The effect of potentially long acting and orally effective analogs of hypothalamic peptide hormones, particularly of melanotropin release inhibiting factor (MIF) and thyrotropin releasing hormone (TRH) on the acute (analgesia, hypothermia, etc.) and chronic effects (tolerance and physical dependence) of opiates, particularly of morphine, will be investigated in mice and rats. Tolerance to and physical dependence on morphine will be induced by the morphine pellet implantation procedure. Tolerance will be assessed by measuring the responses (e.g. analgesic, hypothermic, cataleptic, etc.) to varying doses of morphine in morphine and placebo pellet implanted animals. The degree of physical dependence will be measured by determining the intensity of signs like hypothermia, body weight loss, etc. during abrupt and naloxone-induced withdrawal and of stereotyped jumping, wet dog shakes, etc. during naloxone-induced withdrawal. The mechanism by which the peptides modify opiate tolerance-dependence process will be investigated by examining the functions of brain receptors for dopamine (D1 and D2), opiate (Mu, Delta and Kappa), MIF and TRH. This will be studied by the binding of 3H-ligands to membranes prepared from whole brain and brain regions. In addition, the effect of chronic administration of morphine on the concentration of enkephalins (to be determined by radioimmunoassay) and the activity of enkephalin degrading enzymes will be determined. Since studies in our laboratory have demonstrated for the first time that tifluadom, a Kappa opiate receptor agonist inhibits the binding of 3H-TRH to its receptors in the brain, further studies will be carried out with endogenous and exogenous ligands for Mu, Delta, and Kappa opiate receptors to understand these interactions. These studies may lead not only to understanding of the role of hypothalamic peptides in the chronic action of morphine but may also lead to the development of drugs that inhibit opiate addiction and manage the opiate induced distressing withdrawal syndrome.
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