Opiate‐like Analgesic Activity in General Anaesthetics

Abstract

1 The interaction of naloxone with various anaesthetics was studied both in vivo and in vitro.2 Naloxone (10mg/kg) did not significantly alter the anaesthetic duration of halothane, diethylether, ketamine, pentobarbitone or Althesin.3 Naloxone (10 mg/kg) reduced the analgesic activity of nitrous oxide, ketamine and morphine in the rat tail-flick test. With the exception of pentobarbitone and Althesin, the other anaesthetic agents also induced analgesia but were not antagonized by naloxone. (IC50 = 40 nM). 6 On the stimulated guinea-pig ileum, Met-enkephalin and morphine inhibited the contractions, the IC50 values were 30 nm and 50 nm respectively. The anaesthetics ketamine (IC50 = 10 FM) and Althesin (IC50=8,UM) were active. Xylazine (IC50=12nM) exhibited considerable potency in inhibiting the contractions on this preparation. Naloxone 0.5 p.M produced a 1000 fold shift in the opiate dose-response curve but the anaesthetic responses showed only slight sensitivity to antagonism by naloxone. 7 The activity of Althesin was found to be due to the vehicle in which this anaesthetic is solubilised.8 Whilst several anaesthetic agents showed analgesic activity, specific dihydromorphine binding displacement or guinea pig ileum inhibiting activity, these effects showed variable sensitivity to naloxone.

Do inhalation general anesthetic drugs induce the neuronal release of endogenous opioid peptides?

“…This was confirmed by another study in which naloxone failed to alter the MAC values for halothane, enflurane and isoflurane (Levine et al, 1986). However, comparable doses of naloxone markedly reduced the antinociceptive effect of ketamine and nitrous oxide but not halothane, diethylether or xylazine (Smith et al, 1978;Lawrence and Livingston, 1981). In another study, naloxone and naltrexone asymmetrically shortened the sleeping times induced by ketamine, halothane, or pentobarbital; high-dose naltrexone was less effective than lower doses in producing this analeptic effect suggesting this action was unrelated to blockade of opioid receptors (Kraynack and Gintautas, 1982).…”

“…Naloxone failed to alter the duration of anesthesia induced by halothane, diethylether, ketamine pentobarbital, Althesin (a mixture of alphaxalone and alphadolone) or hyperbaric nitrous oxide as determined by recovery of righting reflex (Bennett, 1978;Smith et al, 1978;Lawrence and Livingston, 1981). This was confirmed by another study in which naloxone failed to alter the MAC values for halothane, enflurane and isoflurane (Levine et al, 1986).…”

INTERACTIONS OF DRUGS ACTIVE AT OPIATE RECEPTORS AND DRUGS ACTIVE AT α2‐RECEPTORS ON VARIOUS TEST SYSTEMS

“…Xylazine has been shown to possess activity in the rat tail flick analgesic test and to be capable of displacing radiolabelled dihydromorphine in rat brain membrane preparations (Lawrence & Livingston, 1981a). Clonidine has been shown to reverse withdrawal symptoms in opiate addicts (Gold, Redmond & Kleber, 1978) and an overlap in the distribution of x2-adrenoceptors and opiate receptors in the rat brain has been demonstrated autoradiographically (Young & Kuhar, 1979;.…”

“…The object of this study was to investigate the interactions between the drugs which react with a2-receptors and those which exert their effects via Guinea-pig ileum bioassay: portions of guinea-pig ileum were suspended in an organ bath in Krebs bicarbonate solution as described by Paton & Vizi (1969 Pert & Snyder (1973) as described by Lawrence & Livingston (1981a) …”

Apneustic respiration of ketamine is not antagonized by naloxone in the cat.

“…The relation of the opiate system to ketamine anesthesia and analgesia is uncertain. Some reports showed that these effects were blocked by the opiate antagonist naloxone (STELLA et al, 1981;FINCK and NGAI, 1982), whereas others found no evidence for such an action (LAWRENCE and LIvINGsToN, 1981;WILEY and DOWNS, 1982). The role of the opiate system in the respiratory effect of ketamine has not yet been elucidated.…”