A Genetic Analysis of Opioid-induced Hyperalgesia in Mice

BACKGROUND: Opioid-induced hyperalgesia (OIH) is a syndrome of increased sensitivity to noxious stimuli, seen after both the acute and chronic administration of opioids, that has been observed in humans and rodent models. This syndrome may reduce the clinical utility of opioids in treating acute and chronic pain. METHODS: In these studies, the authors measured the propensity of 15 strains of inbred mice to develop mechanical manifestations of OIH. These data were subjected to in silico genetic analysis, which resulted in the association of haplotypic blocks within or near several known genes. Both pharmacologic agents and transgenic mice were used to confirm the functional association of the most strongly linked gene with OIH. RESULTS: Both baseline mechanical nociceptive thresholds and the percentage changes in these thresholds after 4 days of morphine treatment were found to be highly strain dependent. The haplotypic blocks most strongly associated with the mechanical OIH data were located within the beta2 adrenergic receptor gene (beta2-AR). Using the selective beta2-AR antagonist butoxamine, the authors observed a dose-dependent reversal of OIH. Furthermore, deletion of the beta2-AR gene sharply reduced the mechanical allodynia present after morphine treatment in the wild-type mouse strain. Analysis of the associated beta2-AR haplotypic block identified single nucleotide polymorphisms potentially explaining in part the strain specific differences in OIH. CONCLUSIONS: Genetic variants of the beta2-AR gene seem to explain some part of the differences between various strains of mice to develop OIH. The association of this gene with OIH suggests specific pharmacologic strategies for reducing the impact of OIH on patients consuming opioids.