared nerve injury model, there was a transient effect of both CGRP antagonists, given intrathecally, on mechanical hypersensitivity in female mice only. Consistent with these findings, intrathecally applied CGRP caused a long-lasting, dose-dependent mechanical hypersensitivity in female mice but more transient effects in males. This CGRP-induced mechanical hypersensitivity was reversed by olcegepant and the KCC2 enhancer CLP257, suggesting a role for anionic plasticity in the dorsal horn in the pain-promoting effects of CGRP in females. In spinal dorsal horn slices, CGRP shifted GABAA reversal potentials to significantly more positive values, but, again, only in female mice. Therefore, CGRP may regulate KCC2 expression and/ or activity downstream of CGRP receptors specifically in females. However, KCC2 hypofunction promotes mechanical pain hypersensitivity in both sexes because CLP257 alleviated hyperalgesic priming in male and female mice. We conclude that CGRP promotes pain plasticity in female rodents but has a limited impact in males.

Original languageEnglish (US)
Pages (from-to)1930-1944
Number of pages15
JournalJournal of Neuroscience
Volume42
Issue number10
DOIs
StatePublished - Mar 9 2022

Keywords

  • CGRP
  • dorsal horn
  • hyperalgesic priming
  • neuropathic pain
  • olcegepant
  • pain

ASJC Scopus subject areas

  • General Neuroscience

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