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. supersensitivity in many instances is nonspecific and has been associated with a partial depolarization secondary to depression of electrogenic Na+, k+ pump dependence upon mu-receptor opioids is the consequence of a partial depolarization and a decrease in electrogenic Na+, K+ pumping in the affected neurons. Strong support for the first half of the hypothesis has now been obtained in myenteric neurons. 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 uses. (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) Extracellular ind intracellular recording from single cells in brainstem slices containing the dorsal motor nucleus (dmX) and nucleus tractus solitarius (NTS).
The specific aims for the next 3 years are the following: 1) Determine if the now established state of partial depolarization of morphine-responsive S cells is the result of altered function of the Na+, K+ pump. 2) Compare the magnitude of hyperpolarization of 2-chloroadenosine and clonidine and of depolarization to nicotine in tolerant and control S neurons. 3) Characterize the sensitivity of neurons of the dorsal motor nucleus of the vagus (dmX) and the nucleus tractus solitarius (NTS) in brainstem slices to acute opioid administration and the impact of chronic treatment with morphine on the sensitivity and electrophysiological characteristics of those neurons.
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