Attenuation of morphine withdrawal signs by intracerebral administration of 18-methoxycoronaridine

• Published in: European journal of pharmacology Vol. 525; no. 1; pp. 98 - 104
• Main Authors: Panchal, Vishal, Taraschenko, Olga D., Maisonneuve, Isabelle M., Glick, Stanley D.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 21-11-2005; Elsevier
• Subjects: Animals; Biological and medical sciences; Brain - drug effects; Brain - physiopathology; Drug Administration Routes; Female; Ibogaine - administration & dosage; Ibogaine - analogs & derivatives; Ibogaine - therapeutic use; Interpeduncular nucleus; Locus coeruleus; Locus Coeruleus - drug effects; Locus Coeruleus - physiopathology; Medial habenula; Medical sciences; Morphine; Morphine - pharmacology; Morphine Dependence - drug therapy; Naltrexone; Naltrexone - pharmacology; Narcotic Antagonists - pharmacology; Narcotics - pharmacology; Pharmacology. Drug treatments; Physical dependence; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome - drug therapy; Medial habenula; Morphine; Physical dependence; Naltrexone; Interpeduncular nucleus; Locus coeruleus; Morphinan derivatives; Narcotic antagonist; Poison withdrawal; Central nervous system; Opiates; Cerebral ventricle; Narcotic analgesic; Encephalon; Dependence; Habenula; Intracerebral administration
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2005.09.060

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 α
3β
4 nicotinic receptors (IC
50
=
0.75 μM), which are predominantly located in the medial habenula and interpeduncular nuclei. Previous work indicating that α
3β
4 nicotinic receptors mediate 18-MC's effects on drug self-administration prompted us to assess whether brain areas having high or moderate densities of α
3β
4 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.