HYPERPOLARIZING EFFECTS OF MORPHINE, CLONIDINE AND 2-CHLOROADENOSINE IN MYENTERIC NEURONS ASSOCIATED WITH TOLERANCE TO MORPHINE

Chronic treatment of guinea pigs with morphine produces nonspecific su bsensitivity (tolerance) of the longitudinal smooth muscle myenteric p lexus (LM/MP) preparation of the guinea pig ileum to morphine, clonidi ne and 2-chloroadenosine correlated with a partial depolarization of m yenteric S neurons. The purpose of our investigation was to gain furth er evidence regarding the cellular mechanism of tolerance. Either morp hine or placebo pellets were implanted s.c. in guinea pigs 7 days befo re the experiment. Subsensitivity was confirmed by a marked decrease o f the inhibitory effect of 0.1 mu M morphine and 0.3 mu M clonidine on neurogenically induced twitches in longitudinal smooth muscle myenter ic plexus preparations from the morphine-pretreated guinea pigs. Intra cellular microelectrode recording established that only myenteric S ne urons that were hyperpolarized by morphine exhibited the depolarized s tate (difference of 7.2 mV), which occurred without a change in the th reshold for initiation of action potentials. S neurons that were hyper polarized by superfusion with solution containing morphine, 0.1 mu M, were acutely hyperpolarized an equivalent amount (6-8 mV) by clonidine , 0.3 mu M, or 2-chloroadenosine, 0.1 mu M. Morphine and clonidine, bu t not 2-chloroadenosine, reduced input resistance. The hyperpolarizati ons and changes in conductance were not different between tolerant and control preparations for any agonist. It is concluded that 1) the rec eptors for the three agonists are colocalized on selected S neurons, 2 ) the transduction process for the hyperpolarizing effect of 2-chloroa denosine is different than that for morphine and clonidine, 3) cross-t olerance among the agonists is not a function of altered receptors or signal transduction processes and 4) the depolarized state is associat ed with tolerance of myenteric S neurons.