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

PMID 17765931


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 M(2) 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(B)R agonist) but not muscimol (a GABA(A)R agonist). Intrathecal saclofen (a GABA(B)R antagonist), but not bicuculline (a GABA(A)R 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 beta-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.

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Saclofen, solid