Wei Zhu, Kirk J Mantione, Federico M Casares, Melinda H Sheehan, Richard M. Kream, George B Stefano
Med Sci Monit 2006; 12(9): BR295-301
Background:Invertebrate nervous systems are regulated by G-coupled protein receptors, chemical transporters, and ion channels responsive to established drugs of abuse including opiates, alcohol, psychostimulants, and nicotine. Thus, invertebrate nervous tissue preparations can be used as predictive model systems by which to evaluate underlying pharmacological mechanisms of addictive processes.
Material/Methods: Ex vivo pharmacological trials were used to determine the comparative effects of the nicotinic agonists and antagonists on the evoked release of labeled morphine from H. americanus nerve cord. The intrinsically low basal levels of endogenous morphine required that we utilize an ex vivo model system involving pre-labeling of intracellular opiate alkaloid pools with high specific activity [sup]125[/sup]I labeled morphine.
Results: Both nicotine and epibatidine promoted evoked release of [sup]125[/sup]I labeled morphine that is selectively linked to activation of invertebrate nicotinic receptors based on pharmacological inhibition by α bungarotoxin (α-BuTx). Epibatidine promoted release at concentrations 2–3 orders of magnitude higher than nicotine. Co-administration of nicotine (60 nM) and the pre-junctional ganglionic nicotinic antagonist hexamethonium (1 µM) produced a marked potentiation of [sup]125[/sup]I labeled morphine release; a pharmacological effect also observed for epibatidine (35 µM) co-administered with the competitive nicotinic antagonist chlorisondamine at 1 µM. The stimulatory effects of ethanol to promote enhanced release of endogenous morphine were not affected by co-administration of α-BuTx at 1 µM.
Conclusions: The stimulatory effects of nicotine on cellular expression and release of endogenous morphine occurs via specific α-BuTx sensitive receptors, suggesting a novel mechanism underlying the reinforcing and addictive properties of nicotine via endogenous morphine.
Keywords: Ethanol - pharmacology, Receptors, Nicotinic - physiology, Pyridines - pharmacology, Nicotinic Antagonists - pharmacology, Nicotinic Agonists - pharmacology, Nicotine - pharmacology, Nephropidae - metabolism, Morphine - metabolism, Hexamethonium - pharmacology, Ganglia, Invertebrate - metabolism, Animals, Bicyclo Compounds, Heterocyclic - pharmacology, Bungarotoxins - pharmacology, alpha7 Nicotinic Acetylcholine Receptor