The role of various hypothalamic releasing and inhibiting hormones and their synthetic analogs in the acute (analgesia, hypothermia, etc) and chronic (tolerance and physical dependence) effects of morphine will be assessed in mice. The drugs to be used will include melanocyte stimulating hormone release inhibiting factor (MIF), thyrotropin releasing hormone (TRH), somatotropin release inhibiting factor (SRIF), luteinizing hormone releasing hormone (LHRH) and their synthetic analogs. Tolerance and dependence on morphine will be produced by pellet implantation method. Tolerance will be assessed by measuring the analgesic, hypothermic and locomotor activity to a challenge dose of morphine to morphine naive and morphine tolerant mice. The degree of physical dependence will be assessed by measuring the intensity of hypothermic response, body weight loss observed during abrupt and antagonist induced withdrawal and also the intensity of stereotyped jumping syndrome seen after precipitated withdrawal. The effect of the above drugs will be determined on the disposition of morphine in plasma and brain and on the stereospecific binding of opiates to the receptors in the brain. Our preliminary work with some drugs indicate that morphine tolerance and physical dependence development can be inhibited without altering the analgesic effects of morphine. The potential applications of such drugs used concomitantly with morphine or other narcotic drugs to relieve pain are obvious. Also such studies will provide useful information on the role of hypothalamic hormones in narcotic effects.