Although mu opioid receptor agonists are the most commonly used opioids for the treatment of moderate to severe pain in the clinic, the side effects of mu opioids such as constipation, respiratory depression, pruritus, abuse liability, and physical dependence limit their value as a medication. Research to identify novel opioids without these side effects is pivotal to advance the health care of humans. Scientists have discovered N/OFQ, a heptadecapeptide that is an endogenous ligand for the novel opioid receptors (now named NOP receptors). The amino acid sequence of the NOP receptor has close homology to each of the classical, well-characterized mu, kappa, delta opioid receptors, but ligands that bind to these classical opioid receptors do not bind to NOP receptors with high affinity. The actions of N/OFQ have much in common with those of opioid peptides at the cellular level. Nevertheless, the behavioral effects of various NOP receptor agonists with different affinity and efficacy have not been systematically studied in primates. The studies proposed in this project will test the hypothesis that functions/behavioral effects of NOP receptors are independent of classical opioid receptors and activation of NOP receptors produces antinociception with fewer side effects and reduced abuse liability in monkeys. In the proposed studies, a variety of physiological and behavioral endpoints will be measured and receptor-selective agonists and antagonists will be used to investigate the functions of NOP receptors. Dose-response curves, time course of each agent, and possible side effects (e.g., scratching, sedation, respiratory depression, cardiovascular changes) will be thoroughly investigated. Proposed studies will help determine whether NOP receptor agonists represent a novel class of opioids that produce analgesia but have fewer side effects in primates. Behavioral effects of NOP receptor agonists will be systematically compared with those of mu opioid analgesics across different, well-established functional/behavioral assays in monkeys. In particular, the therapeutic margin of safety of NOP agonists will be determined in the monkey behavioral models. Our proposed studies, with an emphasis on behavioral effects in the whole organism, are the first attempt to elucidate the functions of NOP receptors in monkeys. These basic studies of behavioral neuropharmacology will establish a valuable translational foundation for understanding of biobehavioral functions of NOP receptors and future research and development of NOP receptor agonists in humans.

Public Health Relevance

Mu opioid analgesics are commonly used for the pain treatment in the clinic. However, side effects of mu opioids limit their value as pain relievers. The purpose of this proposal is to investigate the biobehavioral functions of NOP receptors, currently categorized as the fourth receptor type in the opioid receptor family, in non-human primates. If proposed aims are achieved, it will improve our understanding of physiological functions of the NOP receptor and the safety margin of NOP receptor agonists in primates. More importantly, these studies will facilitate future development and use of NOP receptor agonists in humans. Mu opioid analgesics are commonly used for the pain treatment in the clinic. However, side effects of mu opioids limit their value as pain relievers. The purpose of this proposal is to investigate the biobehavioral functions of NOP receptors, currently categorized as the fourth receptor type in the opioid receptor family, in non-human primates. If proposed aims are achieved, it will improve our understanding of physiological functions of the NOP receptor and the safety margin of NOP receptor agonists in primates. More importantly, these studies will facilitate future development and use of NOP receptor agonists in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
7R01DA032568-02
Application #
8710778
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Rapaka, Rao
Project Start
2012-09-15
Project End
2017-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$337,725
Indirect Cost
$117,229
Name
Wake Forest University Health Sciences
Department
Physiology
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
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Sukhtankar, Devki D; Lagorio, Carla H; Ko, Mei-Chuan (2014) Effects of the NOP agonist SCH221510 on producing and attenuating reinforcing effects as measured by drug self-administration in rats. Eur J Pharmacol 745:182-9
Sukhtankar, Devki D; Lee, Heeseung; Rice, Kenner C et al. (2014) Differential effects of opioid-related ligands and NSAIDs in nonhuman primate models of acute and inflammatory pain. Psychopharmacology (Berl) 231:1377-87
Sukhtankar, Devki D; Zaveri, Nurulain T; Husbands, Stephen M et al. (2013) Effects of spinally administered bifunctional nociceptin/orphanin FQ peptide receptor/*-opioid receptor ligands in mouse models of neuropathic and inflammatory pain. J Pharmacol Exp Ther 346:11-22
Lin, Ann P; Ko, Mei-Chuan (2013) The therapeutic potential of nociceptin/orphanin FQ receptor agonists as analgesics without abuse liability. ACS Chem Neurosci 4:214-24