Morphine-induced motor stimulation, motor incoordination, and hypothermia in adolescent and adult mice

Rationale Given evidence for age-related differences in the effects of drugs of abuse, surprisingly few preclinical studies have explored effects of opioids in adolescents (versus adults). Objectives This study compared the motor stimulating, ataxic, and hypothermic effects of morphine in adolescent, late adolescent, and adult mice. Plasma and brain levels of morphine were assessed to examine possible pharmacokinetic differences among the age groups. Methods Locomotion was measured as occlusions of horizontal infrared light beams, ataxia as failing the horizontal wire test, body temperature by rectal probe, and morphine levels by HPLC-UV. Results Morphine (3.2-56 mg/kg, i.p.) increased locomotion along an inverted U-shaped dose-response curve in adolescent, late adolescent, and adult male C57BL/6J mice. Its potency to stimulate locomotion was similar in all age groups. However, maximal stimulation was higher in adolescents than in late adolescents, and higher in late adolescents than in adults. In contrast, adolescents showed less ataxia than adults when given morphine (5.6-100 mg/kg, i.p.). The hypothermic effects of morphine did not differ among the age groups. Morphine levels, which peaked in plasma at 15 min and in brain at 45 min after i.p. injection, did not show age-related differences. Conclusions The finding that adolescents are not generally more sensitive to morphine than adults, but differ in their sensitivity to effects involving nigrostriatal/mesolimbic dopamine systems, is consistent with evidence of overactivity of these dopamine systems during adolescence relative to adulthood. The age-related differences observed here are unlikely due to pharmacokinetic factors.