The objective of this research is to elucidate the role of free intracellular calcium in the production of antinociception, tolerance and physical dependence by morphine. The involvement of the calcium- modulatory, non-opioid peptides calcitonin (CT) and calcitonin gene-related peptide (CGRP) in opiate tolerance and physical dependence will also be investigated. Exogenous administration of CT and CGRP, homeostatic modulators of calcium, into the brain or the spinal cord modulates the acute antinociceptive effects of morphine. CT and CGRP bind in discrete areas throughout the central nervous system, especially in areas involved in pain transmission and processing. It is hypothesized that chronic morphine administration alters either the levels or the specific binding of CT and/or CGRP at discrete sites in either the brain of the spinal cord, leading in turn to compensatory modulation of calcium either directly or via changes in adenylate cyclase activation and resulting in tolerance development. These hypotheses will be tested by the direct measurement of the basal and depolarization-induced levels of free intracellular calcium, [Ca++]i, using FURA-2 in synaptosomes prepared from brain and spinal cord regions of non-tolerant and tolerant mice and rats. Alterations in [Ca++]i by sCT, CGRP and morphine, alone and in combination, will be examined. In addition the KD and BMAX of sCT and CGRP, the levels of CGRP, and the adenylate cyclase activation by sCT and CGRP will be determined is discrete brain and spinal cord regions of opiate-tolerance and non-tolerant rats by the use of specific binding assays, radioimmunoassays, and cyclic-AMP measurement, respectively. These studies will better define the neuronal mechanisms underlying opiate tolerance and physical dependence in animals and may allow for a greater understanding of the addiction process in man.
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