Mu opioid receptor involvement in enkephalin activation of dopamine neurons in the ventral tegmental area

Many lines of evidence suggest that opioids act in the A10 dopamine (DA) region to activate DA neurons projecting to limbic terminal areas. Thus, injection of morphine and enkephalin analogs into the ventral tegmental area (a major subnucleus of the A10 DA region) produces an increase in spontaneous motor activity that is blocked by DA receptor antagonists and increases DA metabolism in the nucleus accumbens. The present study utilized enkephalin analogs specific for either the mu or delta opioid receptor to evaluate which receptor subtype(s) is activating the A10 DA neurons. It was found that the specific mu agonist, Try-D-Ala-Gly-NMe-Phe-Gly-ol, was significantly more potent than the specific delta agonist, [D-Pen2,5]-enkephalin, at increasing spontaneous motor activity or DA metabolism in the nucleus accumbens, septum, striatum and prefrontal cortex. Further, naloxonazine, a putative antagonist of the mu-1 isoreceptor, significantly attenuated the motor-stimulant effect and increase in DA metabolism produced by intra-ventral tegmental area injection of Tyr-D-Ala-Gly-NMe-Phe-Gly-ol. It was found that the disposition of microinjected Tyr-D-Ala-Gly-NMe-Phe-Gly-ol or [D-Pen2,5]-enkephalin was not responsible for the difference in their potency. It is concluded that the mu receptor and, perhaps, the mu-1 isoreceptor mediate a major portion of the activation of A10 DA neurons previously demonstrated with mixed mu and delta opioid agonists.