Nociceptin/Orphanin FQ, the peptide in the opioid peptide family, and the endogenous ligand for the NOP receptor is widely distributed in the brain and involved in a large number of physiological processes. The high expression level in brain regions involved in nociceptive responses, the dorsal horn of the spinal cord, and dorsal root ganglion has strongly suggested this as a target for pain therapeutics. Nevertheless, neither agonists nor antagonists appear to have significant antinociceptive properties in rodent models of acute pain. Rather than using selective NOP receptor agonists or antagonists, one option would be to use a mixed NOP/mu receptor agonist, based upon the ability of NOP agonists to attenuate reward and tolerance development mediated by mu-receptor activation. Such compounds, such as SR14150, have been demonstrated to have antinociceptive activity without inducing a conditioned place preference. In addition, recent experiments have indicated that NOP agonists have anti-allodynic activity in chronic pain models and suggested a far greater potential for selective NOP agonists as a therapeutic for chronic rather than acute pain. The experiments described in Specific Aim 1 will test the hypothesis that NOP receptors and/or N/OFQ are upregulated in selected brain regions, spinal cord, and DRG of rats subjected to spinal nerve ligation (SNL) or diabetic neuropathy, inducing chronic pain. This will be examined by measuring mRNA level by quantitative rtPCR, and protein by Western analysis, by measuring [35S]GTP S binding in brain regions and spinal cord in SNL, diabetic, and control rats, and by determining the potency of NOP agonists for anti-allodynic activity after i.c.v. and i.t. administration in SNL, diabetic and control rats.
Specific Aim 2 will determine whether the actions of NOP agonists are due to selective inhibition of C-fiber or A primary afferents. Using high or low heating rates C- or A -fibers can be independently activated. In addition, SNL and diabetic neuropathy induce differential sensitivity of these afferents. The ability of NOP agonists to block mechanical allodynia, cold allodynia, and thermal hyperalgesia will be determined to better understand both the ability of these compounds to attenuate the hypersensitivity of C- and A -fibers and also to better understand the potential clinical usefulness of NOP agonists for different chronic pain states. Finally, novel buprenorphine analogs will be synthesized for Specific Aim 3. These compounds will be designed to have higher NOP affinity and activity than buprenorphine to decrease the addiction liability and thus improve upon side effect profile of buprenorphine as an analgesic, and potentially as a drug abuse medication. These compounds, as well as other mixed NOP/mu compounds will be characterized in vitro for binding affinity and intrinsic activity, and in vivo for antinociceptive activity and abuse potential. These experiments will provide a greatly improved understanding of the mechanism by which NOP-active compounds mediate an antinociceptive or anti-allodynic response, and progress selective NOP agonists, and mixed NOP/mu agonists toward clinical use as analgesics with reduced addiction liability.

Public Health Relevance

The most effective analgesics, opiates, have significant side effects, including constipation, respiratory depression, and abuse liability. Furthermore, opiates are less effective for chronic pain, leaving effective treatment of chronic pain a huge unmet need. The studies described here will be used to better understand the mechanism by which NOP receptor agonists have greater antinociceptive potential for chronic rather than acute pain, and identify novel compounds, acting at NOP receptors that could have potential as treatments for both acute and chronic pain, with reduced addiction liability.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01DA023281-08
Application #
8675213
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Rapaka, Rao
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Torrey Pines Institute for Molecular Studies
Department
Type
DUNS #
City
Port Saint Lucie
State
FL
Country
United States
Zip Code
34987
Cippitelli, Andrea; Schoch, Jennifer; Debevec, Ginamarie et al. (2016) A key role for the N/OFQ-NOP receptor system in modulating nicotine taking in a model of nicotine and alcohol co-administration. Sci Rep 6:26594
Toll, Lawrence; Bruchas, Michael R; Calo', Girolamo et al. (2016) Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems. Pharmacol Rev 68:419-57
Li, Yangmei; Cazares, Margret; Wu, Jinhua et al. (2016) Potent μ-Opioid Receptor Agonists from Cyclic Peptides Tyr-c[D-Lys-Xxx-Tyr-Gly]: Synthesis, Biological, and Structural Evaluation. J Med Chem 59:1239-45
Ding, Huiping; Czoty, Paul W; Kiguchi, Norikazu et al. (2016) A novel orvinol analog, BU08028, as a safe opioid analgesic without abuse liability in primates. Proc Natl Acad Sci U S A 113:E5511-8
Ozawa, Akihiko; Brunori, Gloria; Mercatelli, Daniela et al. (2015) Knock-In Mice with NOP-eGFP Receptors Identify Receptor Cellular and Regional Localization. J Neurosci 35:11682-93
Cippitelli, Andrea; Wu, Jinhua; Gaiolini, Kelly A et al. (2015) AT-1001: a high-affinity α3β4 nAChR ligand with novel nicotine-suppressive pharmacology. Br J Pharmacol 172:1834-45
Cox, Brian M; Christie, Macdonald J; Devi, Lakshmi et al. (2015) Challenges for opioid receptor nomenclature: IUPHAR Review 9. Br J Pharmacol 172:317-23
Cippitelli, Andrea; Brunori, Gloria; Gaiolini, Kelly A et al. (2015) Pharmacological stress is required for the anti-alcohol effect of the α3β4* nAChR partial agonist AT-1001. Neuropharmacology 93:229-36
Khroyan, T V; Wu, J; Polgar, W E et al. (2015) BU08073 a buprenorphine analogue with partial agonist activity at μ-receptors in vitro but long-lasting opioid antagonist activity in vivo in mice. Br J Pharmacol 172:668-80
Zielińska, Marta; Ben Haddou, Tanila; Cami-Kobeci, Gerta et al. (2015) Anti-inflammatory effect of dual nociceptin and opioid receptor agonist, BU08070, in experimental colitis in mice. Eur J Pharmacol 765:582-90

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