Mapping of a quantitative trait locus for morphine withdrawal severity

• Published in: Mammalian genome 2004-08, Vol.15 (8), p.610-617
• Main Authors: Kest, Benjamin, Palmese, Christina A, Juni, Aaron, Chesler, Elissa J, Mogil, Jeffrey S
• Format: Article
• Language: English
• Subjects: Analgesics, Opioid - pharmacology; Animal populations; Animals; Drug Tolerance - genetics; Female; Genetics; Lod Score; Male; Mice; Morphine - pharmacology; Morphine Dependence - metabolism; Quantitative Trait Loci; Substance Withdrawal Syndrome - genetics; Substance Withdrawal Syndrome - metabolism
• ISSN: 0938-8990; 1432-1777
• DOI: 10.1007/s00335-004-2367-3

Chronic morphine exposure results in physical dependence, manifested by physical symptoms during naloxone-precipitated withdrawal. Jumping frequency is widely considered the most sensitive and reliable index of withdrawal intensity in mice. Inbred mouse strains surveyed for naloxone-precipitated withdrawal display large and significant strain differences in jumping frequency, including an approximately tenfold difference between C57BL/6 and 129P3 mice. In the present study, (B6 x 129)F2 hybrid mice were given daily morphine injections for four days using an escalating dosing schedule, and naloxone-precipitated withdrawal on day 5 was measured. A full-genome scan for linkage to phenotypic data was performed using polymorphic microsatellite markers. Significant linkage was observed between withdrawal jumping frequencies and a 28 cM-wide region of Chromosome 1 (32-60 cM; peak at 51 cM), accounting for 20% of the overall phenotypic variance. Two other suggestive QTLs were found, on Chromosomes 5 and 10, and an additive model fitting all three loci accounted for 43% of the total variance. F2 mice were also assessed for changes in morphine analgesic potency using the tail-withdrawal test in dose-response studies on days 1 and 4. No linkage was observed between Chromosomes 1, 5, and 10 and morphine analgesic tolerance, suggestive of genetic dissociation of naloxone-precipitated withdrawal from morphine and chronic morphine intake per se. The significant quantitative trait locus for naloxone-precipitated withdrawal severity in morphine-dependent mice, which we name Depmq1, may prove to be of considerable heuristic value once the underlying gene or genes are identified.