Opioidergic and dopaminergic modulation of respiration

Abstract

Opioids, dopamine and their receptors are present in many regions of the bulbar respiratory network. The physiological importance of endogenous opioids to respiratory control has not been explicitly demonstrated. Nonetheless, studies of opioidergic respiratory mechanisms are important because synthetic opiate drugs have respiratory side effects that in some situations pose health risks and limit their therapeutic usefulness. They can depress breathing depth and rate, blunt respiratory responsiveness to CO2 and hypoxia, increase upper airway resistance and reduce pulmonary compliance. The opiate respiratory disturbances are mainly due to agonist activation of mu- and delta-subtypes of receptor and involve specific types of respiratory-related neurons in the ventrolateral medulla and the dorsolateral pons. Endogenous dopaminergic modulation in the CNS and carotid bodies enhances CO2-dependent respiratory drive and depresses hypoxic drive. In the CNS, synthetic agonists with selectivity for D1-and D4-types of receptor slow respiratory rhythm, whereas D2-selective agonists modulate acute and chronic responses to hypoxia. D1-receptor agonists also act centrally to increase respiratory responsiveness to CO2, and counteract opiate blunting of CO2-dependent respiratory drive and depression of breathing. Cellular targets and intracellular mechanisms responsible for opioidergic and dopaminergic respiratory effects for the most part remain to be determined.

Figure 1

Fentanyl hyperpolarizes membrane potential (MP), arrests discharge and reduces input resistance (Rn) of an Inspiratory bulbospinal neuron (BSN). Effects of fentanyl are reversed by Naloxonazine (not shown). A, control rhythm is synchronized with phrenic nerve inspiratory discharge (PNA.). B, Collision testing identifies neuron as bulbospinal. Stars denote antidromically-evoked action potentials. Stimulus-evoked action potential is abolished by collision with spontaneous action potential in lower trace. C, Control recording shows uniformly spaced hyperpolarizing electronic potentials (downward deflections) evoked by constant current pulses, 60mS duration, that are proportional to cell membrane input resistance (Rn). D, intravenous injection of fentanyl hyperpolarizes MP, abolishes action potential discharge and decreases input resistance. E, hyperpolarizing electrotonic potentials identified by black bars under MP traces in panels C and D are enlarged. (Lalley, unpublished figure)

Figure 2

Fentanyl i.v. evokes tonic discharge in propriobulbar Post-I (A.) and bulbospinal Late-E neurons (B.). Dashed lines in each panel denote threshold for action potential discharge under control conditions. Lengths of vertical arrows (A, lower and B, right) denote magnitudes of change in action potential threshold. (Lalley, unpublished figure.)

Figure 3

Increases in discharge intensity and duration evoked by i.v. administration of the D1-dopamine receptor agonist SKF-38393 in a bulbospinal Inspiratory neuron. [Figure from Lalley, 2004b]

Figure 4

Reversal of respiratory network depression by selective D1-dopamine receptor (D1R) agonists in the anesthetized cat. Panel A, reversal of depression by the D1R agonist 6-Chloro-APB (APB) in a single experiment. Records show the onset of network depression by fentanyl (2.), which then proceeds to arrest of phrenic nerve discharges (3. central apnea). APB given thereafter restores discharges to control intensity but at a slower frequency. Traces show the phrenic electroneurogram (bottom trace) and the moving average of phrenic nerve activity (upper trace). Panel B, partial reversal of opiate-induced depression of respiratory responsiveness to CO2 by the DiR agonist Dihydrexidine (DHD) in 6 anesthetized cats. Ordinate, minute phrenic nerve activity as a percent of the maximal control value recorded during hypercapnia. Abscissa, percent end-tidal CO2 (ETCO2) normalized with respect to the control phrenic nerve apnea threshold (apnea threshold set to zero). [Figure modified from Lalley, 2004b]