A spinal muscarinic M2 receptor-GABAergic disinhibition pathway that modulates peripheral inflammation in mice

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

doi:10.1016/j.neuropharm.2007.07.011

A spinal muscarinic M2 receptor-GABAergic disinhibition pathway that modulates peripheral inflammation in mice

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

Research output: Contribution to journal › Article › peer-review

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Abstract

Previous data from our laboratories using the mouse air pouch model demonstrated that intrathecal injection of the cholinomimetic drug, neostigmine, produces a significant peripheral anti-inflammatory effect through activation of spinal muscarinic type 2 receptors. This anti-inflammatory effect is mediated by activation of sympathetic preganglionic neurons and subsequent release of adrenomedullary catecholamines. It has been established that adrenomedullary catecholamine release is controlled by sympathetic preganglionic neurons and that these neurons are modulated by GABAergic inhibitory input. To further establish the neurochemical circuitry underlying spinally mediated anti-inflammation, the present study examined whether spinal muscarinic type 2 receptors are associated with this spinal GABAergic pathway. Intrathecal injection of the M₂ receptor agonist, arecaidine but-2-ynyl ester tosylate (ABET) dose-dependently suppressed zymosan-induced leukocyte migration into the air pouch and increased Fos (neuronal activation marker) expression in sympathetic preganglionic neurons of the T7-T11 spinal cord segments (which mainly project to the adrenal medulla), but not in sympathetic preganglionic neurons of the T1-T6 or T12-L2 segments. These effects of arecaidine but-2-ynyl ester tosylate were completely blocked by intrathecal pretreatment with baclofen (a GABA_BR agonist) but not muscimol (a GABA_AR agonist). Intrathecal saclofen (a GABA_BR antagonist), but not bicuculline (a GABA_AR antagonist), significantly reduced leukocyte migration and increased Fos expression in T7-T11 sympathetic preganglionic neurons. More importantly, this intrathecal saclofen-induced anti-inflammatory effect was completely blocked by adrenalectomy or systemic pretreatment with propranonol (a β-adrenoceptor antagonist). Collectively, these novel findings suggest that activation of spinal muscarinic type 2 receptors suppress spinal GABA_B receptor input and that this disinhibition mechanism ultimately leads to the release of adrenal catecholamines and a subsequent reduction in peripheral inflammation.

Original language	English (US)
Pages (from-to)	677-686
Number of pages	10
Journal	Neuropharmacology
Volume	53
Issue number	5
DOIs	https://doi.org/10.1016/j.neuropharm.2007.07.011
State	Published - Oct 2007

Bibliographical note

Funding Information:
This research was supported by a grant (M103KV010015-06K2201-01510) from Brain Research Center of the 21st Century Frontier Research Program funded by the Ministry of Science and Technology, the Republic of Korea. The publication of this manuscript was also supported by a Research Fund from the Research Institute for Veterinary Science (RIVS) in the College of Veterinary Medicine, Seoul National University, as well as the Brain Korea 21 project, in the College of Veterinary Medicine, Chonnam National University, Korea.

Keywords

Adrenal medulla
Inflammation
Spinal cord
Sympathetic preganglionic neurons

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title = "A spinal muscarinic M2 receptor-GABAergic disinhibition pathway that modulates peripheral inflammation in mice",

abstract = "Previous data from our laboratories using the mouse air pouch model demonstrated that intrathecal injection of the cholinomimetic drug, neostigmine, produces a significant peripheral anti-inflammatory effect through activation of spinal muscarinic type 2 receptors. This anti-inflammatory effect is mediated by activation of sympathetic preganglionic neurons and subsequent release of adrenomedullary catecholamines. It has been established that adrenomedullary catecholamine release is controlled by sympathetic preganglionic neurons and that these neurons are modulated by GABAergic inhibitory input. To further establish the neurochemical circuitry underlying spinally mediated anti-inflammation, the present study examined whether spinal muscarinic type 2 receptors are associated with this spinal GABAergic pathway. Intrathecal injection of the M2 receptor agonist, arecaidine but-2-ynyl ester tosylate (ABET) dose-dependently suppressed zymosan-induced leukocyte migration into the air pouch and increased Fos (neuronal activation marker) expression in sympathetic preganglionic neurons of the T7-T11 spinal cord segments (which mainly project to the adrenal medulla), but not in sympathetic preganglionic neurons of the T1-T6 or T12-L2 segments. These effects of arecaidine but-2-ynyl ester tosylate were completely blocked by intrathecal pretreatment with baclofen (a GABABR agonist) but not muscimol (a GABAAR agonist). Intrathecal saclofen (a GABABR antagonist), but not bicuculline (a GABAAR antagonist), significantly reduced leukocyte migration and increased Fos expression in T7-T11 sympathetic preganglionic neurons. More importantly, this intrathecal saclofen-induced anti-inflammatory effect was completely blocked by adrenalectomy or systemic pretreatment with propranonol (a β-adrenoceptor antagonist). Collectively, these novel findings suggest that activation of spinal muscarinic type 2 receptors suppress spinal GABAB receptor input and that this disinhibition mechanism ultimately leads to the release of adrenal catecholamines and a subsequent reduction in peripheral inflammation.",

keywords = "Adrenal medulla, Inflammation, Spinal cord, Sympathetic preganglionic neurons",

author = "Yoon, {Seo Yeon} and Kwon, {Young Bae} and Kim, {Hyun Woo} and Roh, {Dae Hyun} and Seo, {Hyoung Sig} and Han, {Ho Jae} and Beitz, {Alvin J.} and Lee, {Jang Hern}",

note = "Funding Information: This research was supported by a grant (M103KV010015-06K2201-01510) from Brain Research Center of the 21st Century Frontier Research Program funded by the Ministry of Science and Technology, the Republic of Korea. The publication of this manuscript was also supported by a Research Fund from the Research Institute for Veterinary Science (RIVS) in the College of Veterinary Medicine, Seoul National University, as well as the Brain Korea 21 project, in the College of Veterinary Medicine, Chonnam National University, Korea.",

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AU - Seo, Hyoung Sig

AU - Han, Ho Jae

AU - Beitz, Alvin J.

