Relief of Hypersensitivity After Nerve Injury from Systemic Donepezil

Saranya devi Relief of Hypersensitivity after Nerve Injury from ALN Systemic Donepezil Involves Spinal Cholinergic and γ-Aminobutyric Acid Mechanisms Spinal ACh and GABA Mechanisms for Donepezil Analgesia Masafumi Kimura, M.D.,* Ken-ichiro Hayashida, D.V.M., Ph.D.,† James C. Eisenach, M.D.,‡ KIMURA ET AL. Shigeru Saito M.D.,§ Hideaki Obata, M.D.‖ XX ABSTRACT What We Already Know about This Topic • Donepezil increases central nervous system acetylcholine lev- Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/118/1/173/259568/0000542-201301000-00030.pdf by guest on 28 September 2021 10.1097/ALN.0b013e318277a81c Background: Evoking spinal release of acetylcholine (ACh) els and is used for treatment of dementia produces antinociception in normal animals and reduces • Increases in spinal acetylcholine levels have been implicated in the relief of neuropathic pain hypersensitivity after nerve injury, and some studies suggest January 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 anti- What This Article Tells Us That Is New 118 hypersensitivity effects of donepezil, a central nervous sys- • Donepezil increased spinal acetylcholine levels and γ- tem–penetrating cholinesterase inhibitor, in a rat model of aminobutyric acid levels to reduce nociceptive responses after nerve injury and represents a potential therapeutic pathway to neuropathic pain. reduce pain after nerve injury Methods: Male Sprague-Dawley rats were anesthetized, and L5 spinal nerve ligation was performed unilaterally. With- A antagonist; and CGP 35348 (30 μg), a γ-aminobutyric drawal threshold to a paw pressure test was measured before acid receptor type B antagonist. ACh and GABA concen- and after intraperitoneal administration of donepezil, with trations in the microdialysates from the spinal dorsal horn or without intrathecal antagonists for cholinergic and GAB- were increased after intraperitoneal donepezil treatment Aergic receptors. Microdialysis studies in the ipsilateral dor- (1 mg/kg) in both normal and spinal nerve ligation rats. sal horn of the lumbar spinal cord were also performed to Conclusions: Systemic administration of donepezil reduces measure extracellular ACh and GABA. hypersensitivity after nerve injury by increasing extracellu- Results: Donepezil increased the withdrawal threshold in lar ACh concentration, which itself induces GABA release spinal nerve ligation rats but not in normal rats. The anti- in the spinal cord. Activation of this spinal cholinergic–- hypersensitivity effect of donepezil (1 mg/kg) in spinal GABAergic interaction represents a promising treatment for nerve ligation rats was reduced by intrathecal pretreatment neuropathic pain. 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 ERIPHERAL nerve injury can result in neuropathic P pain that is not alleviated by conventional pain reliev- ers. Currently, the most common drugs for treating neuro- * Graduate Student, § Professor of Anesthesiology, ‖ Associate Professor of Anesthesiology, Department of Anesthesiology, Gunma pathic pain are antidepressants and calcium channel α2-δ University Graduate School of Medicine, Maebashi, Japan. † Assis- ligands such as gabapentin and pregabalin.1 These drugs rely tant Professor of Anesthesiology, ‡ FM James, III Professor of Anes- in part on spinal cholinergic mechanisms for analgesia,2,3 thesiology and Physiology & Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina. which suggests that cholinergic pathways may be critical in Received from the Department of Anesthesiology, Gunma Uni- the therapeutic targeting of neuropathic pain. versity Graduate School of Medicine, Maebashi, Japan. Submitted Cholinesterase inhibitors such as physostigmine and for publication March 15, 2012. Accepted for publication August 30, 4–6 2012. This work was supported by a grant (Grant-In-Aid for Scien- neostigmine produce analgesia to acute pain in humans. tific Research 20591823, to Dr. Obata) from the Ministry of Educa- A recent study demonstrated that the oral administration tion, Culture, Sports, Science and Technology, Tokyo, Japan, and of donepezil, an approved cholinesterase inhibitor for the grants (NS57594 to Dr. Eisenach and DA27690 to Dr. Hayashida) from the National Institutes of Health, Bethesda, Maryland. Timothy symptomatic treatment of Alzheimer dementia, produced an J. Brennan, Ph.D., M.D., served as Handling Editor. antihypersensitivity effect in rats after nerve injury but not in Address correspondence to Dr. Obata: Department of Anesthe- normal animals; this involved a spinal mechanism.7 Although siology, Gunma University Graduate School of Medicine, 