Spinal afferents such as nociceptive afferents and group III-IV muscle afferents are known to exert an acute excitatory effect on breathing when activated. Here, we report the surprising existence of latent spinal afferents which exerted tonic inhibitory influence on breathing subliminally in anesthetized rats, an effect which was reversed upon activation of serotonin-1A receptors (5-HT 1A Rs) in lumbar spinal cord, lesion of pontine lateral parabrachial nucleus or suppression of the adjacent Kölli-ker-Fuse nucleus with NMDA receptor blockade. Smallinterfering RNA knockdown of 5-HT 1A Rs in lumbar spinal cord unequivocally localized the site of 5-HT 1A R-mediated gating of these respiratory-inhibiting interoceptive afferents to relay neurons in the spinal superficial dorsal horn at the lumbar level and not cervical spinal or supraspinal levels. Our results reveal a novel somatosensory/viscerosensory mechanism which exerts tonic inhibitory influence on homeostatic regulation of breathing independent from the classical chemoreflex excitatory pathways, and suggest a hitherto unrecognized therapeutic target in spinal dorsal horn for 5-HT 1A R-based treatment of a variety of respiratory abnormalities.
We have previously shown that post‐I phase duration (TE1) and vagal post‐I motor activity exhibit post‐hypoxic STP that is mediated by NMDA receptor‐expressing early‐E neurons in pontine Kölliker‐Fuse nucleus (KFN), presumably through these neurons’ excitatory influences on medullary post‐I neuronal pools that modulate TE1 and the activity of laryngeal adductive muscles. In this study we examined the changes in firing pattern of various medullary respiratory neurons upon the induction of apneusis by microinjection of NMDA receptor antagonist AP5 at KFN. We found that after apneusis was induced: 1) all medullary post‐I neurons were severely depressed or completely silenced and their post‐hypoxic STP was greatly reduced or completely abolished; 2) discharge period of E‐aug/late‐E neurons was lengthened to span the entire expiratory period; 3) firing patterns of inspiratory‐related neurons (early‐I, aug‐I, pre‐I, and late‐I) were not significantly altered but their firing frequencies were slightly or moderately reduced. These findings indicate that the activities of medullary post‐I neurons (but not other medullary respiratory‐related neurons) are dependent on excitatory drive from NMDA receptor‐expressing KFN early‐E neurons. In the absence of such KFN post‐I excitatory drive, the expiratory phase is solely under the control of medullary E‐aug neurons. (Supported by HL093225)
The A5 region in ventrolateral pons (vl‐pons/A5) is thought to be an auxiliary substrate for the putative pneumotaxic center in the dorsolateral pons that modulates inspiratory‐expiratory phase switching (inspiratory off‐switch), post‐inspiratory activity (post‐I) and expiratory duration (TE). In urethane‐anesthetized, vagotomized and ventilated adult SD rats, we observed that blockade of GABAA receptors at vl‐pons/A5 by unilateral microinjection of bicuculline (BIC) caused prolongation of vagal post‐I motor activity and TE, an effect that was similar to that evoked by electrical or chemical stimulations in this region. Bilateral microinjections of BIC caused further protracted prolongation of TE or even sustained apnea with complete cessation of phrenic activity and prolongation of post‐I activity. Remarkably, the apnea so induced was reversed and rhythmic phrenic discharges gradually resumed upon subsequent blockade of excitatory glutamatergic receptors by bilateral microinjections of CNQX and AP‐5 at the same vl‐pons/A5 sites, or by the application of hypoxic or hypercapnic stimuli. These findings indicated that the vl‐pons/A5 plays an important role in promoting post‐I activity and inspiratory off‐switch subject to a delicate balance between GABAA receptor‐mediated inhibitory and glutamatergic receptor‐mediated excitatory modulations. (Supported by HL093225)
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