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Episodic spinal serotonin receptor activation elicits long‐lasting phrenic motor facilitation by an NADPH oxidase‐dependent mechanism
Author(s) -
MacFarlane P. M.,
Mitchell G. S.
Publication year - 2009
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2009.176982
Subject(s) - nadph oxidase , phrenic nerve , apocynin , receptor , chemistry , 5 ht receptor , serotonin , medicine , endocrinology , pharmacology , anesthesia , respiratory system , oxidative stress
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 × 6 μl 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.