Hyperpolarizing Effects of Morphine, Clonidine and 2-Chloroadenosine in Myenteric Neurons Associated with Tolerance to Morphine

• Published in: The Journal of pharmacology and experimental therapeutics 1997-04, Vol.281 (1), p.41-47
• Main Authors: Meng, J, Malanga, C J, Kong, J Q, Taylor, D A, Fleming, W W
• Format: Article
• Language: English
• Subjects: 2-Chloroadenosine - pharmacology; Animals; Clonidine - pharmacology; Drug Tolerance; Guinea Pigs; In Vitro Techniques; Locus Coeruleus - drug effects; Locus Coeruleus - physiology; Male; Membrane Potentials - drug effects; Morphine - pharmacology; Myenteric Plexus - drug effects; Myenteric Plexus - physiology; Narcotics - pharmacology; Neuromuscular Junction - drug effects; Neuromuscular Junction - physiology
• ISSN: 0022-3565; 1521-0103

Chronic treatment of guinea pigs with morphine produces nonspecific subsensitivity (tolerance) of the longitudinal smooth muscle myenteric plexus (LM/MP) preparation of the guinea pig ileum to morphine, clonidine and 2-chloroadenosine correlated with a partial depolarization of myenteric S neurons. The purpose of our investigation was to gain further evidence regarding the cellular mechanism of tolerance. Either morphine or placebo pellets were implanted s.c. in guinea pigs 7 days before the experiment. Subsensitivity was confirmed by a marked decrease of the inhibitory effect of 0.1 μM morphine and 0.3 μM clonidine on neurogenically induced twitches in longitudinal smooth muscle myenteric plexus preparations from the morphine-pretreated guinea pigs. Intracellular microelectrode recording established that only myenteric S neurons that were hyperpolarized by morphine exhibited the depolarized state (difference of 7.2 mV), which occurred without a change in the threshold for initiation of action potentials. S neurons that were hyperpolarized by superfusion with solution containing morphine, 0.1 μM, were acutely hyperpolarized an equivalent amount (6–8 mV) by clonidine, 0.3 μM, or 2-chloroadenosine, 0.1 μM. Morphine and clonidine, but not 2-chloroadenosine, reduced input resistance. The hyperpolarizations and changes in conductance were not different between tolerant and control preparations for any agonist. It is concluded that 1) the receptors for the three agonists are colocalized on selected S neurons, 2) the transduction process for the hyperpolarizing effect of 2-chloroadenosine is different than that for morphine and clonidine, 3) cross-tolerance among the agonists is not a function of altered receptors or signal transduction processes and 4) the depolarized state is associated with tolerance of myenteric S neurons.