| Agmatine formed by the decarboxylation of L-Arginine by the enzyme L-arginine decarboxylase, has been postulated to be an endogenous ligand for imidazoline receptors (I-R). It has been proved by many experiments in mice and rats finished by our laboratory and some others that sc. agmatine enhances morphine analgesia, inhibits tolerance and substance dependence on morphine in vivo. All these effects of agmatine are based on activation of I-R and inhibition of the adaptation induced by chronic pretreatment of morphine. In this article, we are going to first observe the influence of agmatine administered by intragastric administration (ig) on enhancement of morphine analgesia, tolerance to and substance dependence on morphine in some kinds of animals including monkeys, to determine the mixture of agmatine and morphine, and to compared the potential to induce tolerance and substance dependence between the mixture and morphine in precondition of same analgesic potency.Section A Influence of ig agmtine on pharmacological effect of morphine1. Agmatine given by ig was able to reduce the wring times of mice stimulated by acetic acid compared with those of saline control in a does-dependent manner. However, in some serious mouse or rat experimental models, ig agmatine had no significant analgesia.2. In mouse, rat and monkey experiment models, agmatine given by ig enhanced morphine analgesia in a sound dose-dependent manner. In mouse heat radiation tail-flick assay and 55℃ hot plate assay, agmatine given by ig, at dose of 40mg/kg could reduce the ED50 of morphine analgesia by 40%. The enhancement of agmatine given by ig on morphine analgesia was not further potentiated at the dosage of over 40mg/kg. The same result was observed in rat heat radiation tail-flick assay. In monkey kalium ion permeation assay, ig agmatine 120mg/kg enhanced analgesic effect of morphine30mg/kg from 34% to 100%, which was as strong as that of ig morphine 70mg/kg.3. In mouse 55癈 hot plate assay and monkey kalium ion permeation assay, when animal were pretreated with morphine alone, their responses to the analgesia of ig morphine were decreased obviously, suggesting the formation of tolerance. Agmatine inhibited the tolerance to morphine in mice. Co-administration of agmatine at 40 mg/kg with morphine 70mg/kg prevented the decrease in the analgesic effect of morphine and kept morphine analgesic period two times as long as that pretreated with morphine alone. Agmtine (ig) could prevent the monkeys from the tolerance caused by pretretment with morphine for 9 days. Agmatine has no activity to induce tolerance.4. Chronic pretreatment of the mice, rats and monkeys with morphine administrated by ig could induce substance dependence, suggested by an obvious abstinent syndrome evoked by naloxone. Agmatine (ig) could prevent and cure the abstinent syndrome significantly in morphine dependent mice induced by naloxone. In the condition of ig agmtine 40 mg/kg, the mouse withdrawal jumping numbers was only half as much as those pretreated with morphine alone, the score of withdrawal syndrome of rats was only one third of the morphine group. In the condition of ig agmtine 40 mg/kg and 120 mg/kg, the score of withdrawal syndrome of monkeys was only half and one third of the morphine group.Section B Pharmacodynamics research on the mixture of agmatine and morphineOn the precondition of same analgesic potency, we compared the potential to induce tolerance and dependence between the mixture of agmatine plus morphine (mouse: agmatine 40mg/kg and morphine 50mg/kg; rat: agmatine 40mg/kg and morphine 20mg/kg; monkey: agmatine 120mg/kg and morphine 30mg/kg) and morphine (mouse: morphine 70mg/kg; rat: morphine 30mg/kg; monkey: morphine 70mg/kg) In chronic experiment the mixture kept analgesic effect (PMAP>40%) for over 27 days, which was much longer than that of morphine which kept analgesic effect only 10 days in mice andrats. In monkeys no tolerance occurred in the group pretreated by the mixture in 7 days experiment, otherwise analg... |
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