Sluka Kathleen A, Price Margaret P, Breese Nicole M, Stucky Cheryl L, Wemmie John A, Welsh Michael J
Physical Therapy and Rehabilitation Science Graduate Program, 1-242 Medical Education Building, University of Iowa, Iowa City, IA 52242, USA Neuroscience Graduate Program, University of Iowa, Iowa City, IA 52242, USA Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA Department of Psychiatry, University of Iowa, Iowa City, IA 52242, USA Department of Veterans Affairs Medical Center, Iowa City, IA 52242, USA.
Pain. 2003 Dec;106(3):229-239. doi: 10.1016/S0304-3959(03)00269-0.
Clinically, chronic pain and hyperalgesia induced by muscle injury are disabling and difficult to treat. Cellular and molecular mechanisms underlying chronic muscle-induced hyperalgesia are not well understood. For this reason, we developed an animal model where repeated injections of acidic saline into one gastrocnemius muscle produce bilateral, long-lasting mechanical hypersensitivity of the paw (i.e. hyperalgesia) without associated tissue damage. Since acid sensing ion channels (ASICs) are found on primary afferent fibers and respond to decreases in pH, we tested the hypothesis that ASICs on primary afferent fibers innervating muscle are critical to development of hyperalgesia and central sensitization in response to repeated intramuscular acid. Dorsal root ganglion neurons innervating muscle express ASIC3 and respond to acidic pH with fast, transient inward and sustained currents that resemble those of ASICs. Mechanical hyperalgesia produced by repeated intramuscular acid injections is prevented by prior treatment of the muscle with the non-selective ASIC antagonist, amiloride, suggesting ASICs might be involved. ASIC3 knockouts do not develop mechanical hyperalgesia to repeated intramuscular acid injection when compared to wildtype littermates. In contrast, ASIC1 knockouts develop hyperalgesia similar to their wildtype littermates. Extracellular recordings of spinal wide dynamic range (WDR) neurons from wildtype mice show an expansion of the receptive field to include the contralateral paw, an increased response to von Frey filaments applied to the paw both ipsilaterally and contralaterally, and increased response to noxious pinch contralaterally after the second intramuscular acid injection. These changes in WDR neurons do not occur in ASIC3 knockouts. Thus, activation of ASIC3s on muscle afferents is required for development of mechanical hyperalgesia and central sensitization that normally occurs in response to repeated intramuscular acid. Therefore, interfering with ASIC3 might be of benefit in treatment or prevention of chronic hyperalgesia.
临床上，肌肉损伤引起的慢性疼痛和痛觉过敏会使人丧失能力且难以治疗。慢性肌肉诱导性痛觉过敏的细胞和分子机制尚未完全明确。因此，我们建立了一种动物模型，即向一侧腓肠肌反复注射酸性盐水会导致双侧爪子出现持久的机械性超敏反应（即痛觉过敏），且无相关组织损伤。由于在初级传入纤维上发现了酸敏感离子通道（ASICs），并且它们对pH值降低有反应，我们测试了这样一个假设：支配肌肉的初级传入纤维上的ASICs对于痛觉过敏的发展以及对反复肌肉内注射酸的中枢敏化至关重要。支配肌肉的背根神经节神经元表达ASIC3，并对酸性pH值产生快速、短暂的内向电流和持续电流，类似于ASICs的电流。预先用非选择性ASIC拮抗剂阿米洛利处理肌肉可预防反复肌肉内注射酸所产生的机械性痛觉过敏，这表明ASICs可能参与其中。与野生型同窝小鼠相比，ASIC3基因敲除小鼠在反复肌肉内注射酸时不会出现机械性痛觉过敏。相反，ASIC1基因敲除小鼠产生的痛觉过敏与野生型同窝小鼠相似。对野生型小鼠脊髓广动力范围（WDR）神经元的细胞外记录显示，感受野扩大到包括对侧爪子，对同侧和对侧爪子施加的von Frey细丝的反应增强，并且在第二次肌肉内注射酸后对侧有害捏压的反应增强。这些WDR神经元的变化在ASIC3基因敲除小鼠中不会出现。因此，肌肉传入纤维上ASIC3的激活是机械性痛觉过敏和中枢敏化发展所必需的，而这种痛觉过敏和中枢敏化通常是对反复肌肉内注射酸的反应。因此，干扰ASIC3可能对慢性痛觉过敏的治疗或预防有益。
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