Electrophysiological evidence for voltage-gated calcium channel 2 (Cav2) modulation of mechano- and thermosensitive spinal neuronal responses in a rat model of osteoarthritis.
Electrophysiological evidence for voltage-gated calcium channel 2 (Cav2) modulation of mechano- and thermosensitive spinal neuronal responses in a rat model of osteoarthritis.
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DOI：
10.1016/j.neuroscience.2015.07.073
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发表时间：
2015-10-01
期刊：
影响因子：
3.3
通讯作者：
Dickenson AH
中科院分区：
文献类型：
--
作者：
Rahman W;Patel R;Dickenson AH
TROX-1 对神经元活动的 MIA 依赖性镇痛作用。 Cav2.2 通道功能的改变会导致骨关节炎 (OA) 疼痛。阻断 Cav2.2 通道具有治疗 OA 疼痛的治疗潜力。骨关节炎 (OA) 仍然是西方社会最大的医疗负担之一，其临床表现以慢性衰弱性疼痛为主，但许多患者的治疗策略却不够充分。更好的镇痛药的开发取决于对介导骨关节炎疼痛的分子机制的进一步了解。电压门控钙通道 2.2 (Cav2.2) 在脊髓伤害性传递中发挥着关键作用，因此阻断 Cav2.2 活性为 OA 疼痛治疗提供了一个有吸引力的机会，但唯一获得许可的 Cav2.2 拮抗剂齐考尼肽 (PrilatTM) 的用途有限。 TROX-1 是一种口服、使用依赖性和状态选择性的 Cav2 拮抗剂，主要通过阻断 Cav2.2 发挥镇痛作用，与齐考尼肽相比，治疗窗有所改善。使用 2 mg 碘乙酸钠 (MIA) 诱导 OA 的大鼠模型，我们使用体内电生理学来评估 TROX-1 的脊髓或全身给药对宽动态范围脊髓背角神经元诱发活动的影响，这些神经元响应于施加于大鼠的电、自然机械（动态刷和 von Frey 2、8、26 和 6 g）和热（40、45 和 45 °C）刺激。外周感受野。膝关节 MIA 注射导致同侧后爪机械过敏和负重不对称。脊髓给予 TROX-1（0.1 和 1 μg/50 μl）仅在 MIA 大鼠中对动态刷、机械（冯弗雷丝 (vF) 8、26 和 60 g）和有害热（45 和 48 °C）引起的神经元反应产生显着的剂量相关抑制。全身给予 TROX-1 对 MIA 大鼠的机械（vF 8、26 和 60 g）诱发的神经元反应产生显着抑制。 TROX-1 没有对假手术对照组的任何神经元测量产生任何显着影响。我们的体内电生理学结果证明了 TROX-1 的病理状态依赖性作用，这表明 Cav2（可能是 Cav2.2）通道在介导 OA 疼痛中的功能作用增强。
MIA-dependent antinociceptive effect of TROX-1 on neuronal activity. Alterations in Cav2.2 channel function contribute to osteoarthritic (OA) pain. Blocking Cav2.2 channels has therapeutic potential for treating OA pain. Osteoarthritis (OA) remains one of the greatest healthcare burdens in western society, with chronic debilitating pain-dominating clinical presentation yet therapeutic strategies are inadequate in many patients. Development of better analgesics is contingent on improved understanding of the molecular mechanisms mediating OA pain. Voltage-gated calcium channels 2.2 (Cav2.2) play a critical role in spinal nociceptive transmission, therefore blocking Cav2.2 activity represents an attractive opportunity for OA pain treatment, but the only available licensed Cav2.2 antagonist ziconitide (PrilatTM) is of limited use. TROX-1 is an orally available, use dependent and state-selective Cav2 antagonist, exerting its analgesic effect primarily via Cav2.2 blockade, with an improved therapeutic window compared with ziconitide. Using a rat model of monosodium iodoacetate (MIA), 2 mg, induced OA we used in vivo electrophysiology to assess the effects of spinal or systemic administration of TROX-1 on the evoked activity of wide dynamic range spinal dorsal horn neurons in response to electrical, natural mechanical (dynamic brush and von Frey 2, 8, 26 and 6 g) and thermal (40, 45 and 45 °C) stimuli applied to the peripheral receptive field. MIA injection into the knee joint resulted in mechanical hypersensitivity of the ipsilateral hind paw and weight-bearing asymmetry. Spinal administration of TROX-1 (0.1 and 1 μg/50 μl) produced a significant dose-related inhibition of dynamic brush, mechanical (von Frey filament (vF) 8, 26 and 60 g) and noxious thermal-(45 and 48 °C) evoked neuronal responses in MIA rats only. Systemic administration of TROX-1 produced a significant inhibition of the mechanical-(vF 8, 26 and 60 g) evoked neuronal responses in MIA rats. TROX-1 did not produce any significant effect on any neuronal measure in Sham controls. Our in vivo electrophysiological results demonstrate a pathological state-dependent effect of TROX-1, which suggests an increased functional role of Cav2, likely Cav2.2, channels in mediating OA pain.