Elucidation of dose-effect relationships for different opiate effects using alfentanil in the spontaneously ventilating rat

Abstract

In addition to producing antinociception and mild sedation, opiates diminish spontaneous movement and produce muscle rigidity. Examination of the relationship between different opiate effects may lead to a better understanding of the mechanism and sites of action of opiate anesthesia. Previous studies have compared the dose-effect relationships for morphine and fentanyl between antinociception and loss of righting reflex. However, neither muscle rigidity nor lack of spontaneous movement (as measured by catalepsy) has been fully examined or directly compared with either antinociception or loss of righting reflex. This study, therefore, compared five clinically relevant opiate endpoints (antinociception, muscle rigidity, catalepsy, loss of righting reflex, and respiratory depression) using the μ- selective agonist alfentanil in the spontaneously ventilating rat. Rats were randomized to receive alfentanil (0-500 μg/kg) subcutaneously. For muscle rigidity, 59 rats had electromyographic activity measured with percutaneous hindlimb electrodes. After alfentanil injection, electromyographic data were recorded for 60 min. For antinociception and catalepsy, 49 rats were studied for 120 min after alfentanil. Catalepsy was measured from the time the rat's forelimbs were placed on a 10-cm-high bar until either limb was removed. Antinociception was studied by measuring tail-flick response to hot (55° C) water. For righting reflex, 40 rats were studied for 120 min. Alfentanil- induced respiratory depression was assessed in 40 rats with indwelling tail arterial catheters. Alfentanil was administered after baseline arterial blood gas measurements, and then additional samples were obtained for 45 min. For each effect, data were converted into quantal responses and were then transformed to probit-log dose-response curves for analysis. There were no significant differences in the slope of the dose-response relationships between the four endpoints studied. The effective dose in 50% of animals (ED50) for antinociception (46 μg/kg) differed significantly from that for catalepsy (114 μg/kg), elevation of Pa(CO2) (146 μg/kg), and loss of righting reflex (215 μg/kg), and the ED50 for muscle rigidity (62 μg/kg) differed significantly from that for elevation of Pa(CO2) and loss of righting reflex. The results are discussed in the context of other data on the opioid receptors' mediation of different opiate effects. These techniques and the data obtained will aid in the elucidation of the pharmacology of different opiate effects and their underlying receptor mechanisms.