Effects of ondansetron administration1 on opioid withdrawal syndrome observed in rats
Introduction
Acute and chronic morphine administration to rats modifies serotonin metabolism and 5-HT receptor expression (Martin and Jasinski, 1977; Redmond and Krystal, 1984; Bhargava, 1994). Furthermore, the neurotransmitter serotonin has been demonstrated to be involved in the manifestation of some morphine withdrawal signs. In rodents, serotonin has been reported to affect wet-dog shake behaviour (Kruszewska and Langwinski, 1983) and to be associated with abstinence jumping (Samanin et al., 1980a, Samanin et al., 1980b; Van der Laan and Hillen, 1986). Additionally a role of serotonin has been evidenced in other withdrawal signs such as diarrhoea (Samanin et al., 1980a; Beubler et al., 1984) or hypothermia (Neal and Sparber, 1986b; Gulati and Bhargava, 1990). A reduction in the number of 5-HT receptors in the brain-stem of morphine-dependent rats has been reported (Samanin et al., 1980a). Furthermore during opioid abstinence a modified 5-HT subtype receptor expression is described in rats: 5-HT1 receptors appear to be up-regulated in certain brain regions; 5-HT1A receptors are down expressed in the hypothalamus but 5-HT2 receptors are not affected (Gulati and Bhargava, 1988, Gulati and Bhargava, 1989, Gulati and Bhargava, 1990).
Several authors have attempted to control the morphine withdrawal syndrome by using drugs capable of recognising the 5-HT receptors (Zifa and Fillon, 1992). The administration of 5-HT receptor agonists or antagonists appears to affect certain components of the opioid withdrawal syndrome. The administration of buspirone, a 5-HT1 receptor agonist, has been reported to attenuate opiate abstinence behaviour symptoms in rhesus monkeys (Aceto and Bowman, 1993). In particular, agents reported to have central serotoninergic agonist properties such as quipazine and meta-chlorophenylpiperazine (Samanin et al., 1980a), or a 5-HT2 receptor antagonist, mianserine (Neal and Sparber, 1986a), block the naloxone-induced jumping in morphine-dependent rats. Furthermore, cyproheptadine, a 5-HT2 receptor antagonist, reduces jumping precipitated by naloxone in morphine-treated rats (Cervo et al., 1981). Drugs exhibiting mixed 5-HT1 and 5-HT2 receptor antagonist activity, like methergoline, decrease jumping (Samanin et al., 1980b) or wet-dog shakes (Kruszewska and Langwinski, 1983) in morphine-dependent rats treated with naloxone or methisergide, and attenuate jumping and wet-dog shakes (El-Kadi and Sharif, 1995) in opioid-dependent mice injected with naloxone. The 5-HT1 receptor agonist, hydroxy-dipropyl-amino-tetraline (DPAT), induces hypothermia in abstinent rats (Gulati and Bhargava, 1990).
In addition the 5-HT2 receptor antagonists, ketanserin or pirenperone, have been reported to counteract the hypothermia induced by naloxone in morphine-treated rats (Neal and Sparber, 1986b) while the 5-HT1 and 5-HT2 receptor antagonist, cyproheptadine, aggravates hypothermia in dependent mice withdrawn from morphine (El-Kadi and Sharif, 1995). Additionally the 5-HT1 receptor agonist, meta-chlorophenylpiperazine (Samanin et al., 1980a) and the 5-HT2 receptor antagonist, ketanserin (Beubler et al., 1984), have been reported to block withdrawal diarrhoea in rats.
These findings suggest that serotonin is involved in the production of some withdrawal symptoms and also that several different 5-HT receptor agonists or antagonists decrease naloxone-precipitated withdrawal signs. There is thus a rational basis for seeking and using other 5-HT receptor-affecting agents for the control of opioid abstinence symptomatology. Since the autonomic signs appear to be a more sensitive index of the opioid withdrawal syndrome than are behavioural signs (Buccafusco et al., 1984), it is important to select an agent capable of interfering with behavioural, autonomic and somatosensitive signs. In particular, 5-HT3 receptor antagonists have been reported to interact with 5-HT3 receptors abundantly located on central nervous system dopaminergic neurones (Montgomery et al., 1993). Dopamine release in the nucleus accumbens stimulated by morphine is thus inhibited and the related behaviour is interfered with (Costall et al., 1987; Pei et al., 1993). Specifically the 5-HT3 receptor antagonist, ondansetron, reduces morphine self-administration in rats (Borg and Taylor, 1994) and modifies the morphine place preference conditioning (Acquas et al., 1988; Higgins et al., 1992).
Furthermore in animals and human subjects, ondansetron has been reported to interfere with motility of the gastrointestinal tract (Bradley et al., 1986; Talley et al., 1990; Lamers, 1991), and urinary bladder (Corsi et al., 1991) as well as the pain threshold levels (Giordano and Dyche, 1989; Sufka et al., 1992). Ondansetron was thus a possible candidate for controlling several deprivation signs and for the study of its effects on withdrawal symptoms such as altered faeces and urine excretion values, temperature and pain threshold levels, salivary, jumping and wet-dog shake behaviour.
We now report on the activities exerted by ondansetron on naloxone-precipitated withdrawal in morphine-dependent rats.
Section snippets
General procedures
Male Sprague–Dawley rats (Charles River, Calco) weighing 200±10 g were used in the experiments. The scheme of treatments with saline, morphine, naloxone, morphine plus naloxone and ondansetron is described in Fig. 1. The experiments were performed with four groups of 32 animals each: two groups received chronic saline and the other two received chronic morphine. Precipitated withdrawal was induced in one saline and one morphine group by injection of naloxone. The other two groups, which acted
Excretion of faeces
The changes in faeces excretion observed in all the groups of rats receiving saline, morphine, naloxone or morphine and naloxone are shown in Fig. 2. In the absence of ondansetron (dose 0) a marked increase of faeces excretion was observed in animals treated with morphine and naloxone when compared with all other groups (P<0.05, Tukey test, Fig. 2). Ondansetron administration to animals receiving naloxone, or morphine combined with naloxone significantly decreased faeces excretion (P<0.05,
Discussion
The combination of morphine and naloxone changed the rate of defecation and urination, the rectal temperature, latency times, salivation, jumping and wet-dog shakes as reported in literature (Martin and Jasinski, 1977; Redmond and Krystal, 1984; Bhargava, 1994). The data reported here not only confirm that naloxone precipitates physiological changes in morphine-dependent animals, but provides evidence that ondansetron administration prevents several of these withdrawal signs as discussed in
Conclusions
In the present study, ondansetron administration affected several individually analysed morphine withdrawal signs such as alteration of faeces excretion, pain threshold levels and also behaviour such as jumping and wet-dog shakes, although other authors have reported it to have no influence on salivation and wet-dog shakes in rats (Higgins et al., 1991). The effective doses of ondansetron in the present study were similar to those used in human therapy. Other reports have shown that ondansetron
Acknowledgements
The authors are grateful to Dr. Riccardo Spezia for statistical assistance. This research work was supported by: Regione Lombardia-Assessorato al Coordinamento dei Servizi Sociali-Milan (Italy). The experimental protocol and procedures have been performed according to the regulations of Italian law: D.L. No. 116, 27/01/1992 and with the approval of the local University Committee on Laboratory animals.
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- 1
Zofran is the trade name for ondansetron (injectable solution) manufactured by Glaxo SpA, Verona, Italy.