INTERACTIONS BETWEEN METOCLOPRAMIDE AND MORPHINE: ENHANCED ANTINOCICEPTION AND MOTOR DYSFUNCTION IN RATS

Abstract

1. Opioid analgesics and anti-emetics are often used concomitantly to treat pain and nausea and vomiting in people with malignant disease. We investigated interactions between the opioid analgesic morphine and the anti-emetic metoclopramide, a dopamine D2 receptor antagonist, on nociception and gross motor function. 2. To assess for antinociceptive interactions, 11 Sprague-Dawley rats were injected intraperitoneally with morphine (5.0 mg/kg) or saline in combination with metoclopramide (0.5, 1.5 and 5.0 mg/kg) or saline and, 30 min later, the tail-flick latencies to a noxious thermal stimulus (49 degrees C water) were measured. Immediately thereafter we induced reperfusion hyperalgesia in the rats' tails using a tourniquet cuff and tested nociception again. Because, in addition to its ability to block D2 receptors, metoclopramide is also a weak 5-HT(3) receptor antagonist, we assessed in a further 11 rats whether any antinociceptive interactions occurred between morphine (5.0 mg/kg) and ondansetron (0.2 and 2.0 mg/kg), an anti-emetic that selectively antagonizes 5-HT(3) receptors. To assess for motor interactions, we injected another group of nine rats with morphine (5.0 mg/kg) or saline in combination with metoclopramide (0.5 and 5.0 mg/kg) or saline and tested the ability of the animals to run on an 80 mm diameter rod rotating at 25 r.p.m. for 30 min. 3. Metoclopramide was not inherently analgesic or antihyperalgesic, but the highest dose of metoclopramide (5.0 mg/kg) enhanced the analgesic and antihyperalgesic effects of morphine. Neither dose of ondansetron was analgesic or antihyperalgesic or enhanced the antinociceptive actions of morphine. 4. Only the high dose of metoclopramide compromised running performance when administered with saline. However, coadministering morphine with metoclopramide (both doses) decreased motor performance. 5. Therefore, metoclopramide, possibly through its actions on D2 receptors and not 5-HT(3) receptors, enhances the analgesic and antihyperalgesic effects of morphine, but morphine exacerbates metoclopramide-induced motor dysfunction in rats.