Identification of a sex-specific quantitative trait locus mediating nonopioid stress-induced analgesia in female mice

Jeffrey S. Mogil, Susan P. Richards, Laurie A. O'Toole, Melinda L. Helms, Steve R. Mitchell, Benjamin Kest, John K. Belknap

Research output: Contribution to journalArticlepeer-review

96 Scopus citations


It is increasingly appreciated that the sexes differ in their perception of noxious stimuli and in their responsivity to exogenous and endogenous analgesic manipulations. We previously reported the existence of qualitative sex differences in the neurochemical mediation of nonopioid (i.e., naloxone- insensitive) stress-induced analgesia (SIA) produced by forced swims and suggested that female mice possess a sex-specific SIA mechanism. This female- specific system is now known to be estrogen-dependent, to be ontogenetically organized, and to vary with reproductive status; however, its neurochemical identity remains obscure. In an attempt to identify candidate genes underlying SIA in both sexes, we performed a two-phase quantitative trait locus (QTL) mapping experiment using the BXD/Ty recombinant inbred (RI) set derived from DBA/2J (D2) and C57BL/6J (B6) inbred mouse strains and (B6xD2)F2 hybrid mice derived from these same progenitors. All mice were subjected to 3 min forced swims in 15°C water; nociceptive sensitivity on the 54°C hot-plate assay was assessed immediately before and 2 min after cessation of the swim. We report the localization of a QTL statistically associated with SIA magnitude [p = 0.00000012; logarithm of the odds (LOD) = 6.1] in female mice only. This female-specific QTL, which we name Fsia1, is located on chromosome 8 at 52-84 cM from the centromere and accounts for 17- 26% of the overall trait variance in this sex. The present data provide further evidence of the existence of a female-specific SIA mechanism and highlight the important role of both genetic background and gender in the inhibition of pain.

Original languageEnglish (US)
Pages (from-to)7995-8002
Number of pages8
JournalJournal of Neuroscience
Issue number20
StatePublished - 1997
Externally publishedYes


  • Antinociception
  • Gene mapping
  • Genetics
  • Non-opioid
  • Pain
  • Quantitative trait locus
  • Sex differences
  • Stress-induced analgesia

ASJC Scopus subject areas

  • Neuroscience(all)


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