Opiates play a major role in the management of pain, but not without problems. Side-effects are often limiting and their increased availability has led to major societal problems with their abuse. Most opioids used clinically act through the mu receptor, a G-protein-coupled receptor encoded by the Oprm gene. The wide range of clinical responses to a number of mu opioids raised the question of multiple mu receptor subtypes, a concept that has been confirmed with cloning studies. The mu opioid receptor (MOR-1) has a wide range of splice variants, with similar splicing patterns in mice, rats and humans. There are two groups of variants. One is comprised of full length 7 transmembrane domain receptors with 3'splicing, differing only at the tip of the intracellular C-terminus. The other set involve truncated variants generated from 5'splicing of unclear significance. We recently generated a series of opioid analgesics with unique pharmacological profiles and found that they act through a novel receptor target involving a truncated MOR-1 variant. The objective of this proposal is to further understand these MOR-1 splice variants.
The first aim focuses upon the target for IBNtxA and the six transmembrane domain variants that appear to be a component using a variety of approaches. The second looks at single transmembrane domain variants and their role in morphine analgesia and tolerance while the third explores the effects of 3'splicing in two full length variants.

Public Health Relevance

Opiates remain the mainstay in the treatment of pain, but not without problems. Side-effects often interfere with their ability to control pain and there is increasing concern about their illicit use. A potent analgesic lacking side-effects and abuse potential would be of great value. Most opiates used today act through the mu opiate receptor. However, there now appear to be many forms of this receptor that may be useful in developing new classes of very potent analgesics lacking physical dependence, rewarding behavior and many of the side-effects seen with traditional drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
High Priority, Short Term Project Award (R56)
Project #
2R56DA002615-32A1
Application #
8253285
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Rapaka, Rao
Project Start
1980-05-01
Project End
2014-01-31
Budget Start
2012-02-15
Budget End
2013-01-31
Support Year
32
Fiscal Year
2012
Total Cost
$561,872
Indirect Cost
$254,670
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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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
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
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 μ opioid receptor gene OPRM1 via hnRNPH interactions. J Neurosci 34:11048-66
Pasternak, Gavril W (2014) Opiate pharmacology and relief of pain. J Clin Oncol 32:1655-61
Shang, Yi; LeRouzic, Valerie; Schneider, Sebastian et al. (2014) Mechanistic insights into the allosteric modulation of opioid receptors by sodium ions. Biochemistry 53:5140-9
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
Faskowitz, Andrew J; Kramskiy, Vladimir N; Pasternak, Gavril W (2013) Methadone-induced hypoglycemia. Cell Mol Neurobiol 33:537-42

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