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.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-MDCN-C (02))
Program Officer
Purohit, Vishnudutt
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Sloan-Kettering Institute for Cancer Research
New York
United States
Zip Code
Xu, Jin; Xu, Mingming; Bolan, Elizabeth et al. (2014) Isolating and characterizing three alternatively spliced mu opioid receptor variants: mMOR-1A, mMOR-1O, and mMOR-1P. Synapse 68:144-52
Xu, Jin; Lu, Zhigang; Xu, Mingming et al. (2014) A heroin addiction severity-associated intronic single nucleotide polymorphism modulates alternative pre-mRNA splicing of the ? opioid receptor gene OPRM1 via hnRNPH interactions. J Neurosci 34:11048-66
Kim, Charles; Barbut, Denise; Heinemann, Murk H et al. (2014) Synthetic neurotensin analogues are nontoxic analgesics for the rabbit cornea. Invest Ophthalmol Vis Sci 55:3586-93
Pasternak, Gavril W (2014) Opiate pharmacology and relief of pain. J Clin Oncol 32:1655-61
Lu, Zhigang; Xu, Jin; Xu, Mingming et al. (2014) Morphine regulates expression of *-opioid receptor MOR-1A, an intron-retention carboxyl terminal splice variant of the *-opioid receptor (OPRM1) gene via miR-103/miR-107. Mol Pharmacol 85:368-80
Xu, Jin; Lu, Zhigang; Xu, Mingming et al. (2014) Differential expressions of the alternatively spliced variant mRNAs of the µ opioid receptor gene, OPRM1, in brain regions of four inbred mouse strains. PLoS One 9:e111267
Váradi, András; Palmer, Travis C; Notis, Paula R et al. (2014) Three-component coupling approach for the synthesis of diverse heterocycles utilizing reactive nitrilium trapping. Org Lett 16:1668-71
Grinnell, Steven G; Majumdar, Susruta; Narayan, Ankita et al. (2014) Pharmacologic characterization in the rat of a potent analgesic lacking respiratory depression, IBNtxA. J Pharmacol Exp Ther 350:710-8
Pasternak, Gavril W (2014) Opioids and their receptors: Are we there yet? Neuropharmacology 76 Pt B:198-203
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

Showing the most recent 10 out of 52 publications