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We have previously shown that ionotropic glutamate receptors in the caudal portion of the nucleus tractus solitarii (NTS), especially in the commissural NTS, play a prominent role in the mediation of tracheobronchial cough and that substance P potentiates this reflex. This NTS region could be a site of action of some centrally acting antitussive agents and a component of a drug-sensitive gating mechanism of cough. To address these issues, we investigated changes in baseline respiratory activity and cough responses to tracheobronchial mechanical stimulation following microinjections (30 -50 nl) of centrally acting antitussive drugs into the caudal NTS of pentobarbitone-anesthetized, spontaneously breathing rabbits. [D-Ala 2 ,N-Me-Phe 4 ,Gly 5 -ol]-enkephalin (DAMGO) and baclofen decreased baseline respiratory frequency because of increases in the inspiratory time only at the higher concentration employed (5 mM and 1 mM, respectively). DAMGO (0.5 mM) and baclofen (0.1 mM) significantly decreased cough number, peak abdominal activity, peak tracheal pressure, and increased cough-related total cycle duration. At the higher concentrations, these agents suppressed the cough reflex. The effects of these two drugs were counteracted by specific antagonists (10 mM naloxone and 25 mM CGP-35348, respectively). The neurokinin-1 (NK1) receptor antagonist CP-99,994 (10 mM) abolished cough responses, whereas the NK2 receptor antagonist MEN 10376 (5 mM) had no effect. The results indicate that the caudal NTS is a site of action of some centrally acting drugs and a likely component of a neural system involved in cough regulation. A crucial role of substance P release in the mediation of reflex cough is also suggested.-opioid receptors; GABAB receptors; neurokinin receptors; control of breathing; airway defensive reflexes PREVIOUS STUDIES LED TO THE conclusion that some antitussive drugs act centrally since they inhibit cough when administered by intravertebral arterial or intracerebroventricular route in guinea pigs and cats (7,8). These drugs comprise the opioid receptor agonist codeine, the -opioid receptor agonist morphine, the neurokinin-1 (NK 1 ) receptor antagonist (ϩ)(2R,3R)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994), the NK 2 receptor antagonist {(ϩ)-N-methyl-[4-(4-acetylamino-4-phenylpiperidino)-2-(3,4-di-dichlorophenyl) butyl]benzamide} (SR48968), and the GABA B receptor agonist baclofen. A prominent central antitussive effect has been proven for the selective -opioid receptor agonist [D-Ala 2 ,N-Me-Phe 4 ,Gly 5 -ol]-enkephalin (DAMGO) by using intracerebroventricular administration in the rat (30). However, the central responsive structures and the mechanism of action of these drugs remain to be investigated.It is widely agreed that tracheobronchial rapidly adapting receptors (RARs) are involved in cough mediation, while the role of bronchopulmonary C-fibers and A␦-nociceptive pulmonary afferent fibers in this reflex is controversial (see e.g., 36, 49, 62; for further references, also see Ref. 43). We have ...

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A brainstem region, the paratrigeminal respiratory group (pTRG), has been suggested to play a crucial role in the respiratory rhythm generation in lampreys. However, a detailed characterization of the pTRG region is lacking. The present study performed on isolated brainstem preparations of adult lampreys provides a more precise localization of the pTRG region with regard to both connectivity and neurochemical markers. pTRG neurons projecting to the vagal motoneuronal pool were identified in a restricted area of the rostral rhombencephalon at the level of the isthmic Müller cell I 1 close to sulcus limitans of His. Unilateral microinjections of lidocaine, muscimol, or glutamate antagonists into the pTRG inhibited completely the bilateral respiratory activity. In contrast, microinjections of glutamate agonists enhanced the respiratory activity, suggesting that this region is critical for the respiratory pattern generation. The retrogradely labeled pTRG neurons are glutamatergic and surrounded by terminals with intense substance P immunoreactivity. Cholinergic neurons were seen close to, and intermingled with, pTRG neurons. In addition, ␣-bungarotoxin binding sites (indicating nicotinic receptors) were found throughout the pTRG area and particularly on the soma of these neurons. During apnea, induced by blockade of ionotropic glutamate receptors within the same region, microinjections of 1 M substance P or 1 mM nicotine into the pTRG restored rhythmic respiratory activity. The results emphasize the close similarities between the pTRG and the mammalian pre-Bötzinger complex as a crucial site for respiratory rhythmogenesis. We conclude that some basic features of the excitatory neurons proposed to generate respiratory rhythms are conserved throughout evolution.

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