A female-specific role for Calcitonin Gene-Related Peptide (CGRP) in rodent pain models

Abstract

We aimed to investigate a potentially sexually dimorphic role of Calcitonin Gene-Related Peptide (CGRP) in mouse and rat 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 (IL-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 (SNI) 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 the KCC2 activator, 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 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 mice, but has a limited impact in male mice. Significance Statement: The majority of patients impacted by chronic pain are women. Mechanistic studies in rodents are creating a clear picture that molecular events promoting chronic pain are different in male and female animals. Far more is known about chronic pain mechanisms in male animals. We sought to build on recent evidence showing that CGRP is a more potent and efficacious promoter of headache pain in female than in male rodents. To test this, we used hyperalgesic priming and the spared nerve injury (SNI) neuropathic pain models in mice. Our findings show a clear sex dimorphism wherein CGRP promotes pain in female but not male mice. Our work suggests that CGRP antagonists could be tested for efficacy in women for a broader variety of pain conditions.

Calcitonin Gene-Related Peptide (CGRP) Receptor Antagonism Reduces Motion Sickness Indicators in Mouse Migraine Models

“…Moreover, a clinical meta-analysis of anti-CGRP signaling treatments for nausea in episodic migraine provided strong support for their effectiveness 33 . Interestingly, we also observed that female mice were more severely affected by systemic CGRP than their male counterparts, which correlates with preclinical studies showing stronger tactile sensitivity in female mice when challenged with durally applied CGRP 34 .…”

“…(Table 2). This sexual dimorphism is similar to higher incidence of migraine and VM in female patients 4,38,39 and reports of sexual-dimorphic effects of CGRP both in dura-induced pain, spinal cord neuropathic pain, and preclinical surrogate of allodynia or touch sensitivities 34 . To this end, other studies have demonstrated a sex difference in the expression of CGRP receptor components in the trigeminal nucleus 40 .…”

“…While male and female mice both showed disrupted thermoregulatory responses to systemic CGRP injections, dose response experiments at 0.05 and 1 mg/kg CGRP show that olcegepant can rescue CGRP-induced nausea in mice, but with limited effectiveness in females at the higher concentration (Table 3). This sexual dimorphism is similar to higher incidence of migraine and VM in female patients (29)(30)(31) and reports of sexual-dimorphic effects of CGRP both in dura-induced pain, spinal cord neuropathic pain, and preclinical surrogates for allodynia and photophobia in mice (25,26,32,33). To this end, other studies have demonstrated a sex difference in the expression of CGRP receptor components in the trigeminal nucleus (34).…”

Sexual dimorphism in a neuronal mechanism of spinal hyperexcitability across rodent and human models of pathological pain

“…The copyright holder for this preprint this version posted June 16, 2021. ; https://doi.org/10.1101/2021.06.15.447407 doi: bioRxiv preprint induces pain hypersensitivity only in females in rodent preclinical models of migraine 68 . Recent developments show that this female-specific effect of CGRP may be dependant on prolactin 69 and involves KCC2-dependent disinhibition 70 . Further studies are needed to understand the role of CGRP in mediating the hyperexcitability of SDH neurons in males and females.…”