title: Attenuation of morphine withdrawal signs by intracerebral administration of 18-methoxycoronaridine.
abstract: 18-Methoxyroconaridine (18-MC), a synthetic derivative of ibogaine, reduces morphine self-administration and alleviates several signs of acute opioid withdrawal in rats. Although there is already well documented evidence of the mechanism mediating 18-MC's action to reduce the rewarding effects of morphine, nothing is known about the mechanism responsible for 18-MC's attenuation of opioid withdrawal. In vitro studies have demonstrated that 18-MC is a potent antagonist of alpha3beta4 nicotinic receptors (IC50=0.75 microM), which are predominantly located in the medial habenula and interpeduncular nuclei. Previous work indicating that alpha3beta4 nicotinic receptors mediate 18-MC's effects on drug self-administration prompted us to assess whether brain areas having high or moderate densities of alpha3beta4 receptors might be involved in 18-MC's modulation of opioid withdrawal. To test this possibility, 18-MC was locally administered into the medial habenula, interpeduncular nucleus and locus coeruleus of morphine-dependent rats; this treatment was followed by naltrexone to precipitate a withdrawal syndrome. Pretreatment with various doses of 18-MC into the locus coeruleus significantly reduced wet-dog shakes, teeth chattering, burying and diarrhea, while pretreatment into the medial habenula attenuated teeth chattering, burying, and weight loss. Some doses of 18-MC administered into the interpeduncular nucleus significantly ameliorated rearing, teeth chattering, and burying, while other doses exacerbated diarrhea and teeth chattering. The present findings suggest that 18-MC may act in all three nuclei to suppress various signs of opioid withdrawal.
authors.affiliation: Center for Neuropharmacology and Neuroscience MC-136, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, USA.
authors.forename: Vishal
authors.initials: V
authors.lastname: Panchal
authors.forename: Olga D
authors.initials: OD
authors.lastname: Taraschenko
authors.forename: Isabelle M
authors.initials: IM
authors.lastname: Maisonneuve
authors.forename: Stanley D
authors.initials: SD
authors.lastname: Glick
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology; D004333:Drug Administration Routes; D005260:Female; D007050:Ibogaine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D008125:Locus Coeruleus / Q000187:drug effects* / Q000503:physiopathology; D009020:Morphine / Q000494:pharmacology; D009021:Morphine Dependence / Q000188:drug therapy*; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy*
chemical_list: D009292:Narcotic Antagonists; D009294:Narcotics; D007050:Ibogaine; D009271:Naltrexone; D009020:Morphine; C103345:18-methoxycoronaridine