Fentanyl increases dopamine release in rat nucleus accumbens: Involvement of mesolimbic Mu- and delta-2-opioid receptors

The effects of the mu-receptor agonist fentanyl on extracellular levels of dopamine in rat nucleus accumbens were studied in awake animals by in vivo brain microdialysis. Fentanyl dose-dependently increased the levels of dopamine when given intravenously (mu g/kg) or via a microdialysis probe placed into the ventral tegmental area or the nucleus accumbens (nmol). The effect of fentanyl given into the nucleus accumbens was blocked by systemic administration of the non-selective opioid receptor antagonist naloxone and by accumbens administration of D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Phe-Thr-NH2 (nmol), a mu-opioid receptor antagonist, and naltrindole (nmol), a non-selective delta-opioid receptor antagonist, in a dose-dependent manner. The delta(2)-opioid receptor antagonist, naltriben (nmol), also blocked the effects of fentanyl, whereas the delta(1)-opioid receptor antagonist, (E)-7-benzylidenenaltrexone (nmol), was ineffective. When marginally effective doses of D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Phe-Thr-NH2 and naltriben were given simultaneously, the effect of fentanyl was nearly fully blocked; the pretreatment itself had no effect. Administration of the mu-opioid receptor agonist [D-Ala(2), N-Me-Phe(4),Gly(5)-ol]-enkephalin (nmol), the delta(1)-opioid receptor agonist [D-Pen(2,5)]-enkephalin (nmol) or the delta(2)-opioid receptor agonist [D-Ala(2),Glu(5)]-deltorphin (nmol) into the nucleus accumbens enhanced the amount of accumbal dopamine. This study provides evidence that not only activation of delta(1)- and delta(2)-opioid receptors, but also activation of mu-opioid receptors in the nucleus accumbens increases the release of accumbal dopamine in freely moving rats. We suggest that the effect of intra-accumbens administration of fentanyl upon accumbal release of dopamine is either due to the simultaneous activation of mu-opioid receptors and delta(2)-opioid receptors or due to activation of mu-opioid receptors that interact with delta(2)-opioid receptors in a complex manner. (C) 1999 IBRO. Published by Elsevier Science Ltd.