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Mapping of a quantitative trait locus for morphine withdrawal severity

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Abstract

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 × 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.

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Acknowledgments

This work was supported by PSC/CUNY (BK), CSI/IBR Center for Developmental Neuroscience (CAP, AJ), and NIH grants DA15191 and DE12735 (JSM).

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Authors and Affiliations

  1. Department of Psychology and Center for Developmental Neuroscience, The College of Staten Island, City University of New York, Staten Island, New York, 10314, USA

    Benjamin Kest

  2. Neuropsychology Doctoral Subprogram, Queens College, City University of New York, Flushing, New York, 11367, USA

    Benjamin Kest, Christina A. Palmese & Aaron Juni

  3. Department of Anatomy and Neurobiology, Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, 38163, USA

    Elissa J. Chesler

  4. Department of Psychology and Centre for Research on Pain, McGill University, Montreal, Quebec, H3A 1B1, Canada

    Jeffrey S. Mogil

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  1. Benjamin Kest
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  2. Christina A. Palmese
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  5. Jeffrey S. Mogil
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Correspondence to Benjamin Kest.

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Kest, B., Palmese, C.A., Juni, A. et al. Mapping of a quantitative trait locus for morphine withdrawal severity. Mamm Genome 15, 610–617 (2004). https://doi.org/10.1007/s00335-004-2367-3

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