| Riluzole (2-amino-6- trifluoromethoxy-benzothiazole) is a novel drug, which interfered with inhibition of glutamate acid releasing. It has neuroprotective, anticonvulsive, sedative and anxiolytic properties, but the mechanisms of action are not fully understood. Several effects have been demonstrated, including inhibition of glutamate release, indirect antagonism of excitatory amino acid receptors, stabilization of inactivated sodium channels and inhibition of presynaptic Y -aminobutyric acid (GABA) reuptake. These mechanisms are believed to be involved in the perception of pain and the function of opioids. What we are interested in is whether riluzole has effects on opioid functions like opioid function modulator. Therefore, our present study is designed to systematically observe the effects of riluzole on the morphine pharmacological functions, including pain threshold, morphine analgesia and morphine-induced tolerance in mice, as well as physical dependence in mice and rats and makes further research of its possible mechanism.1. In mouse acetic acid writhing test, writhing number was about 33.4 for vehicle within the period of 15 min after administration of acetic acid, riluzole (l0g/kg, sc) decreased the numbers of writhing to 30. In mouse heat radiation tail-flick assay, riluzole (l0g/kg) prolonged the tail-flick withdrawal latency from 3.2 to 3.7s, and in hot plate test, riluzole (l0mg/kg) prolonged the test latency from 13.3 to 17.3. These results indicate that riluzole given alone has no analgesic effect in mouse tail-flick latencies, mouse hot plate latencies and mouse acetic acid writhing test.2. In mouse acetic acid writhing test, morphine (Img/kg, sc) reduced thenumber of writhing from 33.4 to 19.5, and co-administration of riluzole (2.5 to lOmg/kg, sc) with morphine could further reduce the number of writhing. In heat radiation tail-flick assay, riluzole (l0mg/kg) enhanced morphine (5 mg/kg) analgesia by 13% to 73% in a dose-dependent manner and achieved statistical significance at high dose (l0mg/kg). hi hot plate test, administration of riluzole (sc) 20 min prior to morphine administration also had the statistical significance enhancement on morphine analgesia,3. In hot plate test, single dose of morphine (l00mg/kg, sc) induced acute tolerance indicated by the decrease in analgesic effect of l0mg/kg morphine. The PMAP of morphine (l0mg/kg, sc) was reduced from 93 % to 63 % (n = 10, P < 0.05). Administration of riluzole prior to morphine (l00mg/kg, sc) blocked the declination significantly. The PMAP of morphine (l0mg/kg, sc) in co-pretreatment with riluzole had no significant difference compared with that before pretreatment with morphine l00rng/kg, indicating that acute tolerance was blocked by riluzole. hi chronic tolerance experiment, riluzole inhibited the development of tolerance induced by sc morphine for 3d. When mice were pretreated with morphine alone, their responses to the analgesia of morphine l0mg/kg were decreased obviously. Co-administration of riluzole at 2.5, 5 and l0mg/kg with morphine prevented the decrease in the analgesic effect of morphine compared with those pretreated with morphine alone.4. After pretreatment of the mice with morphine (d,: 30, d,: 40, d3-5: 50 mg/kg, sc) for 5 days, naloxone (5 mg/kg, ip) induced an obvious abstinent syndrome indicated by withdrawal jumps, tremor, shaking, diarrhoea, micturition and loss in body weight. Administration of different dosages of riluzole 20 min prior to morphine evoked a dose-dependent inhibition of the syndrome, including the decrease of withdrawal jumping numbers and jumping percentage in the first 15 min and in loss in body weight of morphine-dependent mice in the first hour afteradministration of naloxone. In the model of repeated (30 mg/kg, tid, sc) administration of morphine for 3 days, naloxone (5 mg/kg, ip) was also able to induce an obvious abstinent syndrome. Riluzole could inhibit the abstinent syndrome significantly induced by naloxone like those mentioned above. These results indic...
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