Relief of Hypersensitivity after Nerve Injury from Systemic Donepezil Involves Spinal Cholinergic and γ-Aminobutyric Acid Mechanisms

• Published in: Anesthesiology (Philadelphia) Vol. 118; no. 1; pp. 173 - 180
• Main Authors: KIMURA, Masafumi, HAYASHIDA, Ken-Ichiro, EISENACH, James C, SAITO, Shigeru, OBATA, Hideaki
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 2013
• Subjects: Anesthesia; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Atropine - pharmacology; Bicuculline - pharmacology; Biological and medical sciences; Cholinergic Agents - blood; Cholinergic Agents - pharmacology; Cholinesterase Inhibitors - pharmacology; Disease Models, Animal; GABA Agents - blood; GABA Agents - pharmacology; GABA Antagonists - pharmacology; GABA-A Receptor Antagonists - pharmacology; gamma-Aminobutyric Acid - blood; gamma-Aminobutyric Acid - pharmacology; Indans - pharmacology; Male; Mecamylamine - pharmacology; Medical sciences; Neuralgia - drug therapy; Nicotinic Antagonists - pharmacology; Organophosphorus Compounds - pharmacology; Parasympatholytics - pharmacology; Peripheral Nerve Injuries; Piperidines - pharmacology; Rats; Rats, Sprague-Dawley; Spinal Nerves - drug effects; Enzyme; Psychotropic; Hypersensitivity; Enzyme inhibitor; Esterases; Antialzheimer agent; Acetylcholinesterase; Carboxylic ester hydrolases; Donepezil; Nootropic agent; Piperidine derivatives; Hydrolases; Anesthesia; Anticholinesterase agent
• ISSN: 0003-3022; 1528-1175
• DOI: 10.1097/ALN.0b013e318277a81c

Evoking spinal release of acetylcholine (ACh) produces antinociception in normal animals and reduces hypersensitivity after nerve injury, and some studies suggest that ACh-mediated analgesia relies on γ-aminobutyric acid (GABA)-ergic signaling in the spinal cord. In this study, the authors tested the spinal mechanisms underlying the antihypersensitivity effects of donepezil, a central nervous system-penetrating cholinesterase inhibitor, in a rat model of neuropathic pain. Male Sprague-Dawley rats were anesthetized, and L5 spinal nerve ligation was performed unilaterally. Withdrawal threshold to a paw pressure test was measured before and after intraperitoneal administration of donepezil, with or without intrathecal antagonists for cholinergic and GABAergic receptors. Microdialysis studies in the ipsilateral dorsal horn of the lumbar spinal cord were also performed to measure extracellular ACh and GABA. Donepezil increased the withdrawal threshold in spinal nerve ligation rats but not in normal rats. The antihypersensitivity effect of donepezil (1 mg/kg) in spinal nerve ligation rats was reduced by intrathecal pretreatment with atropine (30 μg), a muscarinic receptor antagonist; mecamylamine (100 μg), a nicotinic receptor antagonist; bicuculline (0.03 μg), a γ-aminobutyric acid receptor type A antagonist; and CGP 35348 (30 μg), a γ-aminobutyric acid receptor type B antagonist. ACh and GABA concentrations in the microdialysates from the spinal dorsal horn were increased after intraperitoneal donepezil treatment (1 mg/kg) in both normal and spinal nerve ligation rats. Systemic administration of donepezil reduces hypersensitivity after nerve injury by increasing extracellular ACh concentration, which itself induces GABA release in the spinal cord. Activation of this spinal cholinergic-GABAergic interaction represents a promising treatment for neuropathic pain.