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

Nat Neurosci. 2011 Oct 23;14(12):1569-73. doi: 10.1038/nn.2941.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics / therapeutic use*
  • Animals
  • Animals, Newborn
  • Capsaicin / adverse effects
  • Deamino Arginine Vasopressin / therapeutic use
  • Disease Models, Animal
  • Female
  • Genetic Association Studies
  • Habituation, Psychophysiologic / drug effects
  • Habituation, Psychophysiologic / genetics
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Molecular Weight
  • Pain / chemically induced
  • Pain / drug therapy*
  • Pain / genetics*
  • Pain / physiopathology*
  • Pain Measurement / drug effects
  • Pain Measurement / methods
  • Pain Threshold / drug effects*
  • Pain Threshold / physiology
  • Polymorphism, Single Nucleotide / genetics
  • Quantitative Trait Loci
  • Receptors, Vasopressin / deficiency
  • Receptors, Vasopressin / genetics
  • Sex Factors
  • Stress, Psychological / genetics
  • Stress, Psychological / physiopathology
  • Vasopressins / therapeutic use*


  • Analgesics
  • Receptors, Vasopressin
  • Vasopressins
  • Deamino Arginine Vasopressin
  • Capsaicin