Department of Comparative Biosciences, University of Wisconsin, Madison, WI 53706, USA.
J Physiol. 2009 Nov 15;587(Pt 22):5469-81. doi: 10.1113/jphysiol.2009.176982. Epub 2009 Oct 5.
Phrenic long-term facilitation (pLTF) is a serotonin (5-HT)-dependent augmentation of phrenic motor output induced by acute intermittent hypoxia (AIH). AIH-induced pLTF requires spinal NADPH oxidase activity and reactive oxygen species (ROS) formation. Since 5-HT receptor activation stimulates NADPH oxidase activity in some cell types, we tested the hypothesis that episodic spinal 5-HT receptor activation (without AIH) is sufficient to elicit an NADPH oxidase-dependent facilitation of phrenic motor output (pMF). In anaesthetised, artificially ventilated adult male rats, episodic intrathecal 5-HT injections (3 x 6 microl injections at 5 min intervals) into the cerebrospinal fluid (CSF) near cervical spinal segments containing the phrenic motor nucleus elicited a progressive increase in integrated phrenic nerve burst amplitude (i.e. pMF) lasting at least 60 min post-5-HT administration. Hypoglossal (XII) nerve activity was unaffected, suggesting that effective doses of 5-HT did not reach the brainstem. A single 5-HT injection was without effect. 5-HT-induced pMF was dose dependent, but exhibited a bell-shaped dose-response curve. Activation of different 5-HT receptor subtypes, specifically 5-HT(2) versus 5-HT(7) receptors, may underlie the bell-shaped dose-response curve via a mechanism of 'cross-talk' inhibition. Pre-treatment with NADPH oxidase inhibitors, apocynin or diphenylenodium (DPI), blocked 5-HT induced pMF. Thus, episodic spinal 5-HT receptor activation is sufficient to elicit pMF by an NADPH oxidase-dependent mechanism, suggesting common mechanisms of ROS formation with AIH-induced pLTF. An understanding of the mechanisms giving rise to AIH-induced pLTF and 5-HT induced pMF may inspire novel therapeutic strategies for respiratory insufficiency in diverse conditions, such as sleep apnoea, cervical spinal injury or amyotrophic lateral sclerosis.
膈神经长期易化（pLTF）是一种由急性间歇性低氧（AIH）诱导的膈神经运动输出的 5-羟色胺（5-HT）依赖性增强。AIH 诱导的 pLTF 需要脊髓 NADPH 氧化酶活性和活性氧（ROS）的形成。由于 5-HT 受体激活会刺激某些细胞类型的 NADPH 氧化酶活性，因此我们假设，间歇性脊髓 5-HT 受体激活（无 AIH）足以引起 NADPH 氧化酶依赖性膈神经运动输出（pMF）易化。在麻醉、人工通气的成年雄性大鼠中，在含有膈神经运动核的颈段脊髓脑脊液（CSF）附近间歇性鞘内注射 5-HT（3 x 6 微升，间隔 5 分钟）可引起膈神经爆发幅度的逐渐增加，即 pMF，至少持续 60 分钟。舌下神经（XII）神经活动不受影响，表明有效剂量的 5-HT 未到达脑干。单次 5-HT 注射没有效果。5-HT 诱导的 pMF 呈剂量依赖性，但表现出钟形剂量反应曲线。不同 5-HT 受体亚型的激活，特别是 5-HT（2）与 5-HT（7）受体的激活，可能通过“串扰”抑制的机制为钟形剂量反应曲线提供基础。NADPH 氧化酶抑制剂-apocynin 或二苯基碘鎓（DPI）预处理阻断了 5-HT 诱导的 pMF。因此，间歇性脊髓 5-HT 受体激活足以通过 NADPH 氧化酶依赖性机制引起 pMF，这表明与 AIH 诱导的 pLTF 形成的 ROS 形成具有共同机制。对 AIH 诱导的 pLTF 和 5-HT 诱导的 pMF 产生机制的理解可能为睡眠呼吸暂停、颈段脊髓损伤或肌萎缩侧索硬化等多种情况下的呼吸功能不全提供新的治疗策略。
