Contribution of Transient Receptor Potential Ankyrin 1 to Chronic Pain in Aged Mice With Complete Freund's Adjuvant-Induced Arthritis
Contribution of Transient Receptor Potential Ankyrin 1 to Chronic Pain in Aged Mice With Complete Freund's Adjuvant-Induced Arthritis
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DOI：
10.1002/art.38724
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发表时间：
2014-09-01
影响因子：
13.3
通讯作者：
Stucky, Cheryl L.
中科院分区：
文献类型：
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作者：
Garrison, Sheldon R.;Stucky, Cheryl L.
Objective.研究炎症疼痛机械敏感性的年龄相关差异，并确定瞬时受体电位锚蛋白1（TRPA 1）对慢性炎症期间完全弗氏佐剂（CFA）诱导关节炎的年轻和老年小鼠机械超敏反应的贡献。在将CFA注射到足底后爪后，在行为上测量年轻（3月龄）和老年（24月龄）野生型（TRPA 1（+/+））小鼠和TRPA 1缺陷型（TRPA 1（-/-））小鼠的机械敏感性8周。通过组织学分析和后爪测量来评价炎症的严重程度。评估小鼠皮肤隐神经的离体制备物的C-纤维敏感性。在未受伤的野生型小鼠中，老年动物对机械刺激的敏感性低于年轻动物。来自TRPA 1（-/-）小鼠的C纤维的传入记录表明，TRPA 1在两个年龄组中均有助于正常的机械敏感性。注射CFA后，年轻和老年TRPA 1（+/+）小鼠均表现出机械超敏反应。在注射CFA的年轻TRPA 1（-/-）小鼠中，机械超敏反应的峰值发展延迟至第4周，此时它们表现出机械缩爪阈值的急剧下降（9倍），而老年TRPA 1（-/-）小鼠在注射CFA后8周的任何时间都没有表现出机械超敏反应。隐神经的C纤维记录支持这些发现，结果表明年轻和老年TRPA 1（+）/（+）小鼠在CFA注射后8周表现出增加的动作电位放电（分别增加25%和60%）。有趣的是，在注射CFA的TRPA 1（-/-）小鼠中，年轻小鼠的C纤维机械放电显著增加（增加80%），而老年小鼠的C纤维则没有。这些发现揭示了老年和年轻小鼠长期机械行为敏感性的显着差异，并表明TRPA 1可能是响应机械刺激从急性向慢性炎症性疼痛转变的关键因素，以及选择性地在老年小鼠中发展伤害感受器敏化。
Objective. To investigate age-related differences in mechanical sensitivity to inflammatory pain and determine the contribution of transient receptor potential ankyrin 1 (TRPA1) to mechanical hypersensitivity during chronic inflammation in young and aged mice with complete Freund's adjuvant (CFA)-induced arthritis.Methods. Mechanical sensitivity in young (3-month-old) and aged (24-month-old) wild-type (TRPA1(+/+)) mice and TRPA1-deficient (TRPA1(-/-)) mice was measured behaviorally for 8 weeks following injection of CFA into the plantar hind paw. The severity of inflammation was evaluated by histologic analyses and hind-paw measurements. Ex vivo preparations of the skin saphenous nerve from mice were assessed for C-fiber sensitivity.Results. Among naive (uninjured) wild-type mice, aged animals were less sensitive than young animals to mechanical stimuli. Afferent recordings of C-fibers from TRPA1(-/-) mice indicated that TRPA1 contributes to the normal mechanical sensitivity in both age groups. Following injection of CFA, both young and aged TRPA1(+/+) mice exhibited mechanical hypersensitivity. In young TRPA1(-/-) mice injected with CFA, peak development of mechanical hypersensitivity was delayed until week 4, when they exhibited a sharp decrease (9-fold) in the mechanical paw withdrawal threshold, whereas aged TRPA1(-/-) mice did not exhibit mechanical hypersensitivity at any time during the 8 weeks after CFA injection. Recordings of C-fibers from the saphenous nerve supported these findings, with results indicating that both young and aged TRPA1(+)/(+) mice exhibited increased action potential firing at 8 weeks after CFA injection (increases of 25% and 60%, respectively). Interestingly, among TRPA1(-/-) mice injected with CFA, mechanical firing was increased markedly in the C-fibers of young mice (increase of 80%) but not in the C-fibers of aged mice.Conclusion. These findings reveal marked differences in the long-term mechanical behavioral sensitivity of aged and young mice, and suggest that TRPA1 may be a key contributor to the transition from acute to chronic inflammatory pain in response to mechanical stimuli as well as to the development of nociceptor sensitization selectively in aged mice.