Determination of the receptor selectivity of opioid agonists in the guinea‐pig ileum and mouse vas deferens by use of β‐funaltrexamine

1 The effect of the irreversible opioid receptor antagonist, P-funaltrexamine (fi-FNA), on antinociception produced by p-and K-receptor agonists was studied in the rat.2 P-FNA, 20 to 80 mg kg-, s.c., given 24 h before testing, produced a dose-related antagonism of the effects ofmorphine in the paw pressure, hotplate and tail-flick tests. Following the 80 mg kg-' dose, the degree ofantagonism ofmorphine was stable for up to 48 h after dosing, but was reduced by 5 days and had disappeared by 8 days.3 In the paw pressure test, P-FNA, 40 mg kg ', s.c., antagonized the effects of fentanyl, buprenorphine, tifluadom, ethylketocyclazocine and proxorphan; it was without effect against the highly selective K-agonist, U-50,488.4 In light of these results, the possible opioid receptor selectivities of both the agonists and P-FNA are reassessed.

Section: Discussionmentioning

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Reversal by β‐funaltrexamine of the antinociceptive effect of opioid agonists in the rat

Hayes

Skingle

Tyers

1986

“…Fentanyl was chosen as the p-agonist; for its receptor selectivity in binding tests see Magnan et al (1982). U-50,488H (trans-3,4- Leander, 1983;Vonvoigtlander et al, 1983;Burkard, 1984;Hayes et al, 1985;. Drug doses refer to fentanyl and ketamine bases, tifluadom hydrochloride and U-50,488 methane sulphonate.…”

Section: Drugs Drug Administration and Analysismentioning

confidence: 99%

Spinal antinociceptive actions of μ‐ and κ‐opioids: the importance of stimulus intensity in determining ‘selectivity’ between reflexes to different modalities of noxious stimulus

Parsons

Headley

1989

1In electrophysiological experiments in spinalized rats, y-and K-opioids were tested intravenously on the responses of single motoneurones to electronically controlled, alternating noxious heat and noxious pinch stimuli. The effects of u-and K-opioids were compared with those of the general anaesthetic x-chloralose and the dissociative anaesthetic/PCP ligand ketamine. 2 The K-opioids U-50,488 (0.5-16 mg kg'-i.v.) and tifluadom (0.05-1.6 mg kg-1 i.v.) had very similar actions to the p-opioid fentanyl (0.5-16 pg kg '-i.v.). Thus all three agonists reduced thermal and mechanical nociceptive reflexes in parallel and in a dose-dependent manner, but only so long as neuronal responses to the alternating stimuli elicited similar excitability levels in the neurone under study. Ketamine (0.5-16mgkg-1 i.v.) had similar actions to the opioids whereas a-chloralose (20 mg kg -i.v.) had very little effect on neuronal responsiveness. 3 Apparently 'selective' depressions by both p-and K-opioids could be orchestrated by a deliberate mismatch of the intensities of alternating noxious heat and pinch stimuli; as measured by neuronal firing rate, the weaker of the responses to either type of stimulus was invariably reduced to a greater degree. 4 Similar 'selectivity' could be demonstrated for both p-and K-ligands when the weaker and stronger responses were of the same modality, being applied by the same pincher device but with alternating applied force. 5 It is concluded that the 'selective' spinal actions of K-opioids seen in non-thermal over thermal behavioural models of nociception is likely to be related to the relative intensities, rather than the modalities, of the noxious stimuli used. The validity of the interpretation of results obtained in such behavioural studies is discussed.

“…explained much of the data available at the time, recent findings suggest that the hypothesis should be re-examined. In particular, two of the drugs which are ineffective in heat models of nociception, nalbuphine and buprenorphine, have been shown to act predominantly at the p-receptor (Leander, 1983a;Miller et al, 1986;Hayes et al, 1985).…”

Section: Introductionmentioning

confidence: 99%

Differential sensitivity of antinociceptive tests to opioid agonists and partial agonists

Shaw

Rourke

Burns

1988

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.