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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA002598-08
Application #
3207438
Study Section
(DABA)
Project Start
1987-01-01
Project End
1989-12-31
Budget Start
1988-01-01
Budget End
1988-12-31
Support Year
8
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Type
Schools of Pharmacy
DUNS #
121911077
City
Chicago
State
IL
Country
United States
Zip Code
60612
Bhargava, H N (1995) Drugs that modify opioid tolerance, physical dependence, and abstinence symptoms: preclinical and clinical studies. NIDA Res Monogr 147:53-83
Bhargava, H N; Reddy, P L; Gudehithlu, K P (1995) Down-regulation of N-methyl-D-aspartate (NMDA) receptors of brain regions and spinal cord of rats treated chronically with morphine. Gen Pharmacol 26:131-6
Bhargava, H N (1995) Non-competitive antagonism of N-methyl-D-aspartate receptor inhibits tolerance to the analgesic action of U-50,488H, a kappa-opiate receptor agonist in the rat. Gen Pharmacol 26:1055-60
Bhargava, H N; Matwyshyn, G A; Gerk, P M et al. (1994) Effects of naltrexone pellet implantation on morphine tolerance and physical dependence in the rat. Gen Pharmacol 25:149-55
Thorat, S N; Bhargava, H N (1994) Evidence for a bidirectional cross-tolerance between morphine and delta 9-tetrahydrocannabinol in mice. Eur J Pharmacol 260:5-13
Barjavel, M J; Thorat, S N; Bhargava, H N (1994) Enhancement of a kappa-opioid receptor agonist-induced analgesia by L-tyrosine and L-tryptophan. Eur J Pharmacol 258:173-8
Bhargava, H N; Thorat, S N (1994) Effect of dizocilpine (MK-801) on analgesia and tolerance induced by U-50,488H, a kappa-opioid receptor agonist, in the mouse. Brain Res 649:111-6
Bhargava, H N (1994) Nitric oxide synthase inhibition blocks tolerance to the analgesic action of kappa-opiate receptor agonist in the rat. Pharmacology 48:234-41
Bhargava, H N; Matwyshyn, G A; Reddy, P L et al. (1994) Brain and spinal cord kappa opiate receptors and pharmacological responses to U-50,488H in rats of differing ages. Pharmacol Biochem Behav 48:87-91
Thorat, S N; Barjavel, M J; Matwyshyn, G A et al. (1994) Comparative effects of NG-monomethyl-L-arginine and MK-801 on the abstinence syndrome in morphine-dependent mice. Brain Res 642:153-9

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