過度な歩行運動が糖尿病性神経障害性足痛を促進する：ラットモデルでの後肢懸垂トレッドミル運動実験

Excessive walking exercise precipitates diabetic neuropathic foot pain: hind paw suspension treadmill exercise experiment in a rat model.

• Jong Geol Do
• Sun Up Noh
• Seoung Wan Chae
• Kyung Jae Yoon
• Yong-Taek Lee

抄録

過度な機械的負荷が糖尿病性神経障害に及ぼす有害な影響や、糖尿病性神経障害症状が足に多い理由は明らかになっていない。本研究では、ラットを用いた後足懸垂トレッドミル運動モデルを用いて、前足に加わる機械的負荷が、特に糖尿病状態で神経障害性疼痛を促進するかどうかを検討した。32匹のラットを糖尿病(DM)の有無と前足への機械的負荷の強さによって6つのグループに分けた。DM-Hi（高強度）、DM-Lo（低強度）、DM-No（非機械的負荷）、Sham-Hi、Sham-Lo、Sham-No。高強度または低強度の機械的負荷については、トレッドミル歩行運動を、それぞれ後肢懸垂の有無にかかわらず実施した。前足の機械的離脱閾値はDM機械的負荷群（DM-Hi群およびDM-Lo群）のみ8週後に有意に減少し，高強度負荷の方が低強度負荷よりも有意に前足離脱閾値を減少させた．DM-Hi群のみでは、マクロファージ遊走抑制因子（MIF）が有意に増加し、前足の表皮内神経線維（IENF）が有意に減少した。糖尿病状態では、過度の歩行などの機械的過負荷が機械的アロディニアを誘発し、IENFを損傷する可能性が高く、これが糖尿病性神経障害症状が足部に多い理由を説明していると考えられます。この知見は、炎症過程ではなく、MIFなどの細胞内シグナル伝達カスケードのアップレギュレーションに関係している可能性があります。

The harmful effects of excessive mechanical loading on diabetic neuropathy and the reason diabetic neuropathic symptoms are common in feet are unclear. In this study, the hind paw suspension treadmill exercise model was used in rats to investigate whether mechanical loading applied to the front paws precipitates neuropathic pain, especially in diabetic conditions. Thirty-two rats were divided into six groups according to the presence of diabetes (DM) and the intensity of mechanical loading applied to the front paws: DM-Hi (high-intensity); DM-Lo (low-intensity); DM-No (non-mechanical loading); Sham-Hi; Sham-Lo; and Sham-No. DM was induced by streptozotocin injection. For high-intensity or low-intensity mechanical loading, treadmill walking exercise was conducted with or without hind paw suspension, respectively. The mechanical withdrawal threshold of the front paw decreased significantly after 8 weeks only in the DM mechanical loading groups (DM-Hi and DM-Lo), and high-intensity loading more significantly decreased the front-paw withdrawal threshold than low-intensity loading. In the DM-Hi group only, macrophage migration inhibitory factor (MIF) increased significantly, and intra-epidermal nerve fibers (IENF) in the front paws decreased significantly. In diabetic conditions, mechanical overloading such as excessive walking is likely to precipitate mechanical allodynia and damage IENF¸ which could explain why diabetic neuropathic symptoms are common in feet. This finding might be related to up-regulation of intracellular signaling cascades such as MIF, rather than inflammatory processes.