Effect of morphine-induced catalepsy, lethality, and analgesia by a benzodiazepine receptor agonist midazolam in the rat.

Previously we have shown that intrathecal administration of midazolam can increase or decrease morphine-induced antinociception, depending upon relative concentration of these drugs by modulating spinal opioid receptors, and it also can inhibit morphine-induced tolerance and dependence in the rat. Now we report that midazolam also influences catalepsy, lethality, and analgesia induced by morphine in the rat. In the acute treatment, animals were first treated with saline or midazolam (0.03 to 30.0 mg/kg, b.wt., IP), and 30 min later with a second injection of saline or morphine (1.0 to 100.0 mg/kg, b.wt., SC). The catalepsy was measured 60 min after the second injection and lethality was checked after 24 h. Midazolam injection increased the morphine-induced catalepsy and lethality. In the chronic treatment, animals were injected with two injections daily for 11 days. The first injection consisted of saline or midazolam (0.03 to 3.0 mg/kg, b.wt., IP), and 30 min later with a second injection of saline or morphine (10.0 mg/kg, b.wt., IP) was given. Lethality, antinociception, and body weight were measured. Chronic morphine treatment also increased lethality in a dose-dependent manner. Chronic treatment with midazolam and morphine increased the antinociception on day 11, as measured in the tail-flick and hot-plate tests. Midazolam administration also prevented the morphine-induced weight loss. These results suggest a strong interaction between midazolam and morphine in altering catalepsy, lethality, and analgesia in rat.