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

The effects of the u-receptor agonist fentanyl on extracellular levels of dopamine in rat nucleus accumbens were studied in awake animals by in vivo brain microdialysis. Fentanyl dosedependently increased the levels of dopamine when given intravenously (ug/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 systematic 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 u-opioid receptor antagonist, and naltrindole (nmol), a non-selective o-opioid receptor antagonist, in a dose-dependent manner. The o2-opioid receptor antagonist, naltriben (nmol), also blocked the effects of fentanyl, whereas the o1-opioid receptor antagonist, (E)-7-benzylidenen- altrexone (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 u-opioid receptor agonist [D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (nmol), the o1-opioid receptor agonist [D-Pen2,5]-enkephalin (nmol) or the 02-opioid receptor agonist [D-Ala2,Glu4]-deltorphin (nmol) into the nucleus accumbens enhanced the amount of accumbal dopamine. This study provides evidence that not only activation of o1- and o2-opioid receptors, but also activation of u-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 u-opioid receptors and o2-opioid receptors or due to activation of u-opioid receptors that interact with o2-opioid receptors in a complex manner