This is a request for a Research Scientist Award (KO5). Despite their importance in the management of pain, opiates are abused and this remains a major problem. By understanding the roles of the many opioid receptor subtypes in pain control and addictive behavior, it may be possible to develop analgesics without abuse potentia. Opiate receptor multiplicity has expanded to three major classes of receptors (mu, delta and kappa) with subtypes within each class. These receptor subtypes have been associated with specific pharmacological actions in vivo and have been studied in traditional binding assays. The recent cloning of delta, mu and kappa1 receptors has greatly facilitated the study of opioid receptor heterogeneity. For example, we have confirmed the role of spinal delta receptors in enkephalin analgesia using an antisense oligodeoxynucleotide to DOR-l and identified a new putative kappa3 receptor clone based upon sequence homologies. An antisense oligodeoxynucleotide based upon this clone prevents analgesia in vivo by a kappa3 ligand but not morphine. These investigations into opioid receptor heterogeneity will be continued, focusing upon mu and kappa3 receptors. They will include the binding, regulation and second messenger systems of mu and kappa3 receptors in cell lines using traditional biochemical and molecular biological approaches, as well as novel ligands synthesized by my laboratory. Unlike tissue culture, the brain is a highly complex network of neuronal systems. The descriptions of marked regional synergy among various brainstem nuclei and between the brain and the spinal cord underscore the need for in vivo studies. Our studies on synergy within the central nervous system will continue and the roles of the various receptor subtypes will be defined. Investigations into tolerance and the role of nitric oxide (NO) also will be continued while additional studies looking at an important morphine metabolite, morphine 6beta-glucuronide, will be expanded. Our recent identification of an antiopioid sigma1 system within the brain may help explain the wide variability of responses to opioids among strains of mice and possibly people. Additional studies exploring these sigma1/opioid interactions are planned. While understanding opioid pharmacology is crucial, it is important to disseminate this knowledge to the medical community and the general public. This can only lead to a more effective approach to the control of pain and a decrease in the abuse of these important drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Scientist Award (K05)
Project #
1K05DA000220-01
Application #
2116180
Study Section
Special Emphasis Panel (SRCD (04))
Project Start
1994-08-01
Project End
1999-07-31
Budget Start
1994-08-01
Budget End
1995-07-31
Support Year
1
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Faskowitz, Andrew J; Kramskiy, Vladimir N; Pasternak, Gavril W (2013) Methadone-induced hypoglycemia. Cell Mol Neurobiol 33:537-42
Pasternak, Gavril W; Pan, Ying-Xian (2013) Mu opioids and their receptors: evolution of a concept. Pharmacol Rev 65:1257-317
Su, Wendy; Pasternak, Gavril W (2013) The role of multidrug resistance-associated protein in the blood-brain barrier and opioid analgesia. Synapse 67:609-19
Kim, Felix J; Schrock, Joel M; Spino, Christina M et al. (2012) Inhibition of tumor cell growth by Sigma1 ligand mediated translational repression. Biochem Biophys Res Commun 426:177-82
Majumdar, Susruta; Burgman, Maxim; Haselton, Nathan et al. (2011) Generation of novel radiolabeled opiates through site-selective iodination. Bioorg Med Chem Lett 21:4001-4
Kim, Felix J; Kovalyshyn, Ivanka; Burgman, Maxim et al. (2010) Sigma 1 receptor modulation of G-protein-coupled receptor signaling: potentiation of opioid transduction independent from receptor binding. Mol Pharmacol 77:695-703
Kolesnikov, Yuri A; Oksman, Galina; Pasternak, Gavril W (2010) Topical methadone and meperidine analgesic synergy in the mouse. Eur J Pharmacol 638:61-4
Rossi, Grace C; Matulonis, Joshua E; Richelson, Elliott et al. (2010) Systemically and topically active antinociceptive neurotensin compounds. J Pharmacol Exp Ther 334:1075-9
Pasternak, Gavril W (2010) Molecular insights into mu opioid pharmacology: From the clinic to the bench. Clin J Pain 26 Suppl 10:S3-9
Chou, Roger; Fanciullo, Gilbert J; Fine, Perry G et al. (2009) Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain 10:113-30

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