Evidence exists in the literature and from our laboratories to implicate PKC in the mechanism of morphine tolerance. It is clear that its role varies with different levels and durations of morphine tolerance. Its role in tolerance to other opioids has not been studied in detail. The importance of PKC in relation to other neuronal constituents has not been well defined. The overall goal of the work proposed in this application is to carry out a collaborative, comprehensive investigation involving electrophysiological techniques at the cellular level (University of Bristol) with whole animal studies (VCU) to elucidate not only if but also how PKC plays a pivotal role in morphine and other opioid tolerance. Another important goal of the research is to elucidate the relative importance of PKC to other cellular proteins such as PKA, arrestins, GRK etc in opioid tolerance. We propose to study the specific isoforms of PKC and to use knockout mice and siRNA techniques in both laboratories to elucidate the mechanisms involved. Close and continual collaboration between the two groups will provide a mechanism for daily input (email and data transfer) into the design of coordinated experiments in each laboratory. This immediate interchange of result will directly affect the design of the next experiment in the other laboratory working at a different level of integration.
The specific aims of the project are to test the hypotheses that (1) PKC plays the predominant role in acute moderate morphine tolerance, and that PKA along with PKC are involved in chronic higher levels of morphine tolerance,(2) that opioids with a higher efficacy at mu opioid receptors produce a non-PKC dependent desensitization at MORs and tolerance to these agents in the whole animal is less easily reversed by PKC inhibitors, (3) GRKs, phosphatases and Gq-coupled receptors play a role in some opioid tolerances and (4) that presynaptic sites contribute to both MOR desensitization and opioid tolerance in mice. The relevance of this research to public health is appreciated when one considers that tolerance to opioids limits their use in treating patients such as those with cancer who have chronic pain. We need to understand the mechanisms of tolerance if we are going to alleviate this problem. Also it is essential that we elucidate the mechanisms of tolerance and dependence if we are going to solve the enormous health problems caused by drug abuse. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA020836-02
Application #
7278267
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Lin, Geraline
Project Start
2006-09-01
Project End
2011-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
2
Fiscal Year
2007
Total Cost
$247,746
Indirect Cost
Name
Virginia Commonwealth University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
Llorente, Javier; Withey, Sarah; Rivero, Guadalupe et al. (2013) Ethanol reversal of cellular tolerance to morphine in rat locus coeruleus neurons. Mol Pharmacol 84:252-60
Hull, L C; Gabra, B H; Bailey, C P et al. (2013) Reversal of morphine analgesic tolerance by ethanol in the mouse. J Pharmacol Exp Ther 345:512-9
Williams, John T; Ingram, Susan L; Henderson, Graeme et al. (2013) Regulation of ?-opioid receptors: desensitization, phosphorylation, internalization, and tolerance. Pharmacol Rev 65:223-54
Rivero, Guadalupe; Llorente, Javier; McPherson, Jamie et al. (2012) Endomorphin-2: a biased agonist at the ?-opioid receptor. Mol Pharmacol 82:178-88
Llorente, Javier; Lowe, Janet D; Sanderson, Helen S et al. (2012) ?-Opioid receptor desensitization: homologous or heterologous? Eur J Neurosci 36:3636-42
Hoot, Michelle R; Sim-Selley, Laura J; Selley, Dana E et al. (2011) Chronic neuropathic pain in mice reduces ?-opioid receptor-mediated G-protein activity in the thalamus. Brain Res 1406:1-7
McPherson, Jamie; Rivero, Guadalupe; Baptist, Myma et al. (2010) ?-opioid receptors: correlation of agonist efficacy for signalling with ability to activate internalization. Mol Pharmacol 78:756-66
Hull, Lynn C; Rabender, Christopher; Gabra, Bichoy H et al. (2010) Role of CD38, a cyclic ADP-ribosylcyclase, in morphine antinociception and tolerance. J Pharmacol Exp Ther 334:1042-50
Hull, L C; Llorente, J; Gabra, B H et al. (2010) The effect of protein kinase C and G protein-coupled receptor kinase inhibition on tolerance induced by mu-opioid agonists of different efficacy. J Pharmacol Exp Ther 332:1127-35
Hoot, Michelle R; Sim-Selley, Laura J; Poklis, Justin L et al. (2010) Chronic constriction injury reduces cannabinoid receptor 1 activity in the rostral anterior cingulate cortex of mice. Brain Res 1339:18-25

Showing the most recent 10 out of 18 publications