Central and peripheral mechanisms of narcotic antitussives: codeine-sensitive and -resistant coughs

Abstract

Narcotic antitussives such as codeine reveal the antitussive effect primarily via the µ-opioid receptor in the central nervous system (CNS). The κ-opioid receptor also seems to contribute partly to the production of the antitussive effect of the drugs. There is controversy as to whether δ-receptors are involved in promoting an antitussive effect. Peripheral opioid receptors seem to have certain limited roles. Although narcotic antitussives are the most potent antitussives at present, certain types of coughs, such as chronic cough, are particularly difficult to suppress even with codeine. In guinea pigs, coughs elicited by mechanical stimulation of the bifurcation of the trachea were not able to be suppressed by codeine. In gupigs with sub-acute bronchitis caused by SO 2 gas exposure, coughing is difficult to inhibit with centrally acting antitussives such as codeine. Some studies suggest that neurokinins are involved in the development of codeine-resistant coughs. However, evidence supporting this claim is still insufficient. It is very important to characterize opiate-resistant coughs in experimental animals, and to determine which experimentally induced coughs correspond to which types of cough in humans. In this review, we describe the mechanisms of antitussive effects of narcotic antitussives, addressing codeine-sensitive and -resistant coughs, and including our own results.

Antitussive Drugs—Past, Present, and Future

“…In guinea pigs, both cough induced by mechanical stimulation of the lower airways and sulfur dioxide-induced bronchitis are not inhibited by codeine (Takahama et al, 1997;Takahama and Shirasaki, 2007). Although inhibition of citric acid-induced cough by inhaled codeine has been demonstrated in the guinea pig by several authors, cough induced by capsaicin does not appear to be affected (Xiang et al, 1998).…”

Cough Sensors. III. Opioid and Cannabinoid Receptors on Vagal Sensory Nerves

“…Delta opioid receptors are less abundant in these areas, with the exception of the nucleus parabrachialis, which has a high density of delta receptors. It has been suggested that the nucleus tractus solitarius contains the cough centre, as this region primarily receives sensory input from the airways and its stimulation causes cough-like responses (Takahama and Shirasaki 2007). The nucleus tractus solitarius is also more heavily labelled by a mu ligand than by a kappa ligand in guinea pigs and cats (Dashwood et al 1988), and microinjection of codeine into the nucleus tractus solitarius inhibited a fictive cough reflex in the guinea pig (Ohi et al 2005).…”

.MU.-Opioid and N-Methyl-D-aspartate Receptors Are Localized at Laryngeal Motoneurons of Guinea Pigs

“…Inhibiting it at any site of the arc can be expected to cause antitussive effect. 11,15) In general, opioids are thought to suppress preferentially synaptic transmissions in the cough/respiratory neuron network 5,11) and NMDA mechanisms may play some roles in the gating mechanism which integrates the cough-related information coming from the NTS relay neurons and sends the gated signal to the cough/respiratory pattern generator. 10,16) The present results propose another possible site of action where both opioid and NMDA ligands act onto the postsynaptic receptors located in LMNs and modulate the motoneuron excitability.…”