Prevention by the 5‐HT₃ receptor antagonist, ondansetron, of morphine‐dependence and tolerance in the rat

Abstract

1 The effect of ondansetron, a selective 5-hydroxytryptamine3 (5-HT3) receptor antagonist, was studied in morphine-addicted rats. Morphine-dependence and tolerance, induced by drinking increasing concentrations of morphine sulphate in 5% sucrose solution for 3 weeks, were demonstrated by the naloxone-precipitated withdrawal syndrome and tail flick response to a thermal noxious stimulus (water at 50'C), respectively. 2 Morphine-dependence, assessed by naloxone precipitated withdrawal, was undetectable by the 6th day, when the animals drank only tap water for 7 days after the 3-week induction period. 3 When detoxified rats were offered sucrose and morphine solutions for 10 days, the recurrence of opiate solution preference with relapse to dependence and tolerance was observed. 4 Giving ondansetron (0.1 or 1 Mig 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-week morphine induction and the 10-day drinking preference periods. twice daily) did not influence morphine-dependence and tolerance. 6 These findings suggest that ondansetron may be useful for treating opiate addiction and lowering the recidivism rate.

Chronic morphine drinking establishes morphine tolerance, but not addiction in Wistar rats

“…However, those experiments were testing the animals only regarding their morphine tolerance and their behavior after naloxone injection, hence leave the question unanswered if the rats were really addicted to morphine. While some reports (Borg and Taylor, 1994;Hui et al, 1996) indicate that the chronic morphine drinking can indeed establish a drug-craving-like condition, other studies could not confirm this finding (Hinson et al, 1986;Jurna et al, 1992). Also the present study shows that the chronic morphine drinking does not lead to addiction due to the lack of a strong rewarding effect of the drug; however, the morphine-drinking model might give different findings according to the experimental setting of factors like the duration of treatment, the employed dose or the animal type.…”

“…Concerning the treatment period, most articles describing the use of morphine in the drinking water are consistent regarding a treatment for 3 weeks (Borg and Taylor, 1994;Fábián et al, 2003;Hui et al, 1996;West et al, 1997), but as the first week is normally used to increase the morphine concentration stepwise, the rats receive the final morphine concentration only for two weeks. In contrast, the Wistar rats of this study were receiving the same daily dose of morphine during the entire treatment period of 3 weeks.…”

“…Several animal models are established to investigate the influence of morphine, and in most of these models morphine is either given intravenously or subcutaneously by injection or infusion (Hutchings and Dow-Edwards, 1991). All these application methods are part of a chronic treatment for several days or weeks, and the impact of the opiate is usually verified by detecting the presence of morphine tolerance and morphine dependence (Hui et al, 1996;Itoh et al, 1998). Tolerance is investigated by injecting morphine acutely and checking for a reduced sensitivity regarding pain during a tail immersion or hot-plate test, while dependence is investigated by injecting the morphine antagonist naloxone and recording the expression of signs of withdrawal (e.g.…”

“…In contrast to applying morphine by injection or infusion, other models feature an oral intake of the drug by adding morphine into the drinking water (Hui et al, 1996;Fábián et al, 2003). Such an approach offers the possibility to detect addiction, especially regarding the rewarding effect of the drug, much clearer-after a treatment phase and a phase of withdrawal, the animals are tested regarding their drinking preference by offering two bottles as their drinking source, with one bottle without and one with morphine (Borg and Taylor, 1994).…”

“…For example, Hui et al(1996) as well as Borg and Taylor (1994) reported that morphine-treated rats preferred after a withdrawal period the morphine solution more than a morphine-free solution, but Hinson et al(1986) and Jurna et al(1992) could not detect this preference. In addition, while some studies indicate that morphine-drinking rats show both morphine tolerance and signs of withdrawal after injection of naloxone (Gellert and Holtzman, 1978;Hui et al, 1996), others could not confirm the development of tolerance (Jurna et al, 1992). Accordingly, this study aimed to figure out if the chronic consumption of morphine in the drinking water could lead to morphine tolerance and addiction-generating rewarding effects.…”