Genetic variation in morphine analgesic tolerance: A survey of 11 inbred mouse strains
Introduction
Prolonged or repeated morphine administration can result in analgesic tolerance, a diminution of morphine analgesic potency, magnitude, and/or duration. The development of tolerance to morphine, and concomitantly cross-tolerance to other clinically useful opioids, renders subsequent effective pain control difficult and unpredictable. Similar to morphine analgesia, there exists inter-individual variability among humans in response to chronic opioid treatment. Whereas some patients require rapidly escalating opioid doses in conjunction with escalating pain, others find adequate analgesia from stable opioid doses for periods of up to several months (Foley, 1993).
Studies comparing rodent strains have demonstrated the important contribution of genetic background to individual differences in the development and magnitude of tolerance Oliverio and Castellano, 1974, Ho et al., 1977, Gwynn and Domino, 1984, Mas et al., 2000. These studies however were based on data obtained exclusively from the same three inbred strains, typically compared two at a time, thereby limiting the analysis of variability in tolerance liability but also precluding the ability to perform a correlation analysis with other pain-related phenotypes that may be predictive of tolerance itself. Furthermore, there was substantial variability in methodology, including the duration of morphine treatment, the nociceptive assay utilized and/or parameters within even a given nociceptive assay. In almost all studies, only single morphine doses were tested after tolerance induction, precluding the generation of dose–response curves and the subsequent calculation of potency estimates upon which accurate comparisons can be made. The present study attempts a more comprehensive and systematic analysis of the genetic contribution to inter-individual differences in morphine analgesic tolerance. The morphine tolerance liability of 11 inbred mouse strains were determined by assessing the loss of relative analgesic potency through comparisons of half-maximal morphine analgesic dose (AD50) estimates obtained before and after chronic morphine treatment. By comparing many strains in a single study under identical experimental protocols, the present strain survey facilitates comparison between strains previously studied as well as those previously untested, and allows for the correlation of tolerance with other phenotypes such as baseline nociceptive sensitivity and morphine analgesia both before and after chronic morphine treatment.
Section snippets
Subjects and drugs
Male and female adult mice (n=18–20 mice per sex per strain) of the following inbred strains were obtained from The Jackson Laboratory (Bar Harbor, ME): 129P3, A, AKR, BALB/c, C3H/He, C57BL/6, CBA, DBA/2, LP, SJL, and SWR (all “J” substrains). All mice were housed four to a cage with same sex/strain mates in the College of Staten Island Animal Facility. Mice were allowed free access to food (Purina chow) and water in a temperature-controlled (22 °C) environment maintained on a 12:12-h
Baseline withdrawal latencies
There was a significant main effect of strain and sex (both P<.001) on baseline tail-withdrawal latencies, but no significant interaction (P=.40). Therefore, baseline tail-withdrawal latencies obtained before (Day 1) and after (Day 4) chronic morphine treatment are presented for all strains (collapsed across sex) and by sex (collapsed across strains) in Table 1. Withdrawal latencies varied significantly between strains on both Days 1 and 4 (both P<.001). Heritabilities of Days 1 and 4 baseline
Discussion
Studies of morphine tolerance utilizing inbred strains are relatively few, making comparisons and confirmations between studies difficult. Compounding the problem is the use of the same few strains, but with comparisons typically limited to two strains in each study. Among those for whom data are available are C57BL/6 and BALB/c mice, for which we observed approximately equal magnitudes of tolerance. Similar findings were obtained by treating subjects with both higher (Eidelberg et al., 1975)
Acknowledgements
This work was supported by PSC/CUNY 62313 (BK) and NIDCR DE12735 (JSM).
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