Opiates have a unique place in medicine in the treatment of pain, although they also have problems due to the potential of abuse. Most clinically used opioids act through mu opioid receptors. Yet, the wide range of responses among patients to individual drugs and the demonstration of incomplete cross tolerance among mu opioids has raised questions regarding how these drugs could all be acting through a single mu receptor. Pharmacological studies going back over twenty years have suggested the existence of multiple subpopulations of mu receptors, a concept that has now been confirmed with the cloning of splice variants of the cloned mu receptor MOR-1 in mice, rats and humans. Understanding the role of these receptor variants in behavior is important for the optimal use of these drugs. In this application we propose to extend ongoing studies correlating the cloned MOR-1 variants with their functions in vivo. We believe that the effects of mu opioids in vivo reflect the summation of actions from a number of mu receptor variants and that differences among the mu drugs reflects their differing efficacies for these receptor populations. We propose to examine this hypothesis using both antisense mapping, knockout animals and traditional behavioral approaches. We also will map the expression of the variants in these models immunohistochemically. Additional studies will focus on topical mechanisms of opioid action as a model system to examine these variants in a more defined system. Finally, we will expand upon the role of transporters in opioid tolerance. Together, these studies should provide insights into the role of the MOR-1 splice variants on opioid action and a better understanding of the use of these drugs.

Public Health Relevance

Morphine and related mu opiates produce their effects through a set of mu receptors, including both analgesia and most of their side-effects. These mu subtypes have been cloned and characterized at the molecular level. By understanding the functional roles of the various mu receptor subtypes, it may be come possible to develop analgesics lacking these side-effects, and possibly even reinforcing potential.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA007242-23
Application #
8460973
Study Section
Special Emphasis Panel (ZRG1-MDCN-F (02))
Program Officer
Rapaka, Rao
Project Start
1991-06-01
Project End
2015-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
23
Fiscal Year
2013
Total Cost
$422,195
Indirect Cost
$201,035
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
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
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
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
Faskowitz, Andrew J; Kramskiy, Vladimir N; Pasternak, Gavril W (2013) Methadone-induced hypoglycemia. Cell Mol Neurobiol 33:537-42
Pasternak, Gavril W (2012) Preclinical pharmacology and opioid combinations. Pain Med 13 Suppl 1:S4-11
El Maarouf, Abderrahman; Kolesnikov, Yuri; Pasternak, Gavril et al. (2012) Neural cell adhesion molecule and its polysialic acid moiety exhibit opposing and linked effects on neuropathic hyperalgesia. Exp Neurol 233:866-70
Pasternak, Gavril W; Pan, Ying-Xian (2011) Mix and match: heterodimers and opioid tolerance. Neuron 69:6-8

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