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 language | English (US) |
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Pages (from-to) | 829-837 |
Number of pages | 9 |
Journal | Neuropharmacology |
Volume | 51 |
Issue number | 4 |
DOIs | |
State | Published - Sep 1 2006 |
Keywords
- Adrenal medulla
- Clonidine
- Leukocyte migration
- Muscarinic M receptor
- Sympathetic preganglionic neurons