Suppression of Nociceptive Responses by Spinal Mu Opioid Agonists

Effects of Stimulus Intensity and Agonist Efficacy

Abstract

 

To determine the influence of stimulation intensity on dose-response curves of three analgesics in halothane-anesthetized rats, continued immersion of the tail in 52.5°C or 60°C water for 15 s results first in a nociceptive reflex tail movement (tail flick = 2.8 ± 0.4s and 1.4 ± 0.2s, respectively), and a progressive increase in arterial blood pressure (ΔBP = 21 ± 1 and 24 ± 1 mm Hg) and heart rate (ΔHR = 27 ± 2 and 32 ± 2 beats/min). Intrathecally administered μ opioids, morphine (MOR), sufentanil (SUF), and [D-Ala2-N-Phe 4, Gly-ol]-enkephalin (DAG), produced a dose-dependent inhibition of the tail flick and BP response with the relative activity being SUF = DAG > MOR. Although the magnitude of the response evoked by increasing stimulus intensity from 52.5°C to 60°C was increased only mildly (suggesting that both represented essentially supramaximal stimuli), this increase in stimulus intensity resulted in a significant rightward shift in the doseresponse curves (decrease in apparent potency) of the three agonists, with the magnitude of the shift being MOR > SUF = DAG. Thus, the dose ratio (ED₅₀ at 60°C/ED₅₀ at 52.5°C) for these three analgesics given intrathecally on the tail flick and BP response was, respectively, 3.7 ± 0.9 and 6500 ± 465 for MOR; 0.5 ± 0.9 and 2.4 ± 0.9 for SUF; and 0.5 ± 1.2 and 7.0 ± 0.9 for DAG. Unlike SUF and DAG, with the 60°C stimulus, the highest dose of MOR failed to abolish the BP and heart rate response. Previous work with an irreversible antagonist to define receptor occupancy requirements showed that the relative efficacy was SUF = DAG >> MOR. The present studies thus confirm the pharma-codynamically based prediction that for a given change in stimulus intensity, anesthetics with a high efficacy (DAG and SUF) show less shift in their dose response curves with a given increase in stimulus intensity than an agonist with low efficacy (MOR).

(Anesth Analg 1993;77:265-74)