Chronic joint pain drives sex-specific changes in hippocampal glutamatergic signaling and sleep.

Osteoarthritis (OA) is one of the leading causes of pain-related disability. Sleep health and sex-associated differences contribute to OA pain, yet their roles remain poorly defined. Sleep disruption can bidirectionally exacerbate OA pain and independently increase risk of OA, with females showing greater vulnerability. Moreover, chronic pain and poor sleep alter central neurophysiology, including hippocampal synaptic plasticity, yet how these factors relate to OA pain remains unclear. We investigated sex-specific hippocampal glutamatergic function in a monoiodoacetate knee pain mouse model along with mechanical sensitivity and sleep architecture. Both sexes developed mechanical hypersensitivity following injury, but females exhibited poorer sleep outcomes. Injured males demonstrated increased AMPAR-mediated excitatory activity, whereas injured females showed reduced NMDAR activity. Mechanical hypersensitivity correlated with reduced NMDAR/GluN2B function in females, while sex-specific altered AMPAR and NMDAR activity associated with REM sleep. These findings reveal divergent, sex-specific alterations in hippocampal glutamatergic signaling associated with chronic OA pain and sleep disruption. Together, these results suggest that sleep and pain-related synaptic changes reflect interacting processes that differ by sex, highlighting hippocampal excitatory signaling, sleep health, and sex-specific neurophysiology as key contributors to variability in the OA pain experience and potential targets for chronic pain management.