Disrupted stress‐induced analgesia in a neuropathic pain state is rescued by the endocannabinoid degradation inhibitor JZL195

Acute stress normally engages descending brain pathways to produce an antinociceptive response, known as stress‐induced analgesia. Paradoxically, these descending pain modulatory pathways are also involved in the maintenance of the abnormal pain associated with chronic neuropathic pain. It remains unclear how stress‐induced analgesia is affected by neuropathic pain states. We therefore examined the impact of a chronic constriction nerve‐injury (CCI) model of neuropathic pain on restraint stress‐induced analgesia in C57BL/6 mice. Thirty minutes of restraint stress produced analgesia in the hotplate thermal nociceptive assay that was less in CCI compared to control mice who underwent a sham‐surgery. In sham but not CCI mice, stress‐induced analgesia was reduced by the opioid receptor antagonist naltrexone. The cannabinoid CB1 receptor antagonist AM281 did not affect stress‐induced analgesia in either sham or CCI mice. Low‐dose pre‐treatment with the dual fatty acid amide hydrolase and monoacylglycerol lipase inhibitor JZL195 increased stress‐induced analgesia in CCI but not sham mice. The JZL195 enhancement of stress‐induced analgesia in CCI mice was abolished by AM281 but was unaffected by naltrexone. These findings indicate that the acute opioid‐mediated analgesic response to a psychological stressor is disrupted in a nerve‐injury model of neuropathic pain. Importantly, this impairment of stress‐induced analgesia was rescued by blockade of endocannabinoid breakdown via a cannabinoid CB1 receptor dependent mechanism. These findings suggest that subthreshold treatment with endocannabinoid degradation blockers could be used to alleviate the disruption of endogenous pain control systems in a neuropathic pain state. Chronic neuropathic pain (CNP) is a debilitating and difficult to treat condition which is maintained by disruption of pain and stress systems within the brain. A key link between pain and stress is the phenomenon known as stress‐induced analgesia (SIA). This study shows that CNP disrupts SIA by reducing an opioid receptor‐mediated component. This disruption can be rescued by a drug, JZL195, which blocks endogenous cannabinoid degradation and recruits a cannabinoid receptor mediated component of SIA. Thus, targeting the endogenous cannabinoid system has potential to alleviate the brain maladaptations associated with this chronic syndrome.