Acutely administered morphine produces antinociception via mu opioid receptor (MOR)-mediated intracellular changes that include a decrease in calcium concentration, and a decrease in the activity of adenylyl cyclase and protein kinases. Chronic administration of morphine results in tolerance to its antinociceptive effects and a reversal in the direction of these intracellular events. Our recent studies have implicated protein kinases, especially cAMP-dependent protein kinase (PKA) and protein kinase C (PKC), as well as other steps in the phosphatidylinositol cascade in morphine tolerance. We have reported that inhibition of either PKA or PKC, blockade of phospholipase C or blockade of 1P3 receptors all cause a reversal of morphine tolerance. In other studies we have elucidated the involvement of ATP-gated potassium channels in the actions of acute and chronic morphine. Again we found diametrically opposite effects in the acute versus chronic treatment regimens. The overall goal of the proposed studies is to utilize pharmacological, biochemical and anatomical approaches to determine the critical cellular events underlying the tolerance that develops to morphine-induced antinociception. We have proposed a comprehensive model that includes the steps in the MOR-mediated signal transduction cascade that we hypothesize are involved in tolerance to morphine-induced antinociception. The proposed experiments will test our hypotheses that constant phosphorylation of proteins is required for the maintenance of morphine tolerance and that inhibition of protein-kinase-mediated phosphorylation or upstream steps in their signaling cascades reverses morphine tolerance. We propose to elucidate the mechanisms that lead to the reversal of analgesic tolerance by examining mu opioid receptor levels and phosphorylation state, G-protein activation, adenylyl cyclase activity, and the phosphorylation state of L- and N-type calcium channels.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA001647-24A1
Application #
6434021
Study Section
Special Emphasis Panel (ZRG1-MDCN-5 (01))
Program Officer
Lin, Geraline
Project Start
1976-12-01
Project End
2006-12-31
Budget Start
2002-03-01
Budget End
2002-12-31
Support Year
24
Fiscal Year
2002
Total Cost
$262,500
Indirect Cost
Name
Virginia Commonwealth University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298
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Bailey, C P; Llorente, J; Gabra, B H et al. (2009) Role of protein kinase C and mu-opioid receptor (MOPr) desensitization in tolerance to morphine in rat locus coeruleus neurons. Eur J Neurosci 29:307-18
Gabra, Bichoy H; Bailey, Chris P; Kelly, Eamonn et al. (2008) Pre-treatment with a PKC or PKA inhibitor prevents the development of morphine tolerance but not physical dependence in mice. Brain Res 1217:70-7
Haller, Victoria L; Bernstein, Marissa A; Welch, Sandra P (2008) Chronic morphine treatment decreases the Cav1.3 subunit of the L-type calcium channel. Eur J Pharmacol 578:101-7
Gabra, Bichoy H; Smith, Forrest L; Navarro, Hernan A et al. (2008) mGluR5 antagonists that block calcium mobilization in vitro also reverse (S)-3,5-DHPG-induced hyperalgesia and morphine antinociceptive tolerance in vivo. Brain Res 1187:58-66
Stoller, Dawn C; Sim-Selley, Laura J; Smith, Forrest L (2007) Role of kappa and delta opioid receptors in mediating morphine-induced antinociception in morphine-tolerant infant rats. Brain Res 1142:28-36
Smith, Forrest L; Lindsay, Raymond J (2007) Enhancement of bupivacaine local anesthesia with the potassium channel blocker ibutilide. Eur J Pain 11:551-6
Bailey, Chris P; Smith, Forrest L; Kelly, Eamonn et al. (2006) How important is protein kinase C in mu-opioid receptor desensitization and morphine tolerance? Trends Pharmacol Sci 27:558-65
Bernstein, M A; Welch, S P (1999) A method for the determination of activated receptor phosphorylation state following in vivo drug treatment. Brain Res Brain Res Protoc 4:420-4
Bernstein, M A; Welch, S P (1998) Inhibition of protein phosphatases alters the expression of morphine tolerance in mice. Eur J Pharmacol 341:173-7

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