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Vol. 53, Issue 3, 381-416, September 2001

The Molecular and Behavioral Pharmacology of the Orphanin FQ/Nociceptin Peptide and Receptor Family

Jeffrey S. Mogil and Gavril W. Pasternak1

Department of Psychology, McGill University, Montreal, Quebec Canada (J.S.M.); and Laboratory of Molecular Neuropharmacology, Memorial Sloan-Kettering Cancer Center, New York, New York (G.W.P.)

I. Introduction
II. Molecular Biology of the Orphanin FQ/Nociceptin Receptor
    A. Cloning NOP1 and Its Gene
    B. Alternatively Splicing NOP1
    C. Molecular Modifications of NOP1
III. Receptor Binding
IV. NOP1 Receptor Heterogeneity
V. Orphanin FQ/Nociceptin
    A. Structure of Orphanin FQ/Nociceptin
    B. Orphanin FQ/Nociceptin Analogs and Antagonists
    C. Orphanin FQ/Nociceptin Precursors and Their Processing
VI. Anatomy of Orphanin FQ/Nociceptin and Its Receptor
VII. Range of Effects of Orphanin FQ/Nociceptin
VIII. Effects of Orphanin FQ/Nociceptin on Pain
    A. Effects of Supraspinally Administered Orphanin FQ/Nociceptin
    B. Effects of Spinally Administered Orphanin FQ/Nociceptin
    C. Effects of Peripherally Administered Orphanin FQ/Nociceptin
    D. Reconciling the Literature
        1. Noxious Stimulus Modality.
        2. Robustness of Various Phenomena.
        3. Influence of Stress.
        4. Organismic Factors: Species, Strain, and Sex Differences.
        5. Dose Dependence.
        6. Opioid Tone.
    E. Effects of Other NOP1 Receptor Agonists
    F. Phenotypes of Knockout Mice
    G. Effects of NOP1 Down-Regulation or Blockade
        1. Antisense Studies.
        2. Pharmacological Antagonists.
    H. Mechanisms of Orphanin FQ/Nociceptin Actions: Ubiquitous Cellular Inhibition as a Unifying Hypothesis?
IX. Effects of Related Peptides on Pain
    A. Nocistatin
    B. Orphanin FQ/Nociceptin 2
X. Involvement of NOP1 in Other Central Nervous System-Mediated Behaviors
    A. Locomotor Activity and Reward
    B. Anxiety, Fear, and Stress
    C. Tolerance and Dependence
    D. Learning and Memory
    E. Feeding
XI. Conclusions and Future Directions
Acknowledgments
References

The isolation of an opioid receptor-related clone soon led to the isolation and characterization of a new neuropeptide, termed orphanin FQ or nociceptin (OFQ/N). This heptadecapeptide binds to the NOP1 (previously termed ORL1) receptor with exceedingly high affinity, but does not interact directly with classical opioid receptors. Functionally, the actions of OFQ/N are diverse and intriguing. Most work has focused upon pain mechanisms, where OFQ/N has potent anti-analgesic actions supraspinally and analgesic actions spinally. Other OFQ/N activities are less clear. The diversity of responses might reflect NOP1 receptor heterogeneity, but this remains to be established. The actions of this neurochemical system may also be uniquely dependent on contextual factors, both genetic and environmental. This review will address the molecular biology and behavioral pharmacology of OFQ/N and its receptor.

1 Address for correspondence: Dr. Gavril W. Pasternak, Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY. E-mail: pasterng{at}mskcc.org

0031-6997/01/5303-0381$03.00/0
PHARMACOLOGICAL REVIEWS
Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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