Previous animal investigations demonstrating that intrathecal opiates will produce a long lasting and profound analgesia, have resulted in the use of spinal morphine as a mode of therapy in the clinical control of acute and chronic pain. The present proposal represents an expansion of our original work. (1) Pharmacology of the spinal opiate receptor systems in the primate related to analgesia: Intrathecal dose response curves will be obtained for opiate agonists reported to have selective affinity for subpopulations of opiate receptors (morphine, morphicetin, Mu; d-ala2-d-leu5-enkephalin, Delta; bremazocine, U50488, Kappa; nalbuphine, partial agonist). Quantitative antagonism of these antinociceptive effects with systemic naloxone and the rate of intrathecal tolerance development will be examined. Following development of tolerance, we will determine if cross tolerance exists between these intrathecal agonists. This will assess the independence of the spinal receptor populations acted upon by these several agents. (2) Pharmacology of spinal adrenergic receptor systems: Our previous work has demonstrated the significant analgesic effect resulting from intrathecal Alpha2-agonists (e.g. ST-91, a clonidine analogue). Sensitivity to antagonism by yohimbine and the time course of tolerance development will be examined. (3) Interactions of intrathecally administered morphine with Alpha2-agonists, local anesthetics and non-Mu opiate agonists: Previous studies have indicated that there is a potentiative interaction between Alpha2-agonists and opiates. The present studies will systematically examine and quantify the nature of the interaction in terms of their effect on pain, motor and autonomic function. (4) Effect of spinal administration in primate of morphine, ST-91, and morphine + ST-91 on behavior and long term changes in the pain threshold. (5) The effects of intrathecal opiates and St-91 on spinal cord blood flow during hypo and hypercarbia. (6) Distribution and kinetics of intrathecally and epidurally administered opiates. These studies will assess the movement of opiates having different lipid partition coefficients from the epidural and intrathecal space into: cisternal CSF, peripheral venous system, the peridural plexus (Batson's plexus), and the great cerebral veins. These experiments will provide insight into the underlying mechanisms of delayed respiratory depression.
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