This is a request for an ADAMHA Research Scientist Development Award (K02). the long term goal is to develop neuropeptide analogs with oral activity, enzymatic stability and long duration of action in inhibiting morphine tolerance-dependence and abstinence processes. In the present proposal, based on the studies from this laboratory, the following hypotheses will be verified: (a) neuropeptides like Pro-Leu-Gly-NH2 and analogs inhibit morphine tolerance-dependence by acting on the central nervous system (CNS), (b) dopamine (DA) and multiple opiate receptors of specific regions of the CNS are involved in morphine tolerance-dependence and abstinence processes and (c) peptides like Pro-Leu-Gly-NH2 (MIF) and cyclo(Leu-Gly) (CLG) inhibit morphine tolerance-dependence and abstinence processes by affecting DA and opiate receptors. Studies will be carried out in mice and rats to establish if it is a general phenomena or is species dependent. The animals will be made tolerant to and dependent on morphine by subcutaneous implantation of morphine pellets. The degree of tolerance will be assessed by measuring the responses (e.g. analgesia and hypothermia) to varying doses of morphine in morphine and placebo pellet implanted rodents. the degree of physical dependence will be assessed by determining the intensity of symptoms like hypothermia, stereotyped jumping and weight loss during the withdrawal of morphine. The effect of peptides on the development of tolerance to and dependence on morphine and on the symptoms of morphine abstinence will be determined. the binding of DA receptor ligands 3H-SCH 23390 and 3H-domperidone (D1 and D2 receptors, respectively) and of opiate receptor ligands, 3H-DAMGO (mu), 3H-DPDPE (sigma) and 3H-U-69,593 (k) to CNS regions (spinal cord, amygdala, hippocampus, hypothalamus, corpus striatum, pons and medulla, midbrain and cerebral cortex) will be determined. Preliminary studies show that in tolerance-dependence and abstinence processes DA and opiate receptors are affected differentially in CNS regions, hence studies will be carried out with specific brain regions. In order to establish whether CNS changes in DA and opiate receptors are mediated via opiate mechanism the effect of naltrexone on such changes will be determined. Once the specificity of DA and opiate receptor changes is established, then the involvement of second messenger systems (adenylate cyclase and phosphoinositol) will be determined. the effect of different degrees of tolerance induced by implanting different number of pellets during different time intervals on the above biochemical parameters will be monitored. Effect of peptides given intracerebroventricularly on morphine tolerance-dependence will be determined to establish central or peripheral mechanism of action. To test the hypothesis that peptides inhibit morphine tolerance by modifying DA and opiate receptors, their effect on morphine induced changes in specific regions of the CNS will be determined. These studies may lead not only to better understanding of the mechanisms in opiate addiction processes but also to the development of safer drugs in the management of opioid addiction and distressing withdrawal syndrome.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Scientist Development Award - Research (K02)
Project #
5K02DA000130-02
Application #
3069502
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Project Start
1992-09-01
Project End
1997-08-31
Budget Start
1993-09-01
Budget End
1994-08-31
Support Year
2
Fiscal Year
1993
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
Xu, W; Huang, L F; Bauer, L et al. (1999) Synthesis and opiate receptor binding properties of 17-methyl-6,7-dehydro-3,14-dihydroxy-4,5alpha-epoxy-6,7:4',5'-pyrimidin omorphinans. Bioorg Med Chem Lett 9:3375-80
Bhargava, H N; Kumar, S (1999) Sensitization to the locomotor stimulant effect of cocaine modifies the binding of [3H]MK-801 to brain regions and spinal cord of the mouse. Gen Pharmacol 32:359-63
Bian, J T; Bhargava, H N (1998) Effect of chronic administration of L-arginine, NG-nitro-L-arginine or their combination on morphine concentration in peripheral tissues and urine of the mouse. Gen Pharmacol 30:753-7
Bhargava, H N; Kumar, S; Barjavel, M J (1998) Kinetic properties of nitric oxide synthase in cerebral cortex and cerebellum of morphine tolerant mice. Pharmacology 56:252-6
Bhargava, H N; Bian, J T (1998) Effects of acute administration of L-arginine on morphine antinociception and morphine distribution in central and peripheral tissues of mice. Pharmacol Biochem Behav 61:29-33
Sunder Sharma, S; Bhargava, H N (1998) Enhancement of morphine antinociception by ibogaine and noribogaine in morphine-tolerant mice. Pharmacology 57:229-32
Bhargava, H N; Villar, V M; Cortijo, J et al. (1998) Analgesic and thermic effects, and cerebrospinal fluid and plasma pharmacokinetics, of intracerebroventricularly administered morphine in normal and sensitized rats. J Pharm Pharmacol 50:197-203
Bhargava, H N; Cao, Y J (1998) Interactions of cocaine with morphine, U-50,488H and [D-Pen2, D-Pen5]enkaphalin. Peptides 19:563-8
Bhargava, H N; Sharma, S S; Bian, J T (1998) Evidence for a role of N-methyl-D-aspartate receptors in L-arginine-induced attenuation of morphine antinociception. Brain Res 782:314-7
Bhargava, H N; Cao, Y J (1998) Effect of chronic administration of [D-Pen2, D-Pen5] enkephalin on the activity of nitric oxide synthase in brain regions and spinal cord of mice. Peptides 19:113-7

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