Abstract

Quantitative trait locus mapping of chemical/inflammatory pain in the mouse identified the Avpr1a gene, which encodes the vasopressin-1A receptor (V1AR), as being responsible for strain-dependent pain sensitivity to formalin and capsaicin. A genetic association study in humans revealed the influence of a single nucleotide polymorphism (rs10877969) in AVPR1A on capsaicin pain levels, but only in male subjects reporting stress at the time of testing. The analgesic efficacy of the vasopressin analog desmopressin revealed a similar interaction between the drug and acute stress, as desmopressin inhibition of capsaicin pain was only observed in nonstressed subjects. Additional experiments in mice confirmed the male-specific interaction of V1AR and stress, leading to the conclusion that vasopressin activates endogenous analgesia mechanisms unless they have already been activated by stress. These findings represent, to the best of our knowledge, the first explicit demonstration of analgesic efficacy depending on the emotional state of the recipient, and illustrate the heuristic power of a bench-to-bedside-to-bench translational strategy.

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Acknowledgements

This study was supported by US National Institutes of Health grant NS41670 (R.B.F. and J.S.M.), CTSA grant RR02980 and the Louise and Alan Edwards Foundation (J.S.M.). We thank Pfeiffer of America for providing metered spray pumps.

Author information

Author notes

    • Inna Belfer
    •  & Roger B Fillingim

    These authors contributed equally to this work.

Affiliations

  1. Department of Psychology and Centre for Research on Pain, McGill University, Montreal, Quebec, Canada.

    • Jeffrey S Mogil
    • , Robert E Sorge
    • , Michael L LaCroix-Fralish
    • , Shad B Smith
    • , Susana G Sotocinal
    • , Jennifer Ritchie
    • , Jean-Sebastien Austin
    • , Ara Schorscher-Petcu
    • , Kara Melmed
    •  & Jan Czerminski
  2. Emerillon Therapeutics, Montreal, Quebec, Canada.

    • Anny Fortin
  3. College of Dentistry, University of Florida, Gainesville, Florida, USA.

    • Rosalie A Bittong
    • , J Brad Mokris
    • , John K Neubert
    •  & Roger B Fillingim
  4. Department of Psychiatry and Behavioral Sciences, The Johns Hopkins School of Medicine, Baltimore, Maryland, USA.

    • Claudia M Campbell
    •  & Robert R Edwards
  5. Department of Neurosurgery, The Johns Hopkins School of Medicine, Baltimore, Maryland, USA.

    • James N Campbell
  6. National Institute of Mental Health, Bethesda, Maryland, USA.

    • Jacqueline N Crawley
  7. Department of Anesthesiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

    • William R Lariviere
    •  & Inna Belfer
  8. Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, USA.

    • Margaret R Wallace
  9. Department of Psychology, Haverford College, Haverford, Pennsylvania, USA.

    • Wendy F Sternberg
  10. Departments of Otolaryngology, Neurobiology, Communication Sciences and Disorders, and Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

    • Carey D Balaban

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Contributions

R.E.S., M.L.L.-F., S.G.S., J.R., J.-S.A., A.S.-P., K.M., J.C., R.A.B., J.B.M. and W.F.S. conducted the experiments. J.S.M., S.B.S., A.F., W.R.L., C.D.B., I.B. and R.B.F. performed data analyses. J.K.N., C.M.C., R.R.E., J.N. Campbell, M.R.W., I.B. and R.B.F. collected human phenotypic and genotypic data. J.N. Crawley provided transgenic mice and advice on their use. J.S.M., I.B. and R.B.F. supervised the project. J.S.M. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jeffrey S Mogil.

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DOI

https://doi.org/10.1038/nn.2941

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