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

1 Spinal reflexes in the rabbit are suppressed tonically by endogenous opioids. The contributions made to this suppression by pl-, 6-and K-opioid receptors have been investigated by studying the actions ofa range of opioid antagonists and agonists on reflexes evoked by sural nerve stimulation in the ankle extensor gastrocnemius medialis (g.m.), and in the knee flexor semitendinosus (s.t.). 2 When given at a total dose of 88.5 pig kg-' i.v., either of the universal opioid receptor antagonists (-)-naloxone and (-)-quadazocine enhanced the g.m. response to more than 7 times the pre-drug control values, and the s.t. reflex to 1.5 times controls. The effects of quadazocine were stereospecific. The selective 6 antagonist ICI 174864 (3.5 mg kg-' i.v. total) also augmented the g.m. reflex but only to twice pre-drug controls.3 The p-agonists fentanyl (100 pg kg-') and morphine (50mg kg-') suppressed both g.m. and s.t. reflex responses to less than half control levels by a naloxone-reversible mechanism.4 The K-agonists bremazocine (50;pgkg-' total), tifluadom (100;pgkg-'), ethylketocyclazocine (200 pg kg-') and U50488H (1 mg kg-') potentiated the g.m. reflex and had variable effects on the s.t.response. Naloxone usually added to the facilitatory actions of these drugs. K-Opioid receptor agonists also caused a profound, naloxone-reversible depression of arterial blood pressure. 5 It may-be concluded that the endogenous opioid-mediated suppression of spinal reflexes in the rabbit is mediated mainly, if not exclusively, through p-receptors. There are no known endogenous ligands which are specific for the p-receptor, so in the present case it seems that selectivity is determined by the receptor population rather than by the ligand.

Section: The Effects Ofopioid Agonistsmentioning

confidence: 97%

The contributions of μ‐, δ‐and κ‐opioid receptors to the actions of endogenous opioids on spinal reflexes in the rabbit

Clarke¹,

Ford²

1987

“…The K-agonists U-50,488H and tifluadom Both of the K-opioids reduced responses to thermal noxious stimuli, on most cells at doses at the lower end of those used in behavioural tests of nociception (e.g. Romer et al, 1982a,b;Vonvoigtlander et al, 1983;Hayes et al, 1986;Leighton et al, 1988).…”

Section: The P-agonistfentanylmentioning

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.

“…It is effective in preventing p-receptor activation by opioids in both in vitro bioassay systems (Ward et al, 1982a;Hayes et al, 1985;Corbett et al, 1985) and in vivo (Ward et al, 1982b;Hayes et al, 1986;Takemori & Portoghese, 1987). Ligand binding studies in brain homogenates suggest that this action is due to an irreversible reduction in the number of opioid binding sites (Rothman et al, 1983;Ward et al, 1985;Tam & Liu-Chen, 1986), possibly due to Michael addition with a thiol function close to the ligand-recognition site (Tam & Liu-Chen, 1986).…”

mentioning

confidence: 99%

Alkylation with β‐funaltrexamine suggests differences between μ‐opioid receptor systems in guinea‐pig brain and myenteric‐plexus

Franklin

Traynor

1991