The physiological link between neuropathic pain and depression remains unknown despite a high co-morbidity between these two disorders. A mouse model of spared nerve injury (SNI) was employed to test the hypothesis that nerve injury precipitates depression through the induction of inflammation in the brain, and that exposure to chronic social isolation the behavioral and neuroinflammatory consequences of nerve injury. Mice were pair housed or socially isolated for two weeks prior to spared nerve injury, and were subsequently monitored for the development of mechanical allodynia and depressive-like behavior. Brain tissue was then collected and processed for the determination of potential physiological mediators.
Measures of allodynia were similar for neuropathic mice regardless of housing on post-operative days 1 and 3, but by day 7 allodynia was significantly greater for mice that were socially isolated than pair housed. Furthermore, depressive-like behavior, determined via the Porsolt forced swim test, developed only among socially isolated mice with nerve injury. Socially isolated mice with nerve injury also were the only experimental group to exhibit increased frontal cortex IL-1β gene expression; IL-1β is a proinflammatory cytokine that has been implicated in depression.
Central treatment of socially isolated mice with oxytocin (OT), a neuropeptide associated with social bonding, attenuated the effects of peripheral nerve injury on depressive-like behavior and reduced frontal cortex IL-1β protein levels in socially isolated animals. Conversely, pair housed animals treated with a selective oxytocin receptor antagonist developed depressive-like behavior equivalent to that of socially isolated animals and displayed increased IL-1β protein levels within the frontal cortex. In contrast, modulation of central OT transmission had minimal effects on the development of allodynia after peripheral nerve injury.
Finally, this study demonstrated that interference with IL-1β signaling, through administration of IL-1 receptor antagonist (IL-1ra), ameliorated the effects of neuropathic pain on depressive-like behavior. Taken together, these data suggest that social interaction significantly alters the affective and physiological responses to through oxytocinergic modulation of the central IL-1β system.