The cellular basis underlying the development of tolerance and dependence following chronic exposure to opioids is not known. Two different hypotheses have emerged based upon data generated using different neuronal populations and different species. One hypothesis ascribes a highly specific alteration in responsiveness to opioids to alterations in the cellular transduction processes using studies conducted in different brain regions of the rat. The other hypothesis is focused on the cellular adaptive mechanisms which lead to a generalized change in responsiveness extending to a variety of both inhibitory and excitatory substances. The cellular basis for this type of heterologous subsensitivity has been shown by this laboratory to reside in a generalized change in cellular membrane properties in a variety of excitable tissues. Work in this laboratory relative to the role of such adaptive changes in responsiveness have investigated the development of tolerance following chronic opioid treatment using the myenteric plexus and nucleus tractus solitarius of the guinea pig as model systems. The underlying differences which may be responsible for these disparatate (sic) hypotheses could either reside in the neuronal populations being examined or in the species in which the tolerance is being produced. The experiments proposed will employ mainly electrophysiological techniques including intracellular and patch clamp recording from neurons in brain slices from control and animals chronically treated with morphine. The hypothesis to be tested is that the expression of tolerance following chronic opioid treatment differs between the guinea pig and 4 the rat as a result of basic differences in the cellular mechanism of adaptation employed by these two species. To test this hypothesis, the following specific aims will be addressed: 1) To determine if the guinea pig LC displays nonspecific tolerance extending to non-opioid inhibitory agonists; 2) To determine if the rat nTS displays tolerance that is specific for mu-opioid agonists; and 3) To investigate the cellular mechanisms which underlie tolerance in the guinea pig LC and nTS and the rat nTS. The outcome of these experiments will enhance our understanding of opioid tolerance and dependence as well as increase our knowledge about the mechanisms of neuronal adaptation.
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