S-Space College of Veterinary Medicine (수의과대학) Dept. of Veterinary Medicine (수의학과) Journal Papers (저널논문_수의학과)
Intrathecal clonidine suppresses zymosan-induced peripheral leukocyte migration in a mouse air pouch model via activation of spinal muscarinic type 2 receptors and sympathoadrenal medullary activity
- Yoon, Seo Yeon; Kim, Hyun-Woo; Roh, Dae-Hyun; Kwon, Young-Bae; Han, Ho-Jae; Beitzd, Alvin J.; Lee, Jang-Hern
- Issue Date
- Neuropharmacology 5, 829-837
- Clonidine; Leukocyte migration; Muscarinic M2 receptor; Sympathetic preganglionic neurons; Adrenal medulla
- These studies were performed to examine the potential anti-inflammatory effect of intrathecal (IT) clonidine (an α2-adrenoceptor agonist) on zymosan-induced leukocyte migration in a mouse air pouch model. IT clonidine dose-dependently suppressed zymosan-induced leukocyte migration and this effect was blocked by IT idazoxan (an α2-adrenoceptor antagonist) pretreatment. Since a number of studies have previously shown that spinal α2-adrenoceptors are functionally associated with spinal cholinergic activity, we next examined whether spinal acetylcholine (ACh) receptors were also involved in mediating this anti-inflammatory effect of IT clonidine. IT pretreatment with atropine (a muscarinic receptor antagonist), but not hexamethonium (a nicotinic receptor antagonist) completely blocked the anti-migratory effect of IT clonidine. Subsequent experiments showed that IT pretreatment with methoctramine (a muscarinic M2 antagonist), but not pirenzepine (an M1 antagonist) or 4-DAMP (an M3 antagonist), suppressed clonidine's anti-inflammatory effect. Finally, we studied the potential roles of the sympathetic nervous system and the hypothalamo-pituitary–adrenal axis in clonidine's anti-inflammatory effect. Adrenalectomy or systemic injection of propranolol (a β-adrenoceptor antagonist) blocked clonidine's effect. However, pretreatment with RU486 (a corticosteroid antagonist) or peripheral sympathetic denervation using 6-hydroxydopamine had no effect. Furthermore, IT clonidine increased Fos expression in zymosan treated mice exclusively in T7–T11 sympathetic preganglionic neurons (which mainly project to the adrenal medulla), but not those of the T1–T6 or T12–L2 spinal segments. Moreover, IT methoctramine significantly reduced this increase in Fos expression. Collectively, these findings suggest that IT clonidine suppresses peripheral leukocyte migration via a sympathoadrenal medullary pathway, and that this suppressive effect is mediated by spinal M2 receptors.
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