Early methylphenidate exposure enhances morphine antinociception and tolerance in adult rats

Methylphenidate (MPH) is often used to reduce the symptoms of Attention-Deficit/Hyperactivity Disorder. Early MPH treatment in rats has been shown to enhance adult morphine-induced antinociception. Although this enhanced antinociception could improve pain treatment, it could also lead to enhanced tolerance to morphine. This hypothesis was tested by examining the effects of MPH administration during the pre-weanling period on morphine-induced antinociception and tolerance in adulthood. Male and female Sprague-Dawley rats received daily IP injections of saline or MPH (2 or 5 mg/kg) for 10 consecutive days beginning on post-natal day (PD) 11. At 60 days of age, morphine (0, 1.8, 3.2, 5.6, 10.0, and 18 mg/kg) antinociception was assessed. Beginning one day later, rats received two daily injections of either saline or morphine (5 mg/kg) for two consecutive days to induce tolerance. On PD 63 cumulative doses of morphine were administered as before to assess the development of tolerance. Rats pretreated with MPH showed enhanced acute morphine antinociception compared to saline pretreated controls. In addition, tolerance to morphine was greater in rats pretreated with MPH early in life. The magnitude of this decrease in morphine potency was dependent on the dose of MPH, such that animals that received 5 mg/kg of MPH from PD 11 to 20 showed the greatest tolerance. These findings demonstrate that MPH exposure during the pre-weanling period has long-lasting effects that include enhanced morphine antinociception and tolerance.