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.
These studies were performed to examine the potential anti-inflammatory effect of intrathecal (IT) clonidine (an alpha2-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 alpha2-adrenoceptor antagonist) pretreatment. Since a number of studies have previously shown that spinal alpha2-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 beta-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.
Yoon
Seo-Yeon
SY
Department of Veterinary Physiology, College of Veterinary Medicine, Seoul National University, Seoul 151-742, South Korea.
Kim
Hyun-Woo
HW
Roh
Dae-Hyun
DH
Kwon
Young-Bae
YB
Han
Ho-Jae
HJ
Beitz
Alvin J
AJ
Lee
Jang-Hern
JH
D000315:Adrenalectomy / Q000379:methods; D000704:Analysis of Variance; D000818:Animals; D002452:Cell Count / Q000379:methods; D002465:Cell Movement / Q000187:drug effects*; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003000:Clonidine / Q000494:pharmacology*; D004195:Disease Models, Animal; D004347:Drug Interactions; D005728:Ganglia, Sympathetic / Q000166:cytology / Q000187:drug effects; D007150:Immunohistochemistry / Q000379:methods; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D007962:Leukocytes / Q000187:drug effects*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018721:Muscarinic Agonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D016761:Oncogene Proteins v-fos / Q000378:metabolism; D043585:Receptor, Muscarinic M2 / Q000378:metabolism*; D013116:Spinal Cord / Q000473:pathology; D013563:Sympathectomy, Chemical / Q000379:methods; D013565:Sympatholytics / Q000494:pharmacology*; D015054:Zymosan
D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D016761:Oncogene Proteins v-fos; D043585:Receptor, Muscarinic M2; D013565:Sympatholytics; D015054:Zymosan; D002795:Choline O-Acetyltransferase; D003000:Clonidine