Effect of the GABA-agonist baclofen on bronchial responsiveness in asthmatics

Gamma-aminobutyric acid (GABA) is a central inhibitory neurotransmitter. Recently, the presence of GABA and its receptors has been confirmed in peripheral tissues, including the lungs. GABA and the GABA agonist baclofen have been shown in animal studies to inhibit airway responsiveness to various bronchoconstricting agents. The results of these investigations suggest the possibility of a role for baclofen in the therapy of human airway hyperreactivity. To investigate this question, a randomized, double-blind, placebo-controlled, cross-over study was performed to evaluate the effect of a 14-day course of oral baclofen (10 mg three times daily) on pulmonary function and bronchial responsiveness to methacholine in a group of six stable asthmatics. In five of six subjects, hyperresponsiveness was enhanced after therapy with baclofen. Mean (+/- SEM) log PC(20)pre-and post-baclofen were 0.160 +/- 0.247 and -0.223 +/- 0.282, respectively (P=0.023). Baseline pulmonary function (FEV(1)) was unaffected by baclofen. The mechanism(s) underlying this apparent paradoxical enhancement by baclofen of bronchial responsiveness remains speculative, but may be relevant to the recently-proposed concept of dysfunction in asthmatics of prejunctional GABA receptors, whose normal role may be to inhibit cholinergic contraction of bronchial smooth muscle.