AU - Lee, Jang Hern

N1 - Funding Information: This research was supported by a grant (M103KV010015-06K2201-01510) from Brain Research Center of the 21st Century Frontier Research Program funded by the Ministry of Science and Technology, the Republic of Korea. The publication of this manuscript was also supported by a Research Fund from the Research Institute for Veterinary Science (RIVS) in the College of Veterinary Medicine, Seoul National University, as well as the Brain Korea 21 project, in the College of Veterinary Medicine, Chonnam National University, Korea.

PY - 2007/10

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N2 - Previous data from our laboratories using the mouse air pouch model demonstrated that intrathecal injection of the cholinomimetic drug, neostigmine, produces a significant peripheral anti-inflammatory effect through activation of spinal muscarinic type 2 receptors. This anti-inflammatory effect is mediated by activation of sympathetic preganglionic neurons and subsequent release of adrenomedullary catecholamines. It has been established that adrenomedullary catecholamine release is controlled by sympathetic preganglionic neurons and that these neurons are modulated by GABAergic inhibitory input. To further establish the neurochemical circuitry underlying spinally mediated anti-inflammation, the present study examined whether spinal muscarinic type 2 receptors are associated with this spinal GABAergic pathway. Intrathecal injection of the M2 receptor agonist, arecaidine but-2-ynyl ester tosylate (ABET) dose-dependently suppressed zymosan-induced leukocyte migration into the air pouch and increased Fos (neuronal activation marker) expression in sympathetic preganglionic neurons of the T7-T11 spinal cord segments (which mainly project to the adrenal medulla), but not in sympathetic preganglionic neurons of the T1-T6 or T12-L2 segments. These effects of arecaidine but-2-ynyl ester tosylate were completely blocked by intrathecal pretreatment with baclofen (a GABABR agonist) but not muscimol (a GABAAR agonist). Intrathecal saclofen (a GABABR antagonist), but not bicuculline (a GABAAR antagonist), significantly reduced leukocyte migration and increased Fos expression in T7-T11 sympathetic preganglionic neurons. More importantly, this intrathecal saclofen-induced anti-inflammatory effect was completely blocked by adrenalectomy or systemic pretreatment with propranonol (a β-adrenoceptor antagonist). Collectively, these novel findings suggest that activation of spinal muscarinic type 2 receptors suppress spinal GABAB receptor input and that this disinhibition mechanism ultimately leads to the release of adrenal catecholamines and a subsequent reduction in peripheral inflammation.

AB - Previous data from our laboratories using the mouse air pouch model demonstrated that intrathecal injection of the cholinomimetic drug, neostigmine, produces a significant peripheral anti-inflammatory effect through activation of spinal muscarinic type 2 receptors. This anti-inflammatory effect is mediated by activation of sympathetic preganglionic neurons and subsequent release of adrenomedullary catecholamines. It has been established that adrenomedullary catecholamine release is controlled by sympathetic preganglionic neurons and that these neurons are modulated by GABAergic inhibitory input. To further establish the neurochemical circuitry underlying spinally mediated anti-inflammation, the present study examined whether spinal muscarinic type 2 receptors are associated with this spinal GABAergic pathway. Intrathecal injection of the M2 receptor agonist, arecaidine but-2-ynyl ester tosylate (ABET) dose-dependently suppressed zymosan-induced leukocyte migration into the air pouch and increased Fos (neuronal activation marker) expression in sympathetic preganglionic neurons of the T7-T11 spinal cord segments (which mainly project to the adrenal medulla), but not in sympathetic preganglionic neurons of the T1-T6 or T12-L2 segments. These effects of arecaidine but-2-ynyl ester tosylate were completely blocked by intrathecal pretreatment with baclofen (a GABABR agonist) but not muscimol (a GABAAR agonist). Intrathecal saclofen (a GABABR antagonist), but not bicuculline (a GABAAR antagonist), significantly reduced leukocyte migration and increased Fos expression in T7-T11 sympathetic preganglionic neurons. More importantly, this intrathecal saclofen-induced anti-inflammatory effect was completely blocked by adrenalectomy or systemic pretreatment with propranonol (a β-adrenoceptor antagonist). Collectively, these novel findings suggest that activation of spinal muscarinic type 2 receptors suppress spinal GABAB receptor input and that this disinhibition mechanism ultimately leads to the release of adrenal catecholamines and a subsequent reduction in peripheral inflammation.

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A spinal muscarinic M2 receptor-GABAergic disinhibition pathway that modulates peripheral inflammation in mice

Abstract

Bibliographical note

Keywords

UN SDGs

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