Mechanism of opioid-mediated respiratory depression

Abstract

An outline of the history of the development of knowledge concerning the physiological effects of opioids is given as a basis for exploration of the phenomenon of suppression of respiration by these agents. Early observations of the sleep-inducing qualities of opium were followed by recognition that its purified forms had a particular effect in reducing the ventilatory efforts of humans and other mammals, leading to apnea and death if administered acutely in large doses, Two discoveries within the last quarter-century were significant for the understanding of the pharmacological action of opioids on the nervous system: the identification of binding sites—now considered receptor molecules—for opiates in the brain by three groups of investigators in 1973 (Pert & Snyder; Simon, Hiller & Edelman; Terenius), and the identification of endogenous opioid ligands, beginning with the enkephalins in Kostelitz' laboratory in 1975 (Hughes, Smith, Morgan & Fothergill). The medulla oblongata is thought to contain regions necessary for the generation of a signal which drives the muscles of respiration (Legallois, 1812; Lumsden, 1923). Information on the localization of opioid peptides and opioid receptors in this and other parts of the central nervous system involved in respiratory rhythmogenesis is reviewed. Electrophysiological and neuroanatomical experiments on the cellular basis for the action of opioids on respiratory spinal and brainstem neurons are described. Cells were recorded extracellularly in the medulla of anesthetized rats and defined as vagal motoneurons, bulbospinal respiratory neurons or propriobulbar neurons on the basis of their axonal projections and as inspiratory or expiratory by the relationship of their firing patterns to that of the phrenic nerve. Bolus injections of alfentanil, a short acting mu opioid agonist, were given intravenously (8-24μg/kg). In the phrenic nerve signal, frequency and burst amplitude were reduced by about 50% after an initial central apnea and there was a biphasic effect on inspiratory burst duration which had an initial shortening followed by a lengthening which outlasted other changes. Phasic activity of the Superior Laryngeal nerve was more sensitive to alfentanil than that of the Phrenic. Naloxone caused no changes in recorded variables but caused a long-lasting blockade of the effects of alfentanil. Frequency effects of alfentanil were quantitated in thirty-five tests in twenty-eight extracellularly recorded units. The greatest reduction in firing frequency was seen in inspiratory bulbospinal neurons. Inspiratory units were depressed more than expiratory units and both vagal motoneurons and bulbospinal units were reduced in frequency more than propriobulbar units, which were suppressed less than the central respiratory drive as a whole, as measured by the phrenic nerve output, suggesting that the opioidergic effect on breathing occurs by one or more of the following: direct inhibition of inspiratory bulbospinal neurons, presynaptic inhibition of excitatory inputs or activation of inhibitory interneurons. In the anatomical studies phrenic motoneurons and medullary respiratory cells were injected with 2% biocytin or 1% biotinamide after intracellular recordings. The sections of tissue containing labelled cells were also stained immunohistochemically for enkephalin in axon terminals, and microscopic reconstructions of the cell surfaces were made to assess the density of enkephalinergic inputs. Close appositions between enkephalin positive terminals and labelled respiratory cell membranes were examined under high magnification as an indication of synaptic inputs. The density of enkephalinergic close appositions on dendrites of phrenic neurons increased with distance from the soma, but was low in comparison with the density of serotoninergic contacts on the same cells reported in a previous study (Pilowsky, de Castro, Llewellyn-Smith, Lipski & Voss, 1990). At three reconstructed bulbospinal respiratory neurons close appositions of enkephalin immunoreactive boutons were rare, suggesting that opioidergic input at dendrosomatic receptors of medullary bulbospinal neurons is not the primary source of suppression of respiration A model of the mammalian brainstem mechanism originating the respiratory command signal is described containing rhythm-and pattern-forming elements in a single module. It is proposed that the respiratory rhythm generating mechanism contains a core of cells with pacemaker properties which in the adult are normally entrained by the activity of the surrounding network. The effect of opioids in reducing the neural command to respiratory muscles is presented in terms of receptor-mediated effects at ion channels of cells involved in the medullary respiratory network, particularly in the presynaptic inhibition of transmitters conveying circuit activation. Reduction of carbon dioxide sensitivity is speculatively attributed to opioid linked effects on the behaviour of membrane channels at low pH. The widespread occurrence of mu and delta receptors in brainstem respiratory circuits indicates that use of their agonists for analgesia will continue to be associated with adverse respiratory effects: there is no indication at present that receptors mediating analgesia will be distinguishable pharmacologically from those involved in depression of respiration.