A latent serotonin-1A receptor-gated spinal afferent pathway inhibiting breathing

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_1ARs) in lumbar spinal cord, lesion of pontine lateral parabrachial nucleus or suppression of the adjacent Kölliker-Fuse nucleus with NMDA receptor blockade. Small-interfering RNA knockdown of 5-HT_1ARs in lumbar spinal cord unequivocally localized the site of 5-HT_1AR-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_1AR-based treatment of a variety of respiratory abnormalities.