The goal of this proposal is to develop a simplified mammalian preparation with which to examine mechanisms of behavioral tolerance to opiates. The approach taken in these studies is derived from a substantial body of evidence demonstrating that tolerance to the analgesic effect of opiates is profoundly modified by the context in which the analgesic responses are assessed. Such responses include the defensive tail-withdrawal (flick), which can be elicited in both, intact rats, and in rats who have undergone a complete spinal transection. This fact provides an opportunity to examine environmental modulation of opiate tolerance in a chronic, unanesthetized spinal animal, a preparation which may subsequently be amenable to neurophysiological analysis. These experiments will therefore utilize standard nociceptive procedures (the hot plate and tail flick) to evaluate the contribution of environmental contingencies, both associative and nonassociative, to tolerance. Three preparations will be studied: a. intact, unoperated rats, b. intact rats sustaining spinal catheters for the intathecal administration of morphine and c. spinally transected rats. The extend to which behavioral tolerance can be modulated by environmental contingenices will be determined in each of these successively reduced preparations. In concert, these investigations will provide a valuable approach with which to gain insight into both, drug tolerance as well as the biological bases of learning and memory.
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