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Pain sensitivity and vasopressin analgesia are mediated by a gene-sex-environment interaction

Nature Neuroscience volume 14, pages 1569–1573 (2011)Cite this article

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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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Figure 1: Haplotype mapping localizes Nociq2 to a region of distal chromosome 10 upstream of Avpr1a.
Figure 2: Functional evidence for Avpr1a's involvement in pain.
Figure 3: Genetic association of a SNP in AVPR1A (rs10877969) to capsaicin pain ratings.
Figure 4: Evidence for the interaction of stress with desmopressin analgesia in 36 human subjects.
Figure 5: Interaction of AVP/V1AR-mediated analgesia and stress in male mice.

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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.

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Author notes

  1. Inna Belfer and Roger B Fillingim: These authors contributed equally to this work.

Authors and 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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  1. Jeffrey S Mogil
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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.

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Correspondence to Jeffrey S Mogil.

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Mogil, J., Sorge, R., LaCroix-Fralish, M. et al. Pain sensitivity and vasopressin analgesia are mediated by a gene-sex-environment interaction. Nat Neurosci 14, 1569–1573 (2011). https://doi.org/10.1038/nn.2941

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