Opioid receptor subtypes differentially modulate serotonin efflux in the rat central nervous system

Opioid receptor subtypes may have site-specific effects and play different roles in modulating serotonergic neurotransmission in the mammalian central nervous system. To test this hypothesis, we used in vivo microdialysis to measure changes in extracellular serotonin (5-hydroxytryptamine; 5-HT) in response to local infusion of mu-, delta-, and kappa-opioid receptor ligands into the dorsal raphe nucleus (DRN), median raphe nucleus (MRN), and nucleus accumbens (NAcc) of freely behaving rats. The mu-opioids [D-Ala(2)-N-MePhe (4),Gly(5)-ol] enkephalin (DAMGO), endomorphin-1, and endomorphin-2 were administered by reverse dialysis infusion into the DRN. In response, extracellular 5-HT was increased in the DRN, an effect that was blocked by the selective mu-receptor antagonist beta-funaltrexamine, but not by the delta-receptor antagonist N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH (ICI-174,864). Infusion of delta-receptor agonists, [D-Ala(2),D-Len(5)]enkephalin (DADLE), [D-Pen(2,5)]enkephalin (DPDPE), and deltophin-II into the DRN also increased extracellular 5-HT, an effect that was blocked by selective delta-receptor antagonists. In contrast to the DRN, local infusion of mu- and delta-opioids had no effect on 5-HT in the MRN or NAcc. These data indicate that mu- and delta-opioid ligands have a selective influence on serotonergic neurons in the DRN. Finally, the kappa-receptor agonist U-50,488 [trans-(+/-)-3,4-dichloro-N-methyl- N-[2-(1-pyrrolidinyl) cyclohexyl] benzeneacetamide] produced similar decreases in 5-HT during local infusion into the DRN, MRN, and NAcc. These results provide evidence of differential regulation of 5-HT release by opioid receptor subtypes in the midbrain raphe and forebrain.