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 mu-opioid receptor in the central nervous system (CNS). The kappa-opioid receptor also seems to contribute partly to the production of the antitussive effect of the drugs. There is controversy as to whether delta-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 SO2 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.

Figure 1

Effect of co-administration of codeine and SR 48,968, a NK₂ receptor antagonist, on citric acid-induced coughs in conscious guinea-pigs. Conscious guinea-pigs were put into plethysmograph and 10 % citric acid was nebulized for 2 min to elicit a cough response. Cough number was counted for 15 min during and after citric acid stimulation. After more than 4 h, codeine was orally administered at various doses 30 min before the 2^nd stimulation. Then, SR 48,968 (1 mg/kg) or vehicle was intravenously administered 5 min before the 2^nd stimulation. Results were normalized to the pre-administration cough number. Continuous lines indicate the theoretical fitting of the data with single exponential function. Note that co-administration of codeine (10 mg/kg) and SR 48,968 inhibited cough response almost completely, while the antitussive effect induced by codeine alone reached a plateau at 20 mg/kg (33 % of pre-administration value). Antitussive effects produced by co-administration of codeine (10 mg/kg) and SR 48,968 was significantly more potent than that produced by codeine (10 mg/kg) alone (p < 0.05, n = 4 and 6, respectively). SR 48,968 itself inhibited cough response to about 70 % of the time, but the inhibitory effect was not significantly different from the vehicle group. Co-administration of codeine and SR 48,968 had no effect on mechanically-induced sneezing (data not shown). Each value shows mean ± S.E.M. (n = 3 to 7). * p < 0.05, significantly different from the vehicle control.