DIFFERENTIAL RIGHT SHIFTS IN THE DOSE-RESPONSE CURVE FOR INTRATHECAL MORPHINE AND SUFENTANIL AS A FUNCTION OF STIMULUS-INTENSITY

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 = 14.5 +/- 0.3; medium = 8.9 +/- 0.2; high = 5.7 +/- 0.1 sec. After i.t, administration of sufentanil or morphine, there was a dose-dependent, naloxone-reversible elevation in nociceptive threshold. With increased stimulus intensity, 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.