This is a revised, competing renewal application to study the behavioral effects of delta opioid receptor agonists in rhesus monkeys. Two major findings of the last project period were that (a) SNC80 and other non-peptidic delta agonists produced anti-allodynic effects in a model of inflammatory pain, and (b) SNC80 enhanced the analgesic effects but not the sedative effects of mu agonists. These results suggest that delta agonists may be useful in the treatment of inflammatory pain, and combinations of delta and mu opioids may produce enhanced analgesic effects with reduced side effects in comparison to delta or mu agonists alone. We now propose to extend these findings according to four specific aims. First, we propose to examine the delta-receptor pharmacology of delta/mu interactions in assays of sedation and thermal pain. We hypothesize that delta/mu analgesic interactions are stereoselective and dependent on the efficacy of the delta opioid. Second, we propose to examine delta/mu interactions in our assay of inflammatory pain, which models some types of clinical pain commonly treated with opioids (e.g. post-surgical pain). Delta/mu analgesic interactions may vary as a function of the type of pain, and the extent of delta/mu interactions in assays of inflammatory pain is unknown. We hypothesize that delta/mu interactions will be synergistic in assays of inflammatory pain. Third, we propose to examine delta/mu interactions on operant behavioral measures of drug reward. Abuse liability limits the clinical utility of mu agonists, and the discovery of strong analgesics with low abuse liability would be a significant advance in pain treatment. We hypothesize that co-activation of delta receptors will reduce the abuse-related effects of mu agonists. Finally, we propose to evaluate peripheral and spinal mechanisms of delta agonist- induced anti-allodynia in the model of inflammatory pain. Localized peripheral drug injections will be used to test the hypothesis that peripheral delta opioid receptors at the site of inflammation are necessary and/or sufficient for delta agonist-induced anti-allodynia. Intrathecal drug injections will be used to test the hypothesis that spinal delta opioid receptors are necessary and/or sufficient for delta agonist-induced anti-allodynia. We suggest that the proposed studies would enhance understanding of the pharmacological, behavioral and neurobiological determinants of opioid analgesia in non-human primates and may contribute to the development of improved analgesic medications.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA011460-09
Application #
7423876
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Aigner, Thomas G
Project Start
1999-09-01
Project End
2010-04-30
Budget Start
2008-05-01
Budget End
2009-04-30
Support Year
9
Fiscal Year
2008
Total Cost
$242,293
Indirect Cost
Name
Virginia Commonwealth University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
Leitl, Michael D; Negus, S Stevens (2016) Pharmacological modulation of neuropathic pain-related depression of behavior: effects of morphine, ketoprofen, bupropion and [INCREMENT]9-tetrahydrocannabinol on formalin-induced depression of intracranial self-stimulation in rats. Behav Pharmacol 27:364-76
Miller, Laurence L; Altarifi, Ahmad A; Negus, S Stevens (2015) Effects of repeated morphine on intracranial self-stimulation in male rats in the absence or presence of a noxious pain stimulus. Exp Clin Psychopharmacol 23:405-14
Kaufman, Marc J; Janes, Amy C; Frederick, Blaise deB et al. (2013) A method for conducting functional MRI studies in alert nonhuman primates: initial results with opioid agonists in male cynomolgus monkeys. Exp Clin Psychopharmacol 21:323-31
Wise, Laura E; Premaratne, Ishani D; Gamage, Thomas F et al. (2012) l-theanine attenuates abstinence signs in morphine-dependent rhesus monkeys and elicits anxiolytic-like activity in mice. Pharmacol Biochem Behav 103:245-52
Negus, S Stevens; O'Connell, Robert; Morrissey, Ember et al. (2012) Effects of peripherally restricted ? opioid receptor agonists on pain-related stimulation and depression of behavior in rats. J Pharmacol Exp Ther 340:501-9
Yekkirala, Ajay S; Banks, Matthew L; Lunzer, Mary M et al. (2012) Clinically employed opioid analgesics produce antinociception via ?-? opioid receptor heteromers in Rhesus monkeys. ACS Chem Neurosci 3:720-7
Aceto, Mario D; Harris, Louis S; Negus, S Stevens et al. (2012) MDAN-21: A Bivalent Opioid Ligand Containing mu-Agonist and Delta-Antagonist Pharmacophores and Its Effects in Rhesus Monkeys. Int J Med Chem 2012:327257
Negus, S Stevens; Rosenberg, Marisa B; Altarifi, Ahmad A et al. (2012) Effects of the ? opioid receptor agonist SNC80 on pain-related depression of intracranial self-stimulation (ICSS) in rats. J Pain 13:317-27
Banks, Matthew L; Roma, Peter G; Folk, John E et al. (2011) Effects of the delta-opioid agonist SNC80 on the abuse liability of methadone in rhesus monkeys: a behavioral economic analysis. Psychopharmacology (Berl) 216:431-9
Negus, S Stevens; Morrissey, Ember M; Rosenberg, Marisa et al. (2010) Effects of kappa opioids in an assay of pain-depressed intracranial self-stimulation in rats. Psychopharmacology (Berl) 210:149-59

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