The primary goal of this project is to identify and characterize new targets for medication development in the area of pain control and drug abuse. Recent years have seen a resurgence of opioid abuse, as well as the need for additional analgesics with limited abuse potential. Our objectives are to identify new lead drug candidates for further development and to identify and characterize modulatory systems that influence opioid action. The project contains three major aims.
The first aim addresses molecular mechanisms of the anti-opioid sigma1 receptor system, looking for additional splice variants of the recently cloned sigma1 receptor and mechanisms through which these proteins modulate the functional aspects of G-protein coupled receptors. By isolating and cloning additional splice variants, it may be possible to identify novel targets for drug development. Sigma1 agonists potently reverse the analgesic activity of a variety of classes of opioid analgesics while sigma1 antagonists potentiate opioid analgesia.
The second aim will explore the ability of sigma1 systems to selectively enhance opioid analgesia and not other opioid actions, as well as the role of sigma1 receptors in influencing the expression of ATP-binding cassette (ABC) transporters. The most prominent member of this family, P-glycoprotein (i.e. mdr) has been implicated in the blood-brain barrier, as well as providing a system for transporting endogenous neuropeptides/transmitters from the brain to the peripheral circulation. It also plays a major role in morphine tolerance, with chronic morphine upregulating its expression. In addition to Pgp, MRP1 also has been implicated in opioid action. The last aim involves further studies with a series of opioid analogs synthesized in the laboratory during the previous granting period and the synthesis of a series of new tools to assist in the study of opioid systems. By understanding how opioids and their modulatory systems interact, we hope to develop better approaches towards the management of pain and the discovery of new agents. This proposal explores new potential targets for medication development. Through a better understanding of sigma1 receptors it is hoped to maintain pain control while minimizing side-effects and possibly abuse liability while other aspects of the project explore novel opioid analgesics and antagonists with unique pharmacological profiles.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA006241-23
Application #
8264359
Study Section
Special Emphasis Panel (ZRG1-MDCN-C (02))
Program Officer
Purohit, Vishnudutt
Project Start
1990-07-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2014-04-30
Support Year
23
Fiscal Year
2012
Total Cost
$448,940
Indirect Cost
$208,865
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
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Marrone, Gina F; Grinnell, Steven G; Lu, Zhigang et al. (2016) Truncated mu opioid GPCR variant involvement in opioid-dependent and opioid-independent pain modulatory systems within the CNS. Proc Natl Acad Sci U S A 113:3663-8
Grinnell, Steven G; Ansonoff, Michael; Marrone, Gina F et al. (2016) Mediation of buprenorphine analgesia by a combination of traditional and truncated mu opioid receptor splice variants. Synapse 70:395-407
Xu, Jin; Faskowitz, Andrew J; Rossi, Grace C et al. (2015) Stabilization of morphine tolerance with long-term dosing: association with selective upregulation of mu-opioid receptor splice variant mRNAs. Proc Natl Acad Sci U S A 112:279-84
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Pickett, Julie E; Váradi, András; Palmer, Travis C et al. (2015) Mild, Pd-catalyzed stannylation of radioiodination targets. Bioorg Med Chem Lett 25:1761-4
Lu, Zhigang; Xu, Jin; Rossi, Grace C et al. (2015) Mediation of opioid analgesia by a truncated 6-transmembrane GPCR. J Clin Invest 125:2626-30
Váradi, András; Marrone, Gina F; Eans, Shainnel O et al. (2015) Synthesis and characterization of a dual kappa-delta opioid receptor agonist analgesic blocking cocaine reward behavior. ACS Chem Neurosci 6:1813-24
Marrone, Gina F; Majumdar, Susruta; Pasternak, Gavril W (2015) Radioligand Binding Assay for an Exon 11-Associated Mu Opioid Receptor Target. Methods Mol Biol 1335:241-9

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