Genetic variation in morphine analgesic tolerance

Abstract

The present study assessed the analgesic potency of morphine in 11 inbred mouse strains before and after chronic morphine treatment. Using the 49 °C tail-withdrawal test, significant strain differences in morphine AD₅₀ estimates derived from cumulative dose–response curves were noted prior to tolerance induction on Day 1. AD₅₀ estimates were reassessed on Day 4, after three daily systemic morphine injections for 3 days using an escalating dose schedule (10, 20, and 40 mg/kg sc). In 9 of 11 strains, morphine potency was significantly reduced from 2-fold to as much as 11-fold. Two strains (129P3 and LP) displayed no evidence whatsoever of tolerance development. Neither initial baseline withdrawal latency nor morphine analgesic sensitivity was significantly correlated with tolerance magnitude. Also observed were strain-dependent alterations (mostly hyperalgesia) in baseline tail-withdrawal latencies as a result of chronic morphine treatment. The magnitude of hyperalgesia and analgesic tolerance was significantly correlated among strains, implicating common genetic substrates and supporting their proposed association. The present work demonstrates that the presence and magnitude of morphine analgesic tolerance is genotype-dependent and identifies strains with widely divergent liabilities that should facilitate identification of trait-relevant genes.

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.