Differential right shifts in the dose-response curve for intrathecal morphine and sufentanil as a function of stimulus intensity

Abstract

To assess effects of stimulus intensity, dose-response curves in rats for radiant heat-evoked withdrawal of the hind paw was assessed after the intrathecal (i.t.) injection of sufentanil and morphine, mu-opioid agonists differing in intrinsic activity, at Low, Medium, and High stimulus intensities. Baseline latencies observed at the 3 intensities were: low = +/- 0.3; medium = 8.9 +/- 0.2; high = 5.7 +/- 0.1 sec. After i.t. administration of sufentanil or morphine, there was a right shift in the dose-response curves with morphine exhibiting a greater magnitude right shift than that of sufentanil. Dose ratios (ED 50 Medium/ED 50 Low and ED 50 High/ED 50 Low) with 95% CI for sufentanil were, respectively, 2.5 (2.2-2.9) and 7.7 (6.7-8.9), and the dose ratio for morphine (ED 50 Medium/ED 50 Low) was 34 (28-41). At the highest intensity, due to a plateau in the morphine dose-response curve, ED 50 and dose ratio calculations could not be performed. The present study supports the pharmacological model of receptor occupancy, such that the higher efficacy receptor agonist, sufentanil, demonstrated a lesser magnitude right shift than the lower efficacy agonist, morphine, while at the high stimulus intensity, morphine but not sufentanil, was a partial agonist.

Use of Irreversible Antagonists to Determine the Relative Efficacy of μ-Opioids in a Pigeon Drug Discrimination Procedure: Comparison of β-Funaltrexamine and Clocinnamox

“…The quantitative efficacy estimates for sufentanil and l-methadone were also higher than that for morphine and are in agreement with other reports indicating that in assays of antinociception, sufentanil is more resistant than morphine to irreversible antagonism, chronic opioid administration, and increases in nociceptive stimulus intensity (Mjanger and Yaksh, 1991;Dirig and Yaksh, 1995). The present finding that the relative efficacy of fentanyl is comparable with morphine contrasts with findings indicating that fentanyl is less sensitive to antagonism by ␤-FNA and C-CAM than morphine (Adams et al, 1990;Comer et al, 1992;Holtzman, 1997;Morgan and Picker, 1998).…”

The Heritability of Antinociception: Common Pharmacogenetic Mediation of Five Neurochemically Distinct Analgesics

“…It is difficult to see why opioid or cannabinoid tone would affect analgesic potency of other compounds, however. Elmer et al (1997) instead argue for a serial mechanism and point to studies suggesting that a direct relationship exists between stimulus intensity and the fractional receptor occupancy (i.e., the proportion of receptors currently bound by ligand) required to produce antinociception (Dirig and Yaksh, 1995). In their study and the present one, mouse strains more sensitive to nociception effectively experience a higher stimulus intensity, which would thus necessitate a higher dose of analgesic.…”

Morphine Antinociceptive Potency on Chemical, Mechanical, and Thermal Nociceptive Tests in the Rat

“…Not surprisingly, experiments in which the cutoff values are the same despite different stimulus intensities tend to conclude that high-intensity stimuli reduce morphine potency. 4,18 We dealt with this problem by applying a consistent cutoff of 4 standard deviations greater than the control group mean for all of the tests. The cutoff values for intense nociceptive stimuli are noticeably lower than the cutoff values for tests using less-intense stimuli (see Table 1), but the probability of an animal randomly reaching the cutoff value is the same across all tests.…”