Stress‐induced dysphoria is encoded by the Dynorphin‐Kappa Opioid system

Abstract

Sustained stressful experience can induce despair and increase the risk of clinical depression and drug abuse. We found that repeated exposure of mice to stress (forced swim or social‐defeat) activated the dynorphin‐kappa opioid receptor system to produce analgesia, immobility, sensitization of the reward system to cocaine, and reinstatement of extinguished cocaine‐place preference. The cellular and molecular basis of these responses were described in a series of studies demonstrating that chronic stress evoked CRF/Urocortin release and subsequent CRF‐R2 receptor mediated dynorphin release. Surprisingly, aversion caused by stress and CRF were blocked by disruption of the dynorphin kappa opioid system. Dynorphin‐induced dysphoria was found to be mediated by p38 MAPK activated through a GRK3/arrestin dependent mechanism. Stress‐induced release of dynorphin activates kappa receptors broadly in brain. In particular, repeated stress caused activation of both KOR and p38 MAPK co‐expressed in GABAergic neurons. The p38 inhibitor SB203580 selectively blocked dynorphin‐induced aversion. The convergence of stress‐induced aversion on the dynorphin system was unexpected and implicates dynorphin activation of p38 MAPK signaling as a key component mediating the aversive properties of stress.