Endomorphin-2 and endomorphin-1 promote the extracellular amount of accumbal dopamine via nonopioid and mu-opioid receptors, respectively

Activation of mu-opioid receptors in the nucleus accumbens (NAc) is known to increase accumbal dopamine efflux in rats. Endomorphin-2 (Tyr-Pro-Phe-Phe-NH2; EM-2) and endomorphin-1 (Tyr-Pro-Trp-Phe-NH2; EM-1) are suggested to be the endogenous ligands for the mu-opioid receptor. As the ability of EM-2 and EM-1 to alter the accumbal extracellular dopamine level has not yet been studied in freely moving rats, the present study was performed, using a microdialysis technique that allows on-line monitoring of the extracellular dopamine with a temporal resolution of 5 min. A 25 min infusion of either EM-2 or EM-1 into the NAc (5, 25, and 50 nmol) produced a dose-dependent increase of the accumbal dopamine level. The EM-2 (50 nmol)- and EM-1 (25 and 50 nmol)-induced dopamine efflux were abolished by intra-accumbal perfusion of tetrodotoxin (2 mu M). Intra-accumbal perfusion of the mu-opioid receptor antagonist CTOP (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Phe-Thr-NH2; 3 nmol) failed to affect the EM-2 (50 nmol)-induced dopamine release, whereas it significantly inhibited the EM-1 ( 25 and 50 nmol)- induced dopamine release. The EM-1 ( 50 nmol)- induced accumbal dopamine efflux was significantly reduced by the systemic administration of the putative mu1-opioid receptor antagonist naloxonazine ( 15 mg/kg, intraperitoneally ( i. p.), given 24 h before starting the perfusion). Systemic administration of the aspecific opioid receptor antagonist naloxone ( 1 mg/kg, i. p., given 10 or 20 min before starting the perfusion) also failed to affect the EM-2 ( 50 nmol)- induced dopamine efflux, whereas it significantly inhibited the EM-1 ( 25 and 50 nmol)- induced dopamine efflux. The present study shows that the intra-accumbal infusion of EM-2 and EM-1 increases accumbal dopamine efflux by mechanisms that fully differ. It is concluded that the effects of EM-2 are not mediated via opioid receptors in contrast to the effects of EM-1 that are mediated via mu1-opioid receptors in the NAc.