Differential sensitivity of antinociceptive tests to opioid agonists and partial agonists

Abstract

1 The antinociceptive activity of a range of opioid agonists and agonist-antagonist analgesics was determined in mice by use of the 550C hot plate and abdominal constriction assays. 2 Opioid agonists were approximately 10 times more effective in the abdominal constriction assay. 3 The agonist-antagonists produced analgesia only in the abdominal constriction assay, and antagonized the antinociceptive action of opioid agonists in the 550C hot plate test. 4 These differences were shown to be attributable to the different levels of stimulus employed in the two tests. 5 By comparing the antagonist potencies of the agonist-antagonists in the 550C hot plate test with their antinociceptive ED50 values in the abdominal constriction assay, an index of intrinsic activity was calculated.

Discriminative stimulus effects of two doses of fentanyl in rats: pharmacological selectivity and effect of training dose on agonist and antagonist effects of mu opioids

“…Apparent pA 2 values for naltrexone antagonism of fentanyl were similar in rats trained with 0.01 mg/kg fentanyl (7.7) or 0.04 mg/kg fentanyl (7.6). These values are consistent with previous studies of naltrexone as an antagonist of stimulus, rate-altering and analgesic effects of morphine or fentanyl (Dykstra et al 1988;Shaw et al 1988;Dykstra 1990;Walker et al 1994;Walker et al 1996). In agreement with studies of naltrexone antagonism of stimulus effects of morphine, the present results suggest that antagonist potency does not change as a function of training dose of high efficacy agonists (Young et al 1992;Picker et al 1993;Vanecek and Young 1995).…”

“…In generalization tests, mu agonists, a selective kappa agonist, and selected non-opioids were studied for their potency and ability to evoke low-dose or high-dose responses. Mu opioids tested included those that display agonist effects under a wide range of conditions and others that display agonist effects under more limited conditions (Martin and Jasinski 1977;Shaw et al 1988;France and Woods 1990). When a compound evoked different maximal percentages of low-dose and high-dose responses, its ability to antagonize stimulus and rate-altering effects of fentanyl was examined and apparent pA 2 values were determined.…”

Sex and rat strain determine sensitivity to κ opioid-induced antinociception

“…Previous investigations indicate that in assays sensitive to the effects of κ opioids bremazocine and nalorphine can produce submaximal effects and antagonize the effects of more efficacious κ opioids (Leander 1983;Shaw et al 1988;Dykstra 1990;Hunter et al 1990;France et al 1994;Zhu et al 1997;Bidlack and Jadrovski 1999;Cook et al 2000b). Such findings suggest that bremazocine and nalorphine may have low relative efficacy at κ opioid receptors.…”

Pentazocine-Induced Antinociception Is Mediated Mainly by μ-Opioid Receptors and Compromised by κ-Opioid Receptors in Mice

“…Only one difference existed between antinociception to mechanical pain and antinociception to thermal pain in that high-dose pentazocine produced some antinociception to mechanical pain while not producing any significant antinociception to thermal pain. However, several lines of evidence show that KOR agonists or mixed agonist-antagonists with KOR agonistic property exert differential actions on thermal and nonthermal nociceptive stimuli, i.e., they do not inhibit thermal nociceptive responses while inhibiting mechanical as well as visceral chemical nociceptive responses (Schmauss et al, 1983;Schmauss, 1987;Fü rst, 1991;Yaksh, 1997), probably because of differences in neuronal pathways involved in thermal and nonthermal nociceptive information possessing different classes of opioid receptors (Tyers,1980) and/or differences in the intensity of the noxious stimulus and the intrinsic activity of the drug (Delaney et al, 1986;Shaw et al, 1988). Therefore, it seemed plausible that highdose pentazocine produced some antinociception to mechanical pain mediated by KORs as a result of complex interaction between coactivated MORs and KORs, while producing no antinociception to thermal pain by the same mechanisms.…”