Prolonged agonist exposure leads to desensitization of receptor functions in many receptor systems. Although this phenomenon is widespread and well documented, very little information is available regarding the molecular mechanisms involved. A good example with important clinical implications is the desensitization to opiates. Opiates are important analgesic drugs. However, their long-term use leads to the development of tolerance and addition. Little is known about the biochemical mechanisms by which opiates exert their analgesic action and the changes accompanying exposure to these drugs. The main objectives of this research proposal are: to elucidate the signal transduction mechanisms involved in opiate receptor action (with special emphasis on the kappa receptor); to determine the changes in the regulatory pathways following chronic opiate treatment; and to compare the above mechanisms and changes with those found with several other receptors. Our initial experiments along this line have shown that kappa opiate receptors in spinal cord-dorsal root ganglion cocultures are negatively coupled to adenylate cyclase and to voltage-dependent Ca2+ channels. Chronic exposure to kappa opiate agonists has lead to desensitization of opiate actions on both effector systems, and in addition to a large reduction of 2 to 3 fold in the amount of one of specific subunits of the GTP-binding proteins. Utilizing cultured neurons, control and opiate addicted animals, as well as biochemical, electrophysiological and molecular biological tools, we intend to investigate the molecular mechanisms underlying this desensitization process and reveal the relationship between the desensitization and the regulation of GTP binding proteins. This will include: studies of the regulation of GTP-binding protein subunit at the protein and mRNA levels; regulation of GTP-binding protein phosphorylation; modulation of protein kinase C activity; regulation of intracellular Ca2+ concentration and of Ca2+ channel density, etc. These studies should further our understanding of opiate functions under normal and tolerant (desensitized) conditions, could provide tools that should contribute to new clinical strategies in opiate analgesia with diminished danger of addiction and, in addition, should increase our knowledge of the molecular events governing the phenomenon of desensitization of receptor functions.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA006265-02
Application #
3212876
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Project Start
1990-03-01
Project End
1994-02-28
Budget Start
1992-03-01
Budget End
1993-02-28
Support Year
2
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Weizmann Institute of Science
Department
Type
DUNS #
City
Rehovot
State
Country
Israel
Zip Code
76100
Schallmach, Ester; Steiner, Debora; Vogel, Zvi (2006) Adenylyl cyclase type II activity is regulated by two different mechanisms: implications for acute and chronic opioid exposure. Neuropharmacology 50:998-1005
Steiner, Debora; Saya, Daniella; Schallmach, Ester et al. (2006) Adenylyl cyclase type-VIII activity is regulated by G(betagamma) subunits. Cell Signal 18:62-8
Schallmach, Ester; Steiner, Debora; Vogel, Zvi (2006) Inhibition of AC-II activity following chronic agonist exposure is modulated by phosphorylation. J Mol Neurosci 29:115-22
Steiner, Debora; Avidor-Reiss, Tomer; Schallmach, Ester et al. (2005) Regulation of adenylate cyclase type VIII splice variants by acute and chronic Gi/o-coupled receptor activation. Biochem J 386:341-8
Steiner, Debora; Avidor-Reiss, Tomer; Schallmach, Ester et al. (2005) Inhibition and superactivation of the calcium-stimulated isoforms of adenylyl cyclase: role of Gbetagamma dimers. J Mol Neurosci 27:195-203
Nevo, I; Avidor-Reiss, T; Levy, R et al. (2000) Acute and chronic activation of the mu-opioid receptor with the endogenous ligand endomorphin differentially regulates adenylyl cyclase isozymes. Neuropharmacology 39:364-71
Bayewitch, M L; Nevo, I; Avidor-Reiss, T et al. (2000) Alterations in detergent solubility of heterotrimeric G proteins after chronic activation of G(i/o)-coupled receptors: changes in detergent solubility are in correlation with onset of adenylyl cyclase superactivation. Mol Pharmacol 57:820-5
Eckhardt, K; Nevo, I; Levy, R et al. (2000) Morphine-related metabolites differentially activate adenylyl cyclase isozymes after acute and chronic administration. FEBS Lett 470:309-14
Bayewitch, M L; Avidor-Reiss, T; Levy, R et al. (1998) Differential modulation of adenylyl cyclases I and II by various G beta subunits. J Biol Chem 273:2273-6
Rhee, M H; Bayewitch, M; Avidor-Reiss, T et al. (1998) Cannabinoid receptor activation differentially regulates the various adenylyl cyclase isozymes. J Neurochem 71:1525-34

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