Central mechanisms II: pharmacology of brainstem pathways

Abstract

Following systemic administration, centrally acting antitussive drugs are generally assumed to act in the brainstem to inhibit cough. However, recent work in humans has raised the possibility of suprapontine sites of action for cough suppressants. For drugs that may act in the brainstem, the specific locations, types of neurones affected, and receptor specificities of the compounds represent important issues regarding their cough-suppressant actions. Two medullary areas that have received the most attention regarding the actions of antitussive drugs are the nucleus of the tractus solitarius (NTS) and the caudal ventrolateral respiratory column. Studies that have implicated these two medullary areas have employed both microinjection and in vitro recording methods to control the location of action of the antitussive drugs. Other brainstem regions contain neurones that participate in the production of cough and could represent potential sites of action of antitussive drugs. These regions include the raphe nuclei, pontine nuclei, and rostral ventrolateral medulla. Specific receptor subtypes have been associated with the suppression of cough at central sites, including 5-HT1A, opioid (mu, kappa, and delta), GABA-B, tachykinin neurokinin-1 (NK-1) and neurokinin-2, non-opioid (NOP-1), cannabinoid, dopaminergic, and sigma receptors. Aside from tachykinin NK-1 receptors in the NTS, relatively little is known regarding the receptor specificity of putative antitussive drugs in particular brainstem regions. Our understanding of the mechanisms of action of antitussive drugs would be significantly advanced by further work in this area.

Fig. 1

Brainstem regions that have been specifically associated with the actions of antitussive drugs. Outlined areas on the left indicate regions of the brainstem in which cough-related neurones have been recorded. Shaded areas represent regions in which application of cough-suppressant drugs has inhibited cough. The model on the right shows second-order interneurones in pulmonary vagal afferent pathways. Pump cells mediate sensory information from pulmonary slowly adapting receptors and neurones designated “relay” mediate information from cough receptors and rapidly adapting receptors. The notation shows that although a number of different drugs may act on this population of neurones, receptor specificity only for tachykinin neurokinin-1 receptors has been demonstrated (Chen et al. 2003; Sekizawa et al. 2003). NTS nucleus of the tractus solitarius, rVRC rostral ventral respiratory column, cVRC caudal ventral respiratory column