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Title: Receptor mechanisms involved in opioid-induced respiratory depression in the rat
Author: Yeadon, Michael
ISNI:       0000 0001 3574 8746
Awarding Body: University of Surrey
Current Institution: University of Surrey
Date of Award: 1988
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1. The physiology of mammalian respiration and the pharmacology of the potent, synthetic opioids, the fentanyls, are reviewed. The current knowledge of the opioid receptor sub-type involvements in opioid-induced respiratory depression is summarised, together with the experimental methods which have previously been employed in studies of receptor involvement. 2. The comparative binding characteristics of the mu opioid receptor selective ligand [3H]-[D-Ala2-MePhe4-Glyol5] enkephalin ([3H]- DAGO) and the delta receptor ligand [3H]-[D-Pen2,D-Pen5] enkephalin ([3H]-DPDPE) were studied in homogenates of both whole brain and of pons/medulla regions from the rat. The receptor affinities and site-selectivities of five drugs of the fentanyl series (alfentanil, carfentanil, fentanyl, lofentanil and sufentanil) were determined by inhibition studies, using [3H]-DAGO and [3H]-DPDPE as markers of the mu and delta opioid binding sites, respectively. The concentration of delta opioid sites in pons/medulla was found to be approximately one third that of mu sites. The concentrations of both mu and delta sites in whole brain were similar to that of ? sites in pons/medulla. The rank order of affinities of the unlabelled drugs was dissimilar at the mu and delta sites. The most potent fentanyl derivatives exhibited negligible preference for the mu or delta sites, in contrast to the least potent compound, alfentanil, which showed an extremely high mu-site selectivity. 3. The respiratory depressant properties of the fentanyls were investigated in urethane-anaesthetised rats. Ventilatory parameters were measured using a volumetric pressure transducer connected via a Fleisch tube to a tracheal cannula. Intravenous administration of the fentanyls produced an apnea of immediate onset and dose-related duration, in addition to depressing both tidal volume and respiratory frequency, and thus minute volume, in a dose-related manner. The potency ratios of the fentanyls to produce apnea and to depress minute volume were dissimilar. Studies of the effects of alfentanil on arterial blood gases confirmed the reduction in minute volume to be a respiratory depression. 4. A method was developed for the quantification of antagonism of the respiratory effects of opioids by means of infusion of the opioid antagonist, naloxone, to predicted steady-state blood concentrations, which provided accurate measures of pA2. The basis of the technique rests upon determination of the plasma clearance of the antagonist whence appropriate loading doses and zero order infusion rate constants were calculated. The predicted concentrations of naloxone were verified by direct serum measurements using HPLC. 5. Naloxone pA2 values for antagonism of the apnea produced by the fentanyls were identical and indicated sole mediation by the mu opioid receptor, which was confirmed by intravenous administration of receptor-selective opioids. Apnea was produced by DAGO but not by DPDPE or U69,593. This component of the response was shown to be peripherally-mediated and vagally dependent, being abolished by bilateral vagotomy and the quaternary opioid antagonist, N-methyl levallorphan. 6. Naloxone pA2 values for antagonism of the minute volume depressant effects of the fentanyls showed significant differences through the series, implying both a mu and non-mu receptor involvement in this centrally-mediated response, which could still be elicited after vagotomy. A k receptor contribution to respiratory depression was eliminated by investigation of the respiratory effects of U69,593 and U50,488H. The involvement of the delta receptor was suggested by the finding that intracerebroventricular administration of DPDPE produced respiratory depression which was blocked by high doses of naloxone. 7. A study of the cardiovascular effects of the fentanyls confirmed that the different naloxone pA2 values for depression of respiration could not be attributed to this influence. 8. In conclusion, the binding site selectivities of the drugs of the fentanyl series varied inversely with their affinities at the mu and delta sites. In vivo studies have demonstrated that mu receptors alone in the periphery mediate the apneic responses to intravenously administered opioids. Whilst mu receptors in the brain are the most important in the mediation of the minute volume depressant effects of the fentanyls another receptor, possibly delta, contributes to this response. This non-mu contribution is different for each of the fentanyl drugs, broadly in accord with their binding site selectivity exhibited in vitro.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Opioids respiratory effects