Kappa Opioid receptor-induced aversion requires p38 MAPK activation in VTA dopamine neurons

The endogenous dynorphin-kappa opioid receptor (KOR) system encodes the dysphoric component of the stress response and controls the risk of depression-like and addiction behaviors; however, the molecular and neural circuit mechanisms are not understood. In this study, we report that KOR activation of p38 alpha MAPK in ventral tegmental (VTA) dopaminergic neurons was required for conditioned place aversion (CPA) in mice. Conditional genetic deletion of floxed KOR or floxed p38 alpha MAPK by Cre recombinase expression in dopaminergic neurons blocked place aversion to the KOR agonist U50,488. Selective viral rescue by wild-type KOR expression in dopaminergic neurons of KOR-/-mice restored U50,488-CPA, whereas expression of a mutated form of KOR that could not initiate p38 alpha MAPK activation did not. Surprisingly, while p38 alpha MAPK inactivation blocked U50,488-CPA, p38 alpha MAPK was not required for KOR inhibition of evoked dopamine release measured by fast scan cyclic voltammetry in the nucleus accumbens. In contrast, KOR activation acutely inhibited VTA dopaminergic neuron firing, and repeated exposure attenuated the opioid response. This adaptation to repeated exposure was blocked by conditional deletion of p38 alpha MAPK, which also blocked KOR-induced tyrosine phosphorylation of the inwardly rectifying potassium channel (GIRK) subunit Kir3.1 in VTA dopaminergic neurons. Consistent with the reduced response, GIRK phosphorylation at this amino terminal tyrosine residue (Y12) enhances channel deactivation. Thus, contrary to prevailing expectations, these results suggest that kappa opioid-induced aversion requires regulation of VTA dopaminergic neuron somatic excitability through a p38 alpha MAPK effect on GIRK deactivation kinetics rather than by presynaptically inhibiting dopamine release.