Endomorphin-2 and Endomorphin-1 Promote the Extracellular Amount of Accumbal Dopamine via Nonopioid and Mu-Opioid Receptors, Respectively

Abstract

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-NH 2 ; EM-2) and endomorphin-1 (Tyr-Pro-Trp-Phe-NH 2 ; 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 mM). Intra-accumbal perfusion of the mu-opioid receptor antagonist CTOP (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Phe-Thr-NH 2 ; 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.

Mechanisms underlying δ- and μ-opioid receptor agonist-induced increases in extracellular dopamine level in the nucleus accumbens of freely moving rats

“…However, this EM-2-induced accumbal DA efflux cannot be mediated by naloxone-sensitive opioid receptors, as systemic administration of the non-specific opioid receptor antagonist naloxone (1 mg/kg, i.p.) and intra-accumbal perfusion of the μ-opioid receptor antagonist CTOP both failed to alter the EM-2 (50 nmol)-induced increase in accumbal DA (22). Thus, intra-accumbal infusion of EM-2 and EM-1 increases accumbal DA efflux by very different mechanisms.…”

“…μ-opioid receptors are further subdivided into μ 1 -and μ 2 -opioid receptors on the basis of their sensitivity to naloxonazine, a selective antagonist at μ 1 -opioid receptors (25,26). Activation of accumbal μ 1 -opioid receptors is involved in the increase in accumbal DA efflux induced by EM-1 (50 nmol), as naloxonazine inhibited the increase in accumbal DA efflux induced by local administration of EM-1 into the nucleus accumbens (22,27). Because co-administration of the GABA A receptor agonist muscimol or the GABA B receptor antagonist saclofen enhanced EM-1 (25 nmol)-induced accumbal DA efflux, a decrease in accumbal GABAergic activity may mediate the increase in DA efflux induced by μ 1 -opioid receptor stimulation (23,24).…”

“…Intra-accumbal infusion of EM-1 (5, 25, and 50 nmol) induces a transient increase in the level of accumbal DA (22)(23)(24). Systemic administration of the non-specific opioid receptor antagonist naloxone (1 mg/kg, i.p.)…”

Presynaptic Opioid and Nicotinic Receptor Modulation of Dopamine Overflow in the Nucleus Accumbens

“…-Opioid receptor activation inhibits DA release presynaptically As shown above, -and ␦-opioids as well as nicotine have similar effects on dopamine overflow in the NAc, and all three classes of drug enhance NAc shell DA levels and are readily selfadministered in rats (Goldberg and Henningfield, 1988;Pentney and Gratton, 1991;Devine and Wise, 1994;Yoshida et al, 1999;You et al, 1999;Ferrari et al, 2002;Hirose et al, 2005;Okutsu et al, 2006). In light of these observations, we were interested in assessing the effects of -opioid agonists on evoked DA overflow (Schmidt et al, 2002;Woolley et al, 2007).…”

The Endomorphin System and Its Evolving Neurophysiological Role

“…Activation of -opioid receptors in the Nac is known to increase accumbal DA release or DA efflux in rats (Spanagel et al, 1992). Okutsu et al (2006) studied the ability of endomorphins to alter the accumbal extracellular DA level by means of microdialysis in freely moving rats. Infusion of endomorphin-1 or endomorphin-2 into the Nac produced a dose-dependent increase of the accumbal DA level.…”