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...

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The inbred mouse strains, DBA/2J (D2) and C57BL/6J (B6), display differential sensitivity to acute, thermal nociception as measured on the hot-plate (HP) assay. In an ongoing quantitative trait locus (QTL) mapping study designed to reveal genomic loci showing genetic linkage to HP sensitivity, a putative QTL on chromosome 4 (50-80 cM from the centromere) has been identified that appears to account for variability in this trait in male, but not female mice. An obvious candidate gene located in this same chromosomal region is Oprd1, which encodes the murine delta-opioid receptor. In an attempt to evaluate whether Oprd1 represents this sex-specific QTL for HP sensitivity, we tested D2 and B6 mice of both sexes for HP latencies (hindpaw-lift, -lick or -flutter) following systemic injections of saline, or the opioid receptor antagonists naloxone (NAL; 0.1 and 10 mg/kg), nor-binaltorphimine (nor-BNI; 5 mg/kg), naltrindole (NTI; 5 mg/kg), 7-benzylidenenaltrexone (BNTX; 0.7 mg/kg), or naltriben (NTB; 1 mg/kg). High-dose (10 mg/kg) NAL lowered HP latencies in D2, but not B6 mice, suggesting that the higher HP latencies exhibited by D2 mice reflect opioid mechanisms. HP latencies in both strains and both sexes were unaffected by pretreatment with low-dose (0.1 mg/kg) NAL or nor-BNI, suggesting that neither mu nor kappa receptors affect basal nociceptive sensitivity. The delta-receptor antagonist, NTI, and the delta2-specific antagonist, NTB, (but not the delta1-specific antagonist, BNTX) effectively lowered HP latencies in a strain- and sex-dependent manner: D2 male > B6 male > D2 female > B6 female. These data support the possibility that Oprd1 is a QTL mediating HP sensitivity in mice, and more generally illustrate the important roles of genetic background and gender in the perception of pain.

Short-term selective breeding starting from an F2 intercross of two inbred strains is a largely unexploited but potentially useful tool for quantitative trait locus (QTL) mapping. The selection lines can also serve as a valuable confirmation test of recombinant inbred (RI) QTL results when the same two progenitor strains are used. Starting from an F2 from a C57BL/6J (B6) X DBA/2J (D2) cross (B6D2F2), this approach was used in a population of approximately 72 mice per generation bidirectionally selected for two-bottle choice 10% ethanol (alcohol) preference for four generations. The high-preference line diverged significantly from the low line in the first generation with a realized heritability of .32. By generation 4, the preference ratios in the high line were double those seen in the low line. Regions of the genome previously implicated by BXD RI QTL analysis as containing QTLs were searched using microsatellite markers. The test for the presence of QTLs was based on the divergence of marker allele frequencies in the two oppositely selected lines significantly exceeding that expected from random (genetic) drift and allele frequency estimation error. Combining the BXD and two-way selection line results, the most probable QTL was found on chromosome 3 (near the adhl locus; LOD approximately 2.9), other probable QTLs were found with LOD 2.4-2.6.

MEDECS, the mediterranean ecosystem simulator, was developed to model the dynamics of mediterranean- type vegetation in southern California and central Chile. MEDECS is a difference/differential-equation model which simulates the seasonal patterns of resource use and plant response in one-day time steps. It uses submodels of plant growth, decompo sition, and inorganic nutrient release to describe the effects of physiological processes, nutrient availability, and environmental parameters. MEDECS is a compartmental model of the producer-decomposer system. In use, it simulates the seasonal progres sion of changes in each of the compartments. It is being used in on-going research to examine hypotheses about single-species and multiple-species (competi tive) communities of plants.