Localization to chromosome 10 of a locus influencing morphine analgesia in crosses derived from C57BL/ and DBA/2 strains

Belknap, John K.; Mogil, Jeffrey S.; Helms, Melinda L.; Richards, Susan P.; O’Toole, L. A.; Bergeson, Susan E.; Buck, Kari J.

doi:10.1016/0024-3205(95)02040-p

Cited by 91 publications

(54 citation statements)

References 20 publications

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“…A reanalysis of this data set by sex revealed disparities in the apparent strength of the correlation in males versus females in one of these QTL regions, the D8Rik78 region of chromosome 8 (Table 3). None of these QTL regions were similar to those identified previously for baseline hot-plate nociception or morphine analgesia (Belknap and Crabbe, 1992;Belknap et al, 1995).…”

Section: Bxd Ri Qtl Analysissupporting

confidence: 76%

“…Genomic DNA was isolated from spleen by a modification of the protein salting-out method (Miller et al, 1988), as described in Belknap et al (1995). Microsatellites were amplified in 96-well microtiter plates using a modification of standard PCR procedures (Dietrich et al, 1992) with unlabeled commercially available marker primers (Research Genetics, Huntsville, AL).…”

Section: Methodsmentioning

confidence: 99%

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

et al. 1997

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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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Section: Bxd Ri Qtl Analysissupporting

confidence: 76%

Section: Methodsmentioning

confidence: 99%

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

et al. 1997

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“…Confirmation of the strain difference between B6 and D2 mice in oral morphine preference (Belknap, 1990;Belknap et al, 1993) was followed by a quantitative genetic study that mapped a major locus for the trait to chromosome 10 (Berrettini et al, 1994b). This QTL for oral morphine preference, termed Mop2, was confirmed in a follow-up study (Alexander et al, 1996) and support was generated for the concept that it had a broader influence with regard to the pharmacological effects of morphine being involved also in determining morphine-induced analgesia and the density of [ 3 H]naloxone binding sites in the brain (Belknap et al, 1995). Subsequent mapping of the Mu opioid receptor gene (Oprm) to the same chromosomal location as the Mop2 QTL (Kozak et al, 1994;Giros et al, 1995) focused attention on this gene as a strong candidate for mediating differences in opioid-related effects between B6 and D2 mice.…”

Section: Discussionmentioning

confidence: 97%

Confirmation of a Major QTL Influencing Oral Morphine Intake in C57 and DBA Mice Using Reciprocal Congenic Strains

Ferraro

Golden

Smith

et al. 2004

Neuropsychopharmacol

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C57BL/6 (B6) and DBA/2 (D2) mice exhibit disparate behavior when tested for voluntary morphine intake in a two-bottle choice drinking paradigm with B6 mice consuming 10 times more drug than D2 mice. Previous genetic mapping studies identified a locus, Mop2, on the proximal part of chromosome 10 that explained over half of the genetic variance in this mouse model of opioid selfadministration. We constructed a set of reciprocal congenic strains between B6 and D2 mice in which the proximal portion of chromosome 10 has been introgressed from one strain onto the background of the other. We tested mice from this pair of reciprocal strains together with progenitor B6 and D2 mice in a two-bottle choice drinking paradigm with morphine and quinine. The results showed that introgression of chromosome 10 alleles from the B6 strain onto a D2 genetic background increased voluntary morphine intake four-fold compared to progenitor D2 mice. Preference for morphine was also increased significantly in D2.B6-Mop2 mice compared to progenitor D2 mice. Conversely, introgression of chromosome 10 alleles from the D2 strain onto a B6 genetic background decreased morphine intake by half compared to progenitor B6 mice in B6.D2 -Mop2 mice; however, high morphine preference was maintained in this congenic strain most likely due to strong quinine aversion. When quinine was eliminated from the control bottle, morphine preference in B6.D2-Mop2 mice was decreased significantly relative to B6 and D2.B6-Mop2 mice. Overall, these data confirm the existence of a gene(s) on chromosome 10 proximal to D10Mit124 that has a strong influence on the difference in morphine drinking behavior between B6 and D2 mice.

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“…Studies of quantitative trait loci in mice identified a chromosomal region containing the opioid receptor gene as contributing to a substantial amount of the variance in analgesic and reward responses to morphine (Belknap and Crabbe, 1992;Berrettini et al, 1994;Kozak et al, 1994;Belknap et al, 1995;Crabbe et al, 1999). Also, studies of mice with targeted deletion of the opioid receptor gene definitively established this receptor as essential for morphine analgesia, physical dependence, and reward as measured by antinociception, withdrawal, conditioned place preference, and self-administration studies (Matthes et al, 1996;Sora et al, 1997;Kitanaka et al, 1998;Loh et al, 1998;Becker et al, 2000).…”

Section: Selected Identified Genesmentioning

confidence: 99%

Pharmacogenetics and Human Molecular Genetics of Opiate and Cocaine Addictions and Their Treatments

et al. 2005

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Localization to chromosome 10 of a locus influencing morphine analgesia in crosses derived from C57BL/ and DBA/2 strains

Cited by 91 publications

References 20 publications

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

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

Confirmation of a Major QTL Influencing Oral Morphine Intake in C57 and DBA Mice Using Reciprocal Congenic Strains

Pharmacogenetics and Human Molecular Genetics of Opiate and Cocaine Addictions and Their Treatments

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