Intrathecal neostigmine reduces the zymosan-induced inflammatory response in a mouse air pouch model via adrenomedullary activity: Involvement of spinal muscarinic type 2 receptors

Seo Yeon Yoon, Young Bae Kwon, Hyun Woo Kim, Dae Hyun Roh, Seuk Yun Kang, Chan Young Kim, Ho Jae Han, Kee Won Kim, Il Suk Yang, Alvin J. Beitz, Jang Hern Lee

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

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 β-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.

Original languageEnglish (US)
Pages (from-to)275-282
Number of pages8
JournalNeuropharmacology
Volume49
Issue number3
DOIs
StatePublished - Sep 2005

Bibliographical note

Funding Information:
This research was supported by a grant (M103KV010009 03K2201 00940) from Brain Research Center of the 21st Century Frontier Research Program funded by the Ministry of Science and Technology of Republic of Korea. The publication of this manuscript was also supported by a grant (R01-2005-000-10580-0) from the Basic Research Program of the Korea Science & Engineering Foundation as well as the Brain Korea 21 project.

Keywords

  • Acetylcholine
  • Adrenal medulla
  • Inflammation
  • Muscarinic type 2 receptor
  • Neostigmine
  • Spinal cord

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