INHIBITION OF MORPHINE-INDUCED TOLERANCE AND DEPENDENCE BY A BENZODIAZEPINE RECEPTOR AGONIST MIDAZOLAM IN THE RAT

We investigated whether midazolam administration influenced morphine-i nduced antinociception and tolerance and dependence in the rat. Antino ciception was assessed by the tail-flick (TF) and the hot-plate test ( HP 52-degrees-C). Morphine tolerance developed after daily single inje ctions of morphine for 11 days. The effect of midazolam on morphine-in duced antinociception and tolerance was assessed by giving daily injec tions of various doses of midazolam for 11 days. The first injection o f saline or midazolam was given intraperitoneally and 30 min later mor phine (10 mg/kg body weight) was administered subcutaneously. Antinoci ception was monitored by measuring TF and HP latencies 60 min after th e second injection. Midazolam was injected at four different concentra tions: 0.03, 0.1, 0.3, and 3 mg/kg body weight. Chronic administration of morphine resulted in the development of tolerance to antinocicepti on in both TF and HP tests, with rats exhibiting baseline antinocicept ion on Day 9. Animals treated with midazolam alone showed little antin ociception on Days 3-9. However, midazolam administration in morphine- treated animals attenuated morphine-induced tolerance to antinocicepti on on Days 1-11 as measured by the tail-flick test. Midazolam also dec reased the jumping behavior following naloxone injections in morphine- dependent rats. These results suggest that midazolam may prolong the e ffects of morphine by delaying morphine-induced development of toleran ce to antinociception. Midazolam also attenuated a decrease in weight gain induced by chronic injections of morphine.