Direct involvement of orexinergic systems in the activation of the mesolimbic dopamine pathway and related behaviors induced by morphine.
In this study, we investigated the role of orexinergic systems in dopamine-related behaviors induced by the mu-opioid receptor agonist morphine in rodents. Extensive coexpression of tyrosine hydroxylase with orexin receptors was observed in the mouse ventral tegmental area (VTA). The levels of dopamine and its major metabolites in the nucleus accumbens were markedly increased by the microinjection of orexin A and orexin B into the VTA. The subcutaneous morphine-induced place preference and hyperlocomotion observed in wild-type mice were abolished in mice that lacked the prepro-orexin gene. An intra-VTA injection of a selective orexin receptor antagonist SB334867A [1-(2-methylbenzoxazol-6-yl)-3-[1.5]naphthyridin-4-yl urea] significantly suppressed the morphine-induced place preference in rats. Furthermore, the increased level of dialysate dopamine produced by morphine in the mouse brain was significantly decreased by deletion of the prepro-orexin gene. These findings provide new evidence that orexin-containing neurons in the VTA are directly implicated in the rewarding effect and hyperlocomotion induced by morphine through activation of the mesolimbic dopamine pathway in rodents.
Narita
Minoru
M
Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo 142-8501, Japan. narita@hoshi.ac.jp
Nagumo
Yasuyuki
Y
Hashimoto
Seiko
S
Narita
Michiko
M
Khotib
Junaidi
J
Miyatake
Mayumi
M
Sakurai
Takeshi
T
Yanagisawa
Masashi
M
Nakamachi
Tomoya
T
Shioda
Seiji
S
Suzuki
Tsutomu
T
D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D003891:Desipramine / Q000494:pharmacology; D004298:Dopamine / Q000502:physiology*; D005260:Female; D006220:Haloperidol / Q000494:pharmacology; D007276:Injections, Intraventricular; D007279:Injections, Subcutaneous; D047908:Intracellular Signaling Peptides and Proteins; D008032:Limbic System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D017551:Microdialysis; D008845:Microinjections; D009020:Morphine / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D009287:Naphthyridines; D009479:Neuropeptides / Q000172:deficiency / Q000235:genetics; D009714:Nucleus Accumbens / Q000187:drug effects / Q000502:physiology*; D000068797:Orexins; D016627:Oxidopamine / Q000633:toxicity; D011498:Protein Precursors / Q000172:deficiency / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000502:physiology*; D012201:Reward; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000502:physiology*
C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D001583:Benzoxazoles; D047908:Intracellular Signaling Peptides and Proteins; D009287:Naphthyridines; D009479:Neuropeptides; D000068797:Orexins; D011498:Protein Precursors; D012333:RNA, Messenger; D017450:Receptors, Opioid, mu; D009020:Morphine; D016627:Oxidopamine; D014508:Urea; D014446:Tyrosine 3-Monooxygenase; D006220:Haloperidol; D003891:Desipramine; D004298:Dopamine