The cellular basis of tolerance to, and dependence upon, many types of drugs, including opioids, remains unknown. Tolerance to opioids cannot be explained simply on the basis of altered metabolism or disposition of the opioid. It has been suggested 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 adaptive supersensitivity. Adaptive supersensitivity represents a cellular homeostatic mechanism by which a variety of types of cells compensate for chronic changes in the net stimulation they receive. Supersensitvity in many instances in nonspecific and has been associated with a partial depolarization secondary to depression of electrogenic Na+,K+ pump activity. The hypothesis which we propose to test is that tolerance to the hyper-polarizing effects of opioids in myenteric ganglion cells is the consequence of a partial depolarization of the ganglion cells and decrease in electrogenic Na+,K+ pumping. In the current proposal, tolerance to morphine will be induced by implanting pellets of morphine, s.c., in guinea pigs for 7 days. Control animals will receive placebo pellets. Three approaches will be used. (a) Intracellular electrical recording in myenteric ganglion cells. (b) Measurements of sensitivity of the longitudinal muscle/ myenteric plexus preparation to the inhibitory actions of opioids. (c) Quantitative autoradiography of opioid binding sites in the myenteric plexus. The following specific hypotheses will be tested: 1.) A partial depolarization of S neurons, the neurons specifically hyperpolarized by morphine in the LM/MP preparation, is a factor underlying tolerance and dependence. 2.) Such a partial depolarization is the consequence of a reduction in electrogenic Na+/K+ pumping in the S neurons. 3.) In contract to the subsensitivity to inhibitory substances and supersensitivity to stimulatory substances in the LM/MP preparation of tolerant guinea pigs, the average responses of individual S neurons will not differ substantially between control and tolerant preparations. Rather, the responses merely start from an altered level of membrane potential. 4.) Changes in the density of opioid or other receptors is not a major factor contributing to morphine tolerance.
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