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)
Type
Research Project (R01)
Project #
5R01DA007242-24
Application #
8654310
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Rapaka, Rao
Project Start
Project End
Budget Start
Budget End
Support Year
24
Fiscal Year
2014
Total Cost
Indirect Cost
City
New York
State
NY
Country
United States
Zip Code
10065
Marrone, Gina F; Lu, Zhigang; Rossi, Grace et al. (2016) Tetrapeptide Endomorphin Analogs Require Both Full Length and Truncated Splice Variants of the Mu Opioid Receptor Gene Oprm1 for Analgesia. ACS Chem Neurosci 7:1717-1727
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
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
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
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
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

Showing the most recent 10 out of 47 publications