Methylxanthines do not affect rhythmogenic preB枚tC inspiratory network activity but impair bursting of preB枚tC-driven motoneurons

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• 作者：B. Panaitescu ; J. Kuribayashi ; A. Ruangkittisakul ; V. Leung ; M. Iizuka ; K. Ballanyi
• 关键词：C4 ; fourth cervical ; CPA ; cyclopiazonic acid ; DMPX ; 3 ; 7-dimethyl-1-propargylxanthine ; DPCPX ; 8-cyclopentyl-1 ; 3-dipropylxanthine ; Hepes ; hydroxyethyl piperazineethanesulfonic acid ; IRCs ; ictal respiratory changes ; P ; postnatal day ; PDE4 ; phosphodiesterase-4 ; pFRG ; parafacial respiratory group ; preBö ; tC ; pre-Bö ; tzinger complex ; RTN ; retrotrapezoid nucleus ; SERCA ; endoplasmic/sarcoplasmic reticulum ATPase ; T ; thoracic ; VRC ; ventral respiratory column
• 刊名：Neuroscience
• 出版年：26 December, 2013
• 年：2013
• 卷：255
• 期：Complete
• 页码：158-176
• 全文大小：3385 K

文摘

Clinical stimulation of preterm infant breathing with methylxanthines like caffeine and theophylline can evoke seizures. It is unknown whether underlying neuronal hyperexcitability involves the rhythmogenic inspiratory active pre-B枚tzinger complex (preB枚tC) in the brainstem or preB枚tC-driven motor networks. Inspiratory-related preB枚tC interneuronal plus spinal (cervical/phrenic) or cranial hypoglossal (XII) motoneuronal bursting was studied in newborn rat en bloc brainstem-spinal cords and brainstem slices, respectively. Non-respiratory bursting perturbed inspiratory cervical nerve activity in en bloc models at >0.25 mM theophylline or caffeine. Rhythm in the exposed preB枚tC of transected en bloc preparations was less perturbed by 10 mM theophylline than cervical root bursting which was more affected than phrenic nerve activity. In the preB枚tC of slices, even 10 mM methylxanthine did not evoke seizure-like bursting whereas >1 mM masked XII rhythm via large amplitude 1-10 Hz oscillations. Blocking A-type 纬-aminobutyric (GABA_A) receptors evoked seizure-like cervical activity whereas in slices neither XII nor preB枚tC rhythm was disrupted. Methylxanthines (2.5-10 mM), but not blockade of adenosine receptors, phosphodiesterase-4 or the sarcoplasmatic/endoplasmatic reticulum ATPase countered inspiratory depression by muscimol-evoked GABA_A receptor activation that was associated with a hyperpolarization and input resistance decrease silencing preB枚tC neurons in slices. The latter blockers did neither affect preB枚tC or cranial/spinal motor network bursting nor evoke seizure-like activity or mask corresponding methylxanthine-evoked discharges. Our findings show that methylxanthine-evoked hyperexcitability originates from motor networks, leaving preB枚tC activity largely unaffected, and suggest that GABA_A receptors contribute to methylxanthine-evoked seizure-like perturbation of spinal motoneurons whereas non-respiratory XII motoneuron oscillations are of different origin.