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 (μ, κ, and δ), 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.

A Model of the Central Regulatory System for Cough Reflex

“…13,32,48) This is supported by our previous reports 46) that intravenous injection of codeine inhibits the induction of fictive cough by microstimulation of the NTS and that microinjection of codeine into the nTS inhibits the induction of fictive cough by repetitive stimulation of the ipsilateral SLn. In the previous reports, [54][55][56] two medullary areas that have received the most attention regarding the actions of antitussive drugs are the nTS and the caudal ventral respiratory group (VRG). The pontine respiratory group (PRG) and rostral VRG also contain neurons that may participate in the production of cough and could represent potential sites of action of antitussive agents.…”

Role of the dorsomedial medulla in suppression of cough by codeine in cats

“…Some progress has been made in our knowledge of cough neuronal circuits (Haji et al, 2013; Pitts et al, 2016) from the introduction of the revolutionary computational model of the cough generating neuronal network (Shannon et al, 1998) and the first complex description of cough brainstem neuronal circuitry in cat (Oku et al, 1994; Gestreau et al, 1997; Shannon et al, 2004; Jakus et al, 2008). Further significant knowledge has been gained during last decade about cough-related neurotransmission and neuromodulation at the central level (Bolser, 2009; Cinelli et al, 2015) including the mechanisms and sites of action of antitussive drugs (Mutolo et al, 2010; Poliacek et al, 2010). However, significant gaps remain in our understanding of the central regulatory mechanisms for coughing.…”

Central regulation of the cough reflex: Therapeutic implications

“…Codeine and dextromethorphan are used extensively and specifically for the treatment of cough and likely exert their effects through central sites of action [1,2]. The neurokinin receptor antagonists, amongst the more promising class of therapeutics evaluated for cough over the past 20 years, also likely act primarily via actions in the central nervous system (CNS) to prevent or reduce coughing in guinea pigs, rabbits, cats, dogs and pigs [3-10].…”