Susceptibility to opioid addiction is heritable in humans [6]. One dimension of addiction is physical dependence, which can be modeled in rodents. The jumping behavior displayed by morphine-dependent mice after administration of naloxone, a potent opioid receptor antagonist, is a commonly used measure of physical dependence. Naloxone-precipitated jumping is a highly heritable trait amongst inbred mouse strains [7], and the interstrain differences are largely independent of differences in the method of drug administration or the duration of treatment [8,9]. Furthermore, naloxone-precipitated withdrawal has been used to quantify opioid dependence in human volunteers [10]. Despite these facts, no specific genes linked to physical dependence have been identified. We, however, recently used a computational genetic mapping method [11,12] to successfully identify several genetic factors underlying the variability in morphine-induced alterations in pain sensitivity (hyperalgesia) and responsiveness to analgesic medications in mice [13-15]. We therefore investigated whether haplotype-based computational genetic mapping could identify genes affecting susceptibility to opioid dependence in mice, and whether a pharmacological agent targeting the human homolog of the computationally identified murine gene could alleviate the signs and symptoms of withdrawal in humans.
