The Impact of Sex on the Dysfunction of Endogenous Pain Control after Traumatic Brain Injury

Chronic pain is among the most devastating and poorly understood symptoms after traumatic brain injury (TBI). Disruption of endogenous descending pain control pathways may contribute to chronic pain after TBI. In prior work, we found that TBI induces a two-stage pain dysregulation involving acute mechanical hindpaw hypersensitivity that resolves by 28 days post-injury (DPI), followed by chronic failure of descending control of nociception (DCN) lasting up to 180 DPI. However, the impact of sex on the dysfunction of endogenous pain control systems after TBI has not been explored. Using a lateral fluid percussion model of TBI in male and female rats, we assessed mechanical nociceptive responses using von Frey fibers and tested pharmacological interventions targeting established descending pain modulatory systems. We employed the selective noradrenergic (NA) reuptake inhibitor, reboxetine, the selective serotonin reuptake inhibitor, escitalopram, adrenoceptor antagonists' prazosin (α₁-adrenoceptors) and atipamezole (α₂-adrenoceptors), and the serotonin 5-HT₃ receptor antagonist, ondansetron. Findings revealed that acute hindlimb hypersensitivity involved enhanced descending serotonergic pain facilitation via the 5-HT₃ receptor in both sexes. In uninjured rats, pain control relies on descending NA inhibitory signaling via spinal α₂-adrenoceptors. Boosting noradrenaline in the acute phase after TBI with reboxetine reduced acute mechanical pain, but studies with selective adrenoceptor antagonists revealed a persistent switch from an α₂- to an α₁-adrenoceptor-driven antinociceptive pathway after TBI in both males and females. Acute phase mechanical pain resolved by 28 DPI, exposing a chronic phase of DCN failure up to 180 DPI. Reboxetine treatment restored the DCN response in female TBI rat via α₁-adrenoceptor but failed in male TBI rats. Restoration of the DCN response in male TBI rats was restored by enhancing serotonin signaling with escitalopram. These results demonstrate key differences in the susceptibility of endogenous pain modulatory pathways and the adaptations of those pathways between male and female rats after TBI. These findings suggest that sex needs to be considered when designing mechanism-based therapies for pain after TBI.