Sex differences in effectiveness of CGRP receptor antagonism for treatment of acute and persistent headache-like pain in a mouse model of mild traumatic brain injury.

Abstract

Background: Traumatic brain injury (TBI) commonly elicits acute (APTH) and/or persistent (PPTH) post-traumatic headache. Calcitonin gene related peptide (CGRP) has been implicated as a contributor to PTH pathophysiology. We explored the possibility of sexual dimorphism in the effects of CGRP receptor (CGRP-R) blockade in a preclinical model of PTH induced by a mild TBI (mTBI) in male or female mice.

Methods: Mice were lightly anesthetized and placed on a tissue paper stage prior to receiving a sham procedure or mTBI resulting from a closed-head weight drop injury. Behavioral responses to periorbital and hindpaw tactile (von Frey filaments) or thermal (hot plate) stimuli over the first 14 days post-mTBI were evaluated as measures of APTH. The PPTH phase was studied following the resolution of mTBI-induced APTH at days 14 and 28. PPTH was precipitated by exposure to bright lights (i.e., bright light stress, BLS). Olcegepant was delivered subcutaneously either repeatedly beginning 2 h after mTBI to produce a sustained block of CGRP-R signaling across the APTH phase, or as a single administration on days 14 or 28 post-mTBI to evaluate possible effects during the PPTH phase.

Results: mTBI, but not sham-procedure, produced periorbital and hindpaw tactile allodynia, as well as thermal hypersensitivity in mice of both sexes. APTH-related hypersensitivity was transient and resolved by day 14 post-injury. No sex differences were observed in the magnitude or duration of APTH-related pain behaviors. Sustained CGRP-R blockade was, however, significantly more effective in female than male mice in inhibiting pain behaviors in the APTH phase and in preventing the emergence of BLS-induced PPTH. CGRP-R blockade following the resolution of mTBI-induced APTH pain behaviors, on either day 14 or 28, minimally altered BLS-induced PPTH in either sex.

Conclusions: Sustained CGRP-R blockade starting soon after mTBI significantly inhibited APTH and prevented the expression of PPTH with greater analgesic effects in females compared to males. Delayed CGRP-R blockade beginning after resolution of APTH phase was minimally effective in preventing expression of PPTH in either sex. These data are consistent with previous observations that CGRP induces pain behaviors preferentially in females. Early and continuous CGRP blockade following mTBI may represent a viable treatment option for PTH treatment and the prevention of PTH persistence, especially in females.