Episodic spinal serotonin receptor activation elicits long-lasting phrenic motor facilitation by an NADPH oxidase-dependent mechanism.
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.
MacFarlane
P M
PM
Department of Comparative Biosciences, University of Wisconsin, Madison, WI 53706, USA.
Mitchell
G S
GS
D000098:Acetophenones / Q000008:administration & dosage; D000818:Animals; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D007278:Injections, Spinal; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology*; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000502:physiology*; D010791:Phrenic Nerve / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism / Q000502:physiology*; D012701:Serotonin / Q000008:administration & dosage; D013116:Spinal Cord / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*
C522380:5-HT(7) receptor, rat; D000098:Acetophenones; D004791:Enzyme Inhibitors; D011985:Receptors, Serotonin; D012701:Serotonin; C056165:acetovanillone; D019255:NADPH Oxidases