3-39-22, Showa, Maebashi, Japan 371–8511. [email protected]. the detailed mechanism is not fully understood, manipula- Information on purchasing reprints may be found at www.anesthe- tions that increase acetylcholine (ACh) release in the spinal siology.org or on the masthead page at the beginning of this issue. cord produce analgesia via both muscarinic and nicotinic ANESTHESIOLOGY’s articles are made freely accessible to all readers, for 8,9 personal use only, 6 months from the cover date of the issue. receptors. Cholinergic signaling is an attractive target for Copyright © 2012, the American Society of Anesthesiologists, Inc. Lippincott analgesia because it may be involved in endogenous inhibition Williams & Wilkins. Anesthesiology 2013; 118:173–80 of pain10 and may be augmented under painful conditions.7,11 Anesthesiology, V 118 • No 1 173 January 2013 Spinal ACh and GABA Mechanisms for Donepezil Analgesia In the current study, we tested whether the analgesic effi- receptor antagonist, CGP 35348 (10 and 30 μg). Saline cacy of donepezil was increased in the presence of chronic or antagonist solution was administered intrathecally neuropathic injury compared with the normal state because 15 min before intraperitoneal donepezil injection. The of a greater effect on release of ACh concentration in the spi- doses of the antagonists were selected according to previous nal cord. Although previous studies suggest that stimulation studies7,8,19,20 and our preliminary studies. For intrathecal of spinal muscarinic and nicotinic ACh receptors increases administration, drugs were dissolved in saline in a volume γ-aminobutyric acid (GABA) release to inhibit pain trans- of 5 μl and injected in the L5-6 intervertebral space using mission in the spinal cord,12–16 this has never been directly a 30-gauge needle. Donepezil was a gift from Eisai Co. tested. We therefore tested the behavioral reliance of done- (Tokyo, Japan). Other drugs were purchased from Sigma pezil-mediated antihypersensitivity on activation of GABA Co. (St. Louis, MO). Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/118/1/173/259568/0000542-201301000-00030.pdf by guest on 28 September 2021 receptors and whether donepezil-induced increases in ACh would increase GABA release in the spinal cord. Microdialysis Studies ACh Measurement. Microdialysis studies were performed Materials and Methods in normal rats and those 2–3 weeks after SNL surgery in a Surgical Preparation manner as previously described.21 Anesthesia was induced by The study was approved by the Animal Care and Use Com- intraperitoneal injection with urethane (1.2–1.5 g/kg) and mittees of the Gunma University Graduate School of Medi- maintained with 0.5% isoflurane in 100% oxygen through a cine (Maebashi, Japan) and Wake Forest University School of nose cone. The left femoral vein was cannulated for transfu- Medicine (Winston-Salem, North Carolina). Male Sprague- sion of saline at a rate of 1 ml/h. For intraperitoneal injection Dawley rats (250 g) were used in all experiments. Microdi- of donepezil, a 24-gauge intravenous catheter was inserted alysis study for GABA release was performed at Wake Forest into the intraperitoneal space. Rectal temperature was main- University, and other experiments were performed at Gunma tained at 37–38°C by a heating pad placed beneath the ani- University. The animals were housed under a 12-h light– mal. The L3–L5 level of the spinal cord was exposed by a dark cycle, with food and water available ad libitum. Spinal thoracolumbar laminectomy, and the rat was placed in a ste- nerve ligation (SNL) surgery was performed as previously reotaxic apparatus. The microdialysis probe (OD = 0.22 mm, described.17 The animals were anesthetized with inhaled iso- ID = 0.20 mm, length = 2 mm, AI-8-02, Eicom Co., Kyoto, flurane in oxygen, and the right L5 spinal nerve was tightly Japan) was inserted from just lateral to the dorsal root and ligated with 5-0 silk and cut just distal to the ligature as pre- advanced at a 30° angle to a depth of 2 mm using a micro- viously described. The wound was closed, and the animals manipulator (model WR-88; Narishige, Tokyo, Japan). The were allowed to recover for 2 weeks. Animals were singly microdialysis probe was perfused with Ringer’s solution (147 M M M housed after surgery for the remainder of the experiment. m NaCl, 4 m KCl, 2.3 m CaCl2) at a constant flow rate For behavioral studies, each rat was used two to three times (1 μl/min) using a syringe pump (ESP-64, Eicom Co.). After at 4- to 5-day intervals. In total, 82 SNL rats were used. 120 min of constant perfusion, 30-min perfusate fractions were collected

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