The cellular basis of tolerance to many types of drugs, including opiates, remains unknown. Tolerance to opiates cannot be explained simply on the basis of altered metabolism or disposition of the opiate. It has been suggested for many years by various investigators that tolerance to morphine and related substances reflects a change in the sensitivity of cells upon which morphine acts. The changes observed in cells of the myenteric plexus of the ileum from guinea pigs chronically exposed to morphine are strikingly similar to changes observed in association with the phenomenon of postjunctional supersensitivity. Postjunctional supersensitivity represents a cellular homeostatic mechanism by which a variety of types of cells compensate for chronic changes in the net stimulation they receive. Supersensitivity in many instances is nonspecific and has been associated with a partial depolarization scondary to depression of electrogenic Na+, K+ pump activity. The hypothesis which we propose to test is that tolerance to the hyperpolarizing effects of opiates in myenteric ganglion cells is the consequence of a partial depolarizaton of the ganglion cells and a decrease in electrogenic Na+, K+ pumping. The sensitivity of isolated longitudinal muscle-myenteric plexus preparations obtained from control guinea pigs and guinea pigs chronically treated with morphine will be compared using a variety of unrelated excitatory and inhibitory agonists. Concurrently, the electrophysiological characteristics of myenteric ganglion cells will be studied using conventional intracellular recording techniques. By investigating the effects of agonists and pump inhibitors on membrane potential, answers will be sought to the following questions: 1) Is there an electrogenic contribution of the Na+, K+ pump to the membrane potential of type 1 ganglion cells? 2) Are the ganglion cells of animals made tolerant to morphine partially depolarized relative to naive cells? 3) If they are partially depolarized, is the depolarization associated with a reduction in electrogenic pumping?
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