PREVENTION BY THE 5-HT3 RECEPTOR ANTAGONIST, ONDANSETRON, OF MORPHINE-DEPENDENCE AND TOLERANCE IN THE RAT

1 The effect of ondansetron, a selective 5-hydroxytryptamine(3) (5-HT3 ) receptor antagonist, was studied in morphine-addicted rats. Morphine -dependence and tolerance, induced by drinking increasing concentratio ns of morphine sulphate in 5% sucrose solution for 3 weeks, were demon strated by the naloxone-precipitated withdrawal syndrome and tail flic k response to a thermal noxious stimulus (water at 50 degrees C), resp ectively. 2 Morphine-dependence, assessed by naloxone precipitated wit hdrawal, was undetectable by the 6th day, when the animals drank only tap water for 7 days after the 3-week induction period. 3 When detoxif ied rats were offered sucrose and morphine solutions for 10 days, the recurrence of opiate solution preference with relapse to dependence an d tolerance was observed. 4 Giving ondansetron (0.1 or 1 mu g kg(-1); i.p.; twice daily) on the 14th day of, or 7 days prior to, the 3-week induction period reduced dependence and tolerance seen during the 3-we ek morphine induction and the 10-day drinking preference periods. 5 5- Hydroxytryptamine(2) (5-HT2) receptor antagonism by cyproheptadine (10 0 or 250 mu g kg(-1); i.p.; twice daily) did not influence morphine-de pendence and tolerance. 6 These findings suggest that ondansetron may be useful for treating opiate addiction and lowering the recidivism ra te.