This project is in response to a request from NIDA for studies on opioid agonists that are found in commonly abused prescription pain medications. Recent data suggest a substantial increase in abuse of prescription opioid analgesics that are used to treat several clinical concerns, most notably pain. The overall goal of this project is to examine the pharmacodynamics of these opioid agonists. To address this goal, the project has 2 Specific Aims.
Specific Aim 1 is to examine the relative analgesic potency of and production of tolerance to opioid agonists commonly found in prescription pain medications.
Specific Aim 2 is to determine the relative efficacy of these opioid agonists and evaluate the role of efficacy in the development of analgesic tolerance and the regulation of mu-opioid receptors. The opioids to be studied were chosen based on the most recent SAMHSA data in the DAWN survey and the National Survey on Drug Use. The project will test 3 hypotheses. Hypothesis 1 is that the efficacy of opioid agonists determines the development of tolerance. Specifically, high efficacy agonists will produce less tolerance than equi-effective doses of low efficacy agonists in the intact mouse. Hypothesis 2 is that the efficacy of opioid agonists determines the regulation of mu-opioid receptor density in spinal cord of the intact mouse. Specifically, high efficacy agonists will reduce mu-opioid receptor density in the mouse spinal cord, whereas low efficacy agonists will either not affect, or increase mu-opioid receptor density. Hypothesis 3 is that directly changing the efficacy of an opioid ligand will alter the magnitude of tolerance and regulation of mu-opioid receptor density in spinal cord of the intact mouse. It is anticipated that irreversible alkylation of mu-opioid receptors will reduce the efficacy of opioid agonists and will increase opioid tolerance at equi-effective doses and reduce regulation of mu- opioid receptor density. Overall, the results of this project will provide new and important information on the pharmacodynamics and mechanism of action of a group of opioid analgesics that are potential drugs of abuse. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
1R01DA019959-01A1
Application #
7088413
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Purohit, Vishnudutt
Project Start
2006-09-22
Project End
2009-07-31
Budget Start
2006-09-22
Budget End
2007-07-31
Support Year
1
Fiscal Year
2006
Total Cost
$198,000
Indirect Cost
Name
St. John's University
Department
Other Health Professions
Type
Schools of Pharmacy
DUNS #
073134744
City
Queens
State
NY
Country
United States
Zip Code
11439
Madia, Priyanka A; Navani, Dipesh M; Yoburn, Byron C (2012) [(35)S]GTPýýS binding and opioid tolerance and efficacy in mouse spinal cord. Pharmacol Biochem Behav 101:155-65
Navani, Dipesh M; Sirohi, Sunil; Madia, Priyanka A et al. (2011) The role of opioid antagonist efficacy and constitutive opioid receptor activity in the opioid withdrawal syndrome in mice. Pharmacol Biochem Behav 99:671-5
Madia, Priyanka A; Dighe, Shveta V; Sirohi, Sunil et al. (2009) Dosing protocol and analgesic efficacy determine opioid tolerance in the mouse. Psychopharmacology (Berl) 207:413-22
Sirohi, Sunil; Dighe, Shveta V; Madia, Priyanka A et al. (2009) The relative potency of inverse opioid agonists and a neutral opioid antagonist in precipitated withdrawal and antagonism of analgesia and toxicity. J Pharmacol Exp Ther 330:513-9
Dighe, Shveta V; Madia, Priyanka A; Sirohi, Sunil et al. (2009) Continuous morphine produces more tolerance than intermittent or acute treatment. Pharmacol Biochem Behav 92:537-42
Sirohi, Sunil; Dighe, Shveta V; Walker, Ellen A et al. (2008) The analgesic efficacy of fentanyl: relationship to tolerance and mu-opioid receptor regulation. Pharmacol Biochem Behav 91:115-20
Kumar, Priyank; Sunkaraneni, Soujanya; Sirohi, Sunil et al. (2008) Hydromorphone efficacy and treatment protocol impact on tolerance and mu-opioid receptor regulation. Eur J Pharmacol 597:39-45
Sirohi, Sunil; Kumar, Priyank; Yoburn, Byron C (2007) Mu-opioid receptor up-regulation and functional supersensitivity are independent of antagonist efficacy. J Pharmacol Exp Ther 323:701-7
Price, Theodore J; Flores, Christopher M (2007) Critical evaluation of the colocalization between calcitonin gene-related peptide, substance P, transient receptor potential vanilloid subfamily type 1 immunoreactivities, and isolectin B4 binding in primary afferent neurons of the rat and mouse. J Pain 8:263-72
Pawar, Mohit; Kumar, Priyank; Sunkaraneni, Soujanya et al. (2007) Opioid agonist efficacy predicts the magnitude of tolerance and the regulation of mu-opioid receptors and dynamin-2. Eur J Pharmacol 563:92-101

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