1. ¹Department of Pharmacology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda-shi, Chiba, Japan
2. ²Department of Pharmacology, Nihon University School of Dentistry, Chiyoda-ku, Tokyo, Japan
3. ³Department of Dental Anaesthesiology, Nihon University School of Dentistry, Chiyoda-ku, Tokyo, Japan
4. ⁴Division of Oral and Craniomaxillofacial Research, Dental Research Centre, Nihon University School of Dentistry, Chiyoda-ku, Tokyo, Japan
5. ⁵Department of Psychoneuropharmacology, University of Nijmegen, Nijmegen, The Netherlands

Correspondence: Dr T Saigusa, Department of Pharmacology, Nihon University School of Dentistry, 1-8-13, Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan. Tel: +81 3 3219 8126; Fax: +81 3 3219 8136; E-mail: saigusa@dent.nihon-u.ac.jp

⁶Current address: Pharmacology Laboratories, Institute for Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan

Received 18 January 2005; Revised 25 April 2005; Accepted 18 May 2005; Published online 20 July 2005.

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-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 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.