Endomorphin-2 and endomorphin-1 promote the extracellular amount of accumbal dopamine via nonopioid and mu-opioid receptors, respectively.
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 muM). 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.
Okutsu
Hiroko
H
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda-shi, Chiba, Japan.
Watanabe
Shu
S
Takahashi
Ichiro
I
Aono
Yuri
Y
Saigusa
Tadashi
T
Koshikawa
Noriaki
N
Cools
Alexander R
AR
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal; D001923:Brain Chemistry / Q000187:drug effects; D003956:Dialysis / Q000379:methods; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000502:physiology*; D013004:Somatostatin / Q000031:analogs & derivatives / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D014851:Wakefulness
D000701:Analgesics, Opioid; D000779:Anesthetics, Local; D009292:Narcotic Antagonists; D009842:Oligopeptides; D017450:Receptors, Opioid, mu; C105293:endomorphin 1; C049352:phenylalanyl-cyclo(cysteinyltyrosyl-tryptophyl-ornithyl-threonyl-penicillamine)threoninamide; D009270:Naloxone; C105294:endomorphin 2; D013779:Tetrodotoxin; D013004:Somatostatin; D004298:Dopamine