Chronic Joint Pain Drives Sex-Specific Changes in Hippocampal Glutamatergic Signaling and Sleep

Sleep health and sex-associated differences contribute to osteoarthritis (OA) pain, yet their mechanistic roles remain poorly defined. Sleep disruption can both develop after OA pain onset and increase lifetime risk of OA, with females more vulnerability to both. This suggests sleep is a sex-specific modifiable factor and potential treatment target to influence joint pathology and pain. Amongst central pain circuits involved in OA, the hippocampus regulates affective and cognitive dimensions of pain, undergoing maladaptive plasticity in OA. We investigated sex-specific hippocampal glutamatergic function in a monoiodoacetate knee pain model, integrating assessments of mechanical sensitivity and sleep. Both sexes developed pain, but females exhibited poorer sleep health. Pain severity correlated with reduced NMDAR/GluN2B function in females, while altered AMPAR and NMDAR activity associated with REM sleep. These findings reveal sex-specific hippocampal plasticity linked to sleep disruption in chronic OA pain, highlighting central mechanisms and sleep health as targets for sex-tailored therapies.