This is a revised application to study the analgesic effects of novel non-peptidic and systemically-active delta opioid agonists in rhesus monkeys. The use of morphine-like analgesics, which act primarily on mu opioid receptors, is limited by their high abuse potential and by other side-effects such as respiratory depression. Studies with peptidic delta opioids suggest that delta agonists may produce clinically relevant analgesic effects without producing morphine-like side effects. Recently developed non-peptidic delta agonists, such as SNC80 and TAN67, now make it possible for the first time to examine the analgesic effects of systemically-administered delta-selective agonists in primates. Many of these compounds have not been administered before to primates, so the time course, potency and delta-receptor selectivity of novel compounds will first be examined in an assay of food-maintained operant responding. Drugs that function as delta-selective agonists in the assay of food-maintained responding will then be evaluated for their analgesic effects using two assays of analgesia: (1) a model of thermal nociception, and (2) a model of inflammatory pain. We propose to compare the effects of acute and chronic administration of novel delta agonists in these two complementary assays because they model different aspects of pain that are mediated by different mechanisms. Moreover, thermal nociception and inflammatory pain respond differently to analgesic drugs, and initial studies indicate that delta agonists may be especially effective against inflammatory pain. In view of recent evidence that there are gender differences in opioid antinociception in primates, this application also proposes to study novel delta agonists in both male and female monkeys. The proposed studies will evaluate the role of gonadal hormones at different phases of the menstrual cycle in the mediation of delta opioid analgesic effect. Convulsant activity is the single most severe side-effect that has been associated with some novel delta agonists. Preliminary findings show that SNC80 does not produce convulsions in rhesus monkeys even at high doses, but this potentially severe side-effect warrants careful study, because convulsant activity could seriously compromise the clinical usefulness of delta agonists. Accordingly, the proposed studies would also examine the effects of acute and chronic administration of selected delta agonists on electroencephalographic (EEG) activity in male and female rhesus monkeys to assess the degree to which these compounds produce abnormal EEG activity, EEG seizures and/or behavioral convulsions.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA011460-02
Application #
6174711
Study Section
Special Emphasis Panel (ZRG1-IFCN-4 (01))
Program Officer
Thomas, David D
Project Start
1999-09-01
Project End
2003-06-30
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
2
Fiscal Year
2000
Total Cost
$193,566
Indirect Cost
Name
Mc Lean Hospital (Belmont, MA)
Department
Type
DUNS #
City
Belmont
State
MA
Country
United States
Zip Code
02478
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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