Endogenous Opioids Modulate the Increase in Ventilatory Output and Dyspnea during Severe Acute Bronchoconstriction

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Abstract
The aim of this study was to evaluate whether endogenous opioids are involved in the regulation of breathing pattern and respiratory drive during bronchoconstriction induced by methacholine (MCh). We studied six male asymptomatic asthmatics 18 to 35 yr of age. In a preliminary study we determined the concentration of MCh causing a 60% fall in FEV1 (PC60 FEV1). On two subsequent days, we measured breathing pattern, dyspnea sensation (Borg scale), mouth occlusion pressure (P0.1) and FEV1 before and 10 min after an intravenous injection of either naloxone (0.1 mg/kg) or saline according to a randomized double-blind crossover design. A MCh concentration equal to the PC60 FEV1 was then inhaled, and measurements were repeated 5 min later. Neither placebo nor naloxone affected baseline breathing pattern, P0.1, and FEV1. Naloxone pretreatment did not influence airway response to MCh; the mean percent fall in FEV1 was 65.9 .+-. 1.3 and 64.7 .+-. 1.2% (mean .+-. 1 SE) on the placebo day and the naloxone day, respectively. After MCh inhalation no significant changes in .ovrhdot.VE, VT, and breathing frequency occurred when patients received placebo. However, P0.1 increased from 1.48 .+-. 0.17 to 3.43 .+-. 0.70 cm H2O (p < 0.05), and VT/TI fell from 0.66 .+-. 0.08 to 0.52 .+-. 0.04 L/s (p < 0.05). Naloxone pretreatment resulted in an increase in breathing frequency (from 18.2 .+-. 1.7 to 22.8 .+-. 2.6 breaths/min; p < 0.05) and VT/TI (from 0.58 .+-. 0.06 to 0.74 .+-. 0.05 L/s; p < 0.05) after MCh. The increase in P0.1 from 1.30 .+-. 0.16 to 4.82 .+-. 0.93 cm H2O caused by MCh was significantly greater than that observed in the placebo study (p < 0.05). Dyspnea after MCh was significantly lower (p < 0.05) in the placebo (3.4 .+-. 0.8) than in the naloxone study (5.1 .+-. 0.9). These findings suggest that the activity of endogenous opioids is increased during severe MCh-induced bronchoconstriction and that they lower the ventilatory output and the sensation of dyspnea.