Differential brainstem Fos-like immunoreactivity after laryngeal-induced coughing and its reduction by codeine

We used the expression of the immediate-early gene c-fos, a marker of neuronal activation, to localize brainstem neuronal populations functionally related to fictive cough (FC). In decerebrate, paralyzed, and ventilated cats, the level of Fos-like immunoreactivity (FLI) was examined in five groups of animals: (1) controls, sham-operated unstimulated animals; (2) coughing cats, including both animals in which FC was elicited by unilateral electrical stimulation of the superior laryngeal nerve (SLN) and (3) those in which FC was elicited by bilateral SLN stimulation; (4) stimulated-treated cats, in which bilateral SLN stimulation was applied after selective blockade of FC by codeine; and (5) codeine controls, sham-operated unstimulated cats subjected to administration of codeine. Fifteen brainstem structures were compared for numbers of labeled cells. Because codeine selectively blocks FC, brainstem nuclei activated specifically during FC were identified as regions showing increased FLI after FC and significant reductions in FLI after FC suppression by codeine in stimulated-treated cats. In coughing animals, we observed a selective immunoreactivity in the interstitial and ventrolateral subdivisions of the nucleus of the tractus solitarius, the medial part of the lateral tegmental field, the internal division of the lateral reticular nucleus, the nucleus retroambiguus, the para-ambigual region, the retrofacial nucleus, and the medial parabrachial nucleus. FLI in all these nuclei was significantly reduced in stimulated-treated cats. Our results are consistent with the involvement of neurons overlapping the main brainstem respiratory-related regions as well as the lateral tegmental field and the lateral reticular nucleus in the neural processing of laryngeal-induced FC.