title: Low doses of dextromethorphan attenuate morphine-induced rewarding via the sigma-1 receptor at ventral tegmental area in rats.
abstract: Chronic use of morphine causes rewarding and behavioral sensitization, which may lead to the development of psychological craving. In our previous study, we found that a widely used antitussive dextromethorphan (known as a low affinity NMDA receptor antagonist), at doses of 10-20 mg/kg (i.p.), effectively decreased morphine rewarding in rats. In this study, we further investigated the effects and mechanisms of low doses of DM (μg/kg range) on morphine rewarding and behavioral sensitization. A conditioned place preference test was used to determine the rewarding and a locomotor activity test was used to determine the behavioral sensitization induced by the drug(s) in rats. When a low dose of DM (3 or 10 μg/kg, i.p.) was co-administered with morphine (5 mg/kg, s.c.), the rewarding effect, but not behavioral sensitization, induced by morphine was inhibited. The inhibiting effect of DM could be blocked by systemically administering a sigma-1 receptor antagonist, BD1047 (3 mg/kg, i.p.). When BD1047 (5 nmole/site) was locally given at the VTA, it also blocked the effects of a low dose of DM in inhibiting morphine rewarding. Our findings suggest that the activation of the sigma-1 receptor at the VTA may be involved in the mechanism of low doses of DM in inhibiting the morphine rewarding effect and the possibility of using extremely low doses of DM in treatment of opioid addiction in clinics.
authors.affiliation: Department of Psychiatry, College of Medicine and Hospital, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Shiou-Lan
authors.initials: SL
authors.lastname: Chen
authors.forename: Kuei-Ying
authors.initials: KY
authors.lastname: Hsu
authors.forename: Eagle Yi-Kung
authors.initials: EY
authors.lastname: Huang
authors.forename: Ru-Band
authors.initials: RB
authors.lastname: Lu
authors.forename: Pao-Luh
authors.initials: PL
authors.lastname: Tao
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D000996:Antitussive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D003213:Conditioning, Psychological / Q000187:drug effects; D003915:Dextromethorphan / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005029:Ethylenediamines / Q000494:pharmacology; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012201:Reward; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism*; D000097605:Sigma-1 Receptor
chemical_list: D000701:Analgesics, Opioid; D000996:Antitussive Agents; D003915:Dextromethorphan; D005029:Ethylenediamines; D009020:Morphine; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C097963:N-(2-(3,4-Dichlorphenyl)ethyl)-N,N',N'-trimethyl-1,2-ethandiamin