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

Seo Yeon Yoon, Hyun Woo Kim, Dae Hyun Roh, Young Bae Kwon, Ho Jae Han, Alvin J. Beitz, Jang Hern Lee

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)829-837
Number of pages9
JournalNeuropharmacology
Volume51
Issue number4
DOIs
StatePublished - Sep 1 2006

Keywords

  • Adrenal medulla
  • Clonidine
  • Leukocyte migration
  • Muscarinic M receptor
  • Sympathetic preganglionic neurons

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