Pain‐related depression of the mesolimbic dopamine system in rats

Abstract

Some stressors produce prodepressant behavioral effects by activating endogenous kappa opioid systems that in turn depress mesolimbic dopamine release. This study evaluated the role of this mechanism in pain‐related behavioral depression in rats. Adult male Sprague‐Dawley rats were prepared either with intracranial electrodes targeting the medial forebrain bundle (for behavior studies of intracranial self‐stimulation; ICSS) or cannulae for microdialysis measures of nucleus accumbens dopamine (NAcc DA). Changes in ICSS and NAcc DA were examined after treatment with a chemical noxious stimulus (intraperitoneal injection of dilute acid) or an exogenous kappa agonist (U69593). Additional studies examined sensitivity of acid and U69593 effects to blockade by two analgesics (the nonsteroidal antiinflammatory drug ketoprofen and the mu opioid receptor agonist morphine) or by the kappa antagonist norbinaltorphimine (norBNI). Both acid and U69593 depressed ICSS and NAcc DA release. However, the pain‐related effects of acid were blocked by pretreatment with ketoprofen and morphine, but not by norBNI. Conversely, effects of U69593 were blocked by norBNI but not by ketoprofen, and were only attenuated by morphine. These results support a role for the mesolimbic dopamine system, but not endogenous kappa opioid systems, in mediating pain‐related depression of behavior in rats.