A KCNJ6 (Kir3.2, GIRK2) gene polymorphism modulates opioid effects on analgesia and addiction but not on pupil size

KCNJ6 coding for potassium inwardly rectifying channels (Kir3.2, GIRK2) is important for opioid receptor transmission. The KCNJ6 rs2070995 AA genotype has been associated with increased opioid analgesic requirements in Japanese. We analyzed its consequences for other opioid effects.Genotyping was done in 85 methadone-substituted former heroin addicts, 352 opioid-treated chronic pain patients, and in 51 healthy volunteers where miotic effects of levomethadone had been measured. Expression of Kir3.2 in the Edinger-Westphal nucleus of rat brains was analyzed by means of immunohistochemistry.Average daily methadone substitution doses during the first therapy year were larger in the AA genotype (n=4, 119.7+/-49.6 mg/day) than in other rs2070995 genotypes (77.5+/-26.2 mg/day, P=0.003) whereas AA carriers lacked opioid withdrawal symptoms. A similar tendency toward less opioid effectiveness was observed toward higher opioid dosing demands for analgesia in the AA genotype (n=17, opioid dose 2.03+/-0.45 log mg oral morphine equivalents per day, controls: 1.81+/-0.52 log mg oral morphine equivalents/day, P=0.093). In contrast, no pharmacogenetic effects were observed on miotic opioid effects. This could be traced back to the absence of Kir3.2 from the Edinger-Westphal nucleus in rat brains, a key cerebral structure governing pupil constriction.The association of the KCNJ6 rs2070995 AA genotype with increased opioid requirements extends from analgesia to opiate substitution therapy. Opioid induced miosis is exempted for molecular histological reasons.