Identification of a Sex-Specific Quantitative Trait Locus Mediating Nonopioid Stress-Induced Analgesia in Female Mice

Abstract

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 femalespecific 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)F 2 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 ϭ 0.00000012; logarithm of the odds (LOD) ϭ 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. Key words: sex differences; genetics; antinociception; stressinduced analgesia; gene mapping; quantitative trait locus; nonopioid; painIt is well known that the C NS contains circuitry that evolved to inhibit ascending nociceptive signals. These endogenous pain inhibition mechanisms can be activated by direct electrical stimulation or pharmacologically, but they evolved to be activated by exposure to environmental stressors, a phenomenon known as stress-induced analgesia (SIA) (Kelly, 1986). Multiple SIA systems are known to exist; in the simplest dissociation they can be divided into opioid or nonopioid forms, on the basis of their sensitivity to antagonism by the prototypic opioid receptor blockers naloxone or naltrexone (Lewis et al., 1980;Watkins and Mayer, 1982;Terman et al., 1984).It is possible to observe opioid or nonopioid SIA after the application of the same laboratory stressor by altering stress severity parameters. For instance, in Swiss-Webster mice, swims of longer duration and /or colder temperature produce increasingly nonopioid SIA, that is, SIA increasingly refractory to naloxone/naltrexone antagonism Mogil et al., 1993Mogil et al., , 1996b but see Tierney et al., 1991).Much is known regarding the neurochemical and anatomical details of endogenous opioid pain inhibition mechanisms (Basbaum and Fields, 1984). Opioid peptide neurotransmitters are released and act on opioid recep...

Genetic analysis of the stress-responsive adrenocortical axis

“…Several of our QTLs are in homologous or overlapping regions with previously identified QTLs for glucocorticoidrelated phenotypes (see Table 8) as well as QTLs for behavioral responses to stress. For example, Srcrt-3/Sradr-3 is in an overlapping region with a rat QTL for basal Cort (27) and a rat QTL for expression of a stress-induced heat shock protein (15) and lies in the homologous region for several stress-induced behavioral QTL in mice (24,40,45). Srcrt-1 is in a region homologous to a QTL for human fasted cortisol (25) as well as a QTL previously identified for Cort in response to ethanol consumption in mice (29).…”

“…To date, QTLs have been detected for several physiological and/or behavioral responses to various stressors (e.g., Refs. 12,14,21,24,40). QTLs for basal corticosterone (Cort) levels have also been identified (20,25,27).…”

The melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans

“…However, estrogen appears to be permissive rather than modulating, because females are MK-801 insensitive at all stages of the estrous cycle (6). To shed light on the genetic and neurochemical basis of sex-specific analgesia, we used quantitative trait locus (QTL) mapping to investigate swim SIA in both sexes of a (C57BL͞6J ϫ DBA͞ 2J)F 2 intercross (B6D2F2) (7). QTL mapping is a technique in which the coinheritance of continuous traits and polymorphic DNA markers (e.g., microsatellites or single nucleotide polymorphisms) can be used to broadly identify the chromosomal location of genes responsible for trait variability (8).…”

β-Endorphin and Alcoholism

“…It is widely appreciated that females have lower incidence of alcoholism than males (Hunt and Zakhari, 1995), and these differences are theorized to manifest differences in coping response between sexes (Hettema et al, 2003). A burgeoning body of research supports the contention that females are more sensitive to stress than males (see Kleim et al, 2010;Maestripieri et al, 2010;Paris et al, 2010;Pratchett et al, 2010 for recent reviews of the human literature and Bangasser et al, 2010;Mogil et al, 1997;and Palanza 2001 for some basic research findings). For example, females, whose use and abuse of alcohol are increasing dramatically, also appear to be more sensitive to stress-induced changes in EtOH sensitivity (see Greenfield et al, 2010;Hudson & Stamp, 2010;PrzybycienSzymanska et al, 2010;Sartor et al, 2010).…”