GABA_B receptor-mediated selective peripheral analgesia by the non-proteinogenic amino acid, isovaline

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• 作者：R.A. Whitehead ; E. Puil ; C.R. Ries ; S.K.W. Schwarz ; R.A. Wall ; J.E. Cooke ; I. Putrenko ; N.A. Sallam ; B.A. MacLeod ; ^{bmacleod@mail.ubc.ca}
• 关键词：BSA ; bovine serum albumin ; BHS ; Behavioural Hypoactivity Score ; CNS ; central nervous system ; DAPI ; 4&prime ; -6-diamidino-2-phenylindole ; GABA ; glycine and 纬-aminobutyric acid ; MIA ; monoiodoacetate ; PBS ; phosphate-buffered saline ; PGE2 ; prostaglandin E2
• 刊名：Neuroscience
• 出版年：2012
• 期刊代码：50_03064522
• 类别：neu
• 出版时间：28 June, 2012
• 卷：213
• 期：Complete
• 页码：154-160
• 文件大小：573 K

摘要

Peripherally restricted analgesics are desirable to avoid central nervous system (CNS) side effects of opioids. Nonsteroidal anti-inflammatory drugs produce peripheral analgesia but have significant toxicity. GABA_B receptors represent peripheral targets for analgesia but selective GABA_B agonists like baclofen cross the blood-brain barrier. Recently, we found that the CNS-impermeant amino acid, isovaline, produces analgesia without apparent CNS effects. On observing that isovaline has GABA_B activity in brain slices, we examined the hypothesis that isovaline produces peripheral analgesia mediated by GABA_B receptors. We compared the peripheral analgesic and CNS effect profiles of isovaline, baclofen, and GABA (a CNS-impermeant, unselective GABA_B agonist). All three amino acids attenuated allodynia induced by prostaglandin E2 injection into the mouse hindpaw and tested with von Frey filaments. The antiallodynic actions of isovaline, baclofen, and GABA were blocked by the GABA_B antagonist, CGP52432, and potentiated by the GABA_B modulator, CGP7930. We measured Behavioural Hyperactivity Scores and temperature change as indicators of GABAergic action in the CNS. ED₉₅ doses of isovaline and GABA produced no CNS effects while baclofen produced substantial sedation and hypothermia. In a mouse model of osteoarthritis, isovaline restored performance during forced exercise to baseline values. Immunohistochemical staining of cutaneous layers of the analgesic test site demonstrated co-localization of GABA_B1 and GABA_B2 receptor subunits on fine nerve endings and keratinocytes. Isovaline represents a new class of peripherally restricted analgesics without CNS effects, mediated by cutaneous GABA_B receptors.