Membrane potential changes and/or discharges from 36 inspiratory neurons were recorded intracellularly in the dorsal respiratory group (DRG; i.e., the ventrolateral subdivision of the nucleus tractus solitarii) in decerebrate, paralyzed, and ventilated cats. Electrical activities were recorded from both somata (n = 10) and axons (n = 26). Activities during quiet breathing were compared with those observed during fictive coughing and swallowing evoked by repetitive electrical stimulation of afferent fibers of the superior laryngeal nerve (SLN). These nonrespiratory behaviors were evident in paralyzed animals as characteristic discharge patterns of the phrenic, abdominal, and hypoglossal nerves. Twenty-six neurons exhibiting antidromic action potentials in response to electrical stimuli applied to the cervical (C3-5) spinal cord were classified as inspiratory bulbospinal neurons (IBSNs). These neurons were considered as premotoneurons. The remaining 10 inspiratory neurons (I-NAA) were not antidromically activated by electrical stimuli applied to either cervical spinal cord or ipsilateral cervical vagus. These neurons are thought to be propriobulbar neurons. We recorded the activity of 31 DRG inspiratory neurons (24 IBSNs and 7 I-NAA) during coughing. All but one (a late-recruited IBSN) discharged a burst of action potentials during the coughing-related phrenic nerve activity. Typically, ramp-like membrane depolarization trajectories and discharge frequencies during coughing were similar to those observed during inspiration. We recorded the activity of 33 DRG inspiratory neurons (23 IBSNs and 10 I-NAA) during swallowing. Most (28/33) neurons were briefly activated, i.e., discharged a burst of action potentials during swallowing, but peak discharge frequency decreased compared with that measured during inspiration. The membrane potentials of nine somata exhibited a brief bell-shaped depolarization during swallowing, the amplitude of which was similar to that observed during inspiration. These results suggest that some inspiratory premotoneurons and propriobulbar neurons of the DRG might be involved in nonrespiratory motor activities, even if clearly antagonistic to breathing (e.g., swallowing). We postulate the existence in the medulla oblongata of adult mammals of neurons exhibiting a "functional flexibility".
1. The patterns of membrane potential changes of phrenic motoneurons were compared during fictive vomiting, fictive coughing, and fictive swallowing in decerebrate, paralyzed cats. These fictive behaviors were identified by motor nerve discharge patterns similar to those recorded from the muscles of nonparalyzed animals. Phrenic motoneurons (n = 54) were identified by antidromic activation from the thoracic phrenic nerve. Intracellular recordings were obtained from 27 motoneurons during fictive vomiting, 40 during fictive coughing, and 27 during fictive swallowing. Sixteen motoneurons were recorded during both fictive coughing and fictive swallowing, eight during both fictive coughing and fictive vomiting, and two during both fictive vomiting and fictive swallowing. Seven motoneurons were studied during all three behaviors. 2. Fictive vomiting, typically evoked by electrical stimulation of abdominal vagal afferents, was characterized by a series of bursts of coactivation of phrenic and abdominal motor nerves, culminating in an expulsion phase in which abdominal discharge was prolonged both with respect to phrenic discharge and to abdominal discharge during the preceding retching phase. During fictive vomiting, phrenic motoneurons depolarized abruptly, and the amplitude of depolarization was significantly greater than during control inspirations. They then repolarized slowly throughout the phrenic burst, rapidly repolarizing at the end of each phrenic burst during retching and reaching a level similar to that observed during expiration. During the expulsion phase, the pattern was initially the same. However, after the cessation of phrenic discharge, the membrane potential repolarized slowly until the end of the abdominal burst, exhibiting greater synaptic noise than during expiration. One phrenic motoneuron, presumably innervating the periesophageal region of the diaphragm, received a strong hyperpolarization just before the onset of the emetic episode and fired for shorter periods during fictive vomiting than did other phrenic motoneurons.(ABSTRACT TRUNCATED AT 250 WORDS)
In decerebrate, paralyzed, and ventilated cats, we recorded the activity of 100 spontaneously active phrenic motor axons during the increased phrenic discharges characteristic of fictive vomiting (FV) and coughing (FC). During control respiratory cycles, approximately one-half the neurons were recruited in the first decile of inspiration; recruitment continued throughout inspiration. During FV, the duration of phrenic discharge was halved; 20 of 26 motoneurons studied were recruited in the first decile of the burst. During FC, recruitment times did not change compared with control, although the duration of the phrenic burst doubled. Discharge frequencies increased and recruitment order of phrenic motoneurons was virtually unaffected during FC and FV. Limited recruitment of previously inactive neurons in the filaments from which we recorded was found during FV and FC. During FV, 1 previously inactive motoneuron was recruited in 16 filaments containing 25 spontaneously active motor axons. During FC, 3 new motoneurons were recruited in addition to the 64 already active in 35 filaments. Recruitment during FV and FC was absent even when recording from filaments known, on the basis of antidromic activation, to contain inactive motor axons. During FV, 10 of 26 motoneurons began their discharges with doublets (interspike interval < 10 ms); doublets occurred in only 4 of 67 motoneurons during FC. Already active phrenic motoneurons contributed to the intense phrenic activity associated with both respiratory (coughing) and nonrespiratory (vomiting) behavior by increases in discharge frequency, earlier recruitment, and doublets; the contribution of previously quiescent motoneurons remains uncertain.
The possible roles of interneurons in the C4-C5 cervical spinal cord in conveying central drives to phrenic motoneurons during different behaviour patterns were investigated using intracellular recordings in decerebrate, paralysed, artificially ventilated cats. Eleven cells were tentatively classified as respiratory interneurons since they: (i) could not be antidromically activated from the ipsilateral whole intrathoracic phrenic nerve, and (ii) exhibited large membrane potential changes during eupnea (7.3 mV +/- 3.6, range 2-13.5 mV) or non-respiratory behaviour patterns. Six neurons depolarized in phase with phrenic discharge; four others depolarized during the expiratory phase; one neuron exhibited depolarization during the end of both expiration and inspiration. A variety of responses was observed during fictive coughing, vomiting, and swallowing. The results are consistent with C4-C5 expiratory interneurons conveying inhibition to phrenic motoneurons during different behaviour patterns. The responses of inspiratory and multiphasic neurons suggest that the roles of these interneurons are mode complex than simply relaying central excitatory or inhibitory drive to phrenic motoneurons.
The synthesis, structure-activity relationships, and biological properties of a novel series of potent and selective phosphodiesterase type 4 (PDE4) inhibitors are described. These new aminodiazepinoindoles displayed in vitro PDE4 activity with submicromolar IC(50) values and PDE4 selectivity vs PDE1, -3, and -5. Specifically, one compound (CI-1044, 10e) provided efficient in vitro inhibition of TNFalpha release from hPBMC and hWB with IC(50) values of 0.34 and 0.84 microM, respectively. This compound was found to exhibit potent in vivo activity in antigen-induced eosinophil recruitment in Brown-Norway rats (ED(50) = 3.2 mg/kg po) and in production of TNFalpha in Wistar rats (ED(50) = 2.8 mg/kg po). No emetic side effects at therapeutic doses were observed in ferrets.
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