Potent, short-acting opiate agonists are widely used in anesthesia because they do not cause significant cardiovascular depression. But the profound analgesic effect of high-dose opiates is accompanied by intense generalized muscle rigidity and respiratory depression. These side effects of the opiates severely limit their clinical value. A thorough understanding of the opioid receptor pharmacology of desirable (anesthesia and analgesia) and undesirable (muscle rigidity, respiratory depression, and abuse potential) opiate effects will have important implications for the development of opiate analgesics and anesthetics without major side effects. The proposed experiments are designed to determine in rats: 1) which opioid receptors mediate opiate-induced muscle rigidity; 2) which opioid receptors mediate opiate-induced respiratory depression; 3) what role depressed respiratory drive versus increased chest wall muscle tone (due to muscle rigidity) plays in the respiratory depression seen with high-dose opiates; and 4) which opioid receptors mediate opiate-induced anesthesia. A key question to be addressed is whether the most important desirable effect of high dose opiate administration (anesthesia) can be pharmacologically separated from the two clinically most important undesirable side-effects (muscle rigidity and respiratory depression) on the basis of opioid receptor specificity. Muscle rigidity will be investigated by measuring the electromyographic activity from hindlimb and abdominal muscles. Respiratory function will be assessed using both dual- chamber plethysmography to measure minute ventilation and using arterial blood gases. Opiate anesthesia will be assessed by the absence of the righting reflex as well as by the heart rate and movement responses to a noxious stimulus (tail pressure). The opioid receptor pharmacology of each effect will be examined using selective agonists and antagonists. Drugs will be administered directly into the lateral ventricles of the brain. The main hypothesis these experiments will test is that the desirable effects of opiates (analgesia and anesthesia) will be separable from the undesirable effects (muscle rigidity and respiratory depression) on the basis of opioid receptor pharmacology. Data will be compared by analyzing log dose-response curves and potency ratios to assess the relative separation between desirable and undesirable effects for each receptor- selective drug studied. A secondary hypothesis to be tested will be that opiate-induced truncal rigidity contributes significantly to the respiratory compromise and acidosis seen after large opiate doses. The knowledge of opioid receptor pharmacology derived from this work will form a rational framework within which to develop and clinically use new opiate drugs.
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