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Of Stress, Pain, Gender, and the Arginine Vasopressin Receptor

Variations in the vasopressin-1A receptor combine with stress level and gender to affect sensitivity to pain. Mogil et al. have unearthed an intriguing interaction between gender, stress, and variants of the gene encoding the vasopressin-1A receptor (V1AR) in sensitivity to pain. Different inbred mouse strains show phenotypically distinct responses to pain, enabling Mogil et al. to build on their previous work employing quantitative trait locus (QTL) mapping to implicate a 3.4-Mb region of mouse chromosome 10 containing 11 unique transcripts in strain-dependent sensitivity to formalin (an assay of inflammatory pain). Haplotype mapping enabled localization of the QTL to a region upstream of Avpr1a, which encodes V1AR, and quantitative real-time reverse-transcription polymerase chain reaction showed increased Avpr1a expression in a pain-resistant strain compared with a pain-sensitive strain. Moreover, Avpr1a–/– mice displayed enhanced responsiveness to inflammatory pain. Genotypic analysis of two single-nucleotide polymorphisms (SNPs) in the human AVPR1A gene in a cohort of volunteers in whom sensitivity to inflammatory capsaicin-induced pain had been assessed revealed no genetic association of either SNP with overall mean pain ratings. However, for rs10877969, a SNP in the AVPR1A promoter, there was a three-way interaction between genotype, stress level, and gender: For male subjects reporting stress at the time of testing, those with the AA genotype rated pain higher than those with the GG or GA phenotype. Moreover, the ability of a synthetic form of vasopressin (desmopressin) to decrease capsaicin-induced pain also depended on perceived stress (low stress was associated with desmopressin analgesia, with the clearest relationship between stress and analgesia apparent in rs10877969 AA men). Experiments in mice revealed a similar dependence of vasopressin-induced analgesia on stress, with vasopressin effectively reducing pain in mice habituated to the environment but not in nonhabituated mice. Further analysis indicated that stress itself had an analgesic effect and that this depended on Avpr1a. Whereas nonhabituated male Avpr1a–/– mice displayed enhanced responsiveness to inflammatory pain, as previously noted, this enhanced sensitivity was not apparent in habituated mice, and the difference in pain sensitivity between male mice in strains with high or low expression of Avpr1a was lost when mice were habituated. The authors thus conclude that vasopressin, acting through V1AR, mediates stress-induced analgesia, with the efficacy of the response depending on gender and AVPR1A genotype. Wiltshire et al. provide commentary. J. S. Mogil, R. E. Sorge, M. L. Lacroix-Fralish, S. B. Smith, A. Fortin, S. G. Sotocinal, J. Ritchie, J.-S. Austin, A. Schorscher-Petcu, K. Melmed, J. Czerminski, R. A. Bittong, J. B. Mokris, J. K. Neubert, C. M. Campbell, R. R. Edwards, J. N. Campbell, J. N. Crawley, W. R. Lariviere, M. R. Wallace, W. F. Sternberg, C. D. Balaban, I. Belfer, R. B. Fillingim, Pain sensitivity and vasopressin analgesia are mediated by a gene-sex-environment interaction. Nat. Neurosci. 14, 1569–1573 (2011). [PubMed] T. Wiltshire, W. Maixner, L. Diatchenko, Relax, you won’t feel the pain. Nat. Neurosci. 14, 1496–1497 (2011). [PubMed]