title: Intrathecal neostigmine reduces the zymosan-induced inflammatory response in a mouse air pouch model via adrenomedullary activity: involvement of spinal muscarinic type 2 receptors.
abstract: Intrathecal (IT) injection of neostigmine (a cholinesterase inhibitor) has been reported to produce a significant anti-nociceptive effect in a number of inflammatory pain models. However, a potential anti-inflammatory effect of IT neostigmine in these models has not been investigated. In the present study, we have examined the 'anti-inflammatory effect of IT injection of neostigmine' (AI-NEO) using a standard mouse air pouch model by evaluating the effect of AI-NEO on zymosan-induced leukocyte migration and myeloperoxidase (MPO) release. IT neostigmine was found to suppress both leukocyte migration and MPO degranulation in a dose dependent manner. We then established which subtypes of cholinergic receptors were involved in this AI-NEO. IT pretreatment with atropine (a muscarinic receptor antagonist) but not hexamethonium (a nicotinic receptor antagonist) completely blocked the IT neostigmine anti-inflammatory effect. Subsequent experiments showed that IT pretreatment with methoctramine (a muscarinic type 2 (M2) receptor antagonist), but not pirenzepine (M1 receptor antagonist) or 4-DAMP (M3 receptor antagonist), suppressed the AI-NEO. We then evaluated whether adrenal glandular activity was important in the AI-NEO. Adrenalectomy significantly blocked the AI-NEO, while intraperitoneal pretreatment with the beta-adrenoceptor antagonist (propranolol), but not the corticosteroid antagonist (RU486) reversed AI-NEO. In conclusion, these results indicate that IT neostigmine facilitates the activation of spinal M2 receptors and this activation ultimately leads to release of adrenal catecholamines which contribute to the anti-inflammatory effect observed at the site of tissue inflammation.
authors.affiliation: Department of Veterinary Physiology, College of Veterinary Medicine and School of Agricultural Biotechnology, Seoul National University, Seoul, South Korea.
authors.forename: Seo-Yeon
authors.initials: SY
authors.lastname: Yoon
authors.forename: Young-Bae
authors.initials: YB
authors.lastname: Kwon
authors.forename: Hyun-Woo
authors.initials: HW
authors.lastname: Kim
authors.forename: Dae-Hyun
authors.initials: DH
authors.lastname: Roh
authors.forename: Seuk-Yun
authors.initials: SY
authors.lastname: Kang
authors.forename: Chan-Young
authors.initials: CY
authors.lastname: Kim
authors.forename: Ho-Jae
authors.initials: HJ
authors.lastname: Han
authors.forename: Kee-Won
authors.initials: KW
authors.lastname: Kim
authors.forename: Il-Suk
authors.initials: IS
authors.lastname: Yang
authors.forename: Alvin J
authors.initials: AJ
authors.lastname: Beitz
authors.forename: Jang-Hern
authors.initials: JH
authors.lastname: Lee
mesh_terms: D000305:Adrenal Cortex Hormones / Q000502:physiology; D000313:Adrenal Medulla / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D000315:Adrenalectomy; D000388:Air; D000818:Animals; D000893:Anti-Inflammatory Agents; D002395:Catecholamines / Q000502:physiology; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D007249:Inflammation / Q000139:chemically induced / Q000517:prevention & control*; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009388:Neostigmine / Q000008:administration & dosage / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D043585:Receptor, Muscarinic M2 / Q000187:drug effects / Q000502:physiology*; D011987:Receptors, Steroid / Q000037:antagonists & inhibitors; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology*; D015054:Zymosan / Q000037:antagonists & inhibitors* / Q000633:toxicity
chemical_list: D000305:Adrenal Cortex Hormones; D000893:Anti-Inflammatory Agents; D002395:Catecholamines; D002800:Cholinesterase Inhibitors; D018733:Nicotinic Antagonists; D043585:Receptor, Muscarinic M2; D011987:Receptors, Steroid; D009388:Neostigmine; D015054:Zymosan