Rahman W, Dickenson A H
Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.
Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.
Neuroscience. 2015 Jun 4;295:103-16. doi: 10.1016/j.neuroscience.2015.03.042. Epub 2015 Mar 25.
Voltage-gated sodium channel blockers are not traditionally recommended for osteoarthritis (OA) pain therapy, but given the large peripheral drive that follows OA development there is a rationale for their use. Using a rat model of monosodium iodoacetate (MIA)-induced OA we used in vivo electrophysiology to assess the effects of the Nav1.7- and Nav1.8-selective antagonists, ProTxII and A-803467 respectively, on the evoked activity of spinal dorsal horn neurons in response to electrical, mechanical and thermal stimuli applied to the peripheral receptive field. These studies allow examination of the roles of these channels in suprathreshold stimuli, not amenable to behavioral threshold measures. Spinal administration of ProTxII significantly reduced neuronal responses evoked by mechanical punctate (von Frey (vF) 8-60g) and noxious thermal (45 and 48°C) stimuli in MIA rats only. A-803467 significantly inhibited neuronal responses evoked by vF 8-60g and 48°C heat after spinal administration; significantly inhibited responses evoked by brush, vFs 26-60g and 40-48°C stimuli after systemic administration; significantly inhibited the electrically evoked Aδ-, C-fiber, post-discharge, Input and wind-up responses and the brush, vFs 8-60g and 45-48°C evoked neuronal responses after intra plantar injection in the MIA group. In comparison A-803467 effects in the sham group were minimal and included a reduction of the neuronal response evoked by vF 60g and 45°C heat stimulation after spinal administration, no effect after systemic administration and an inhibition of the evoked response to 45°C heat after intra plantar injection only. The observed selective inhibitory effect of ProTxII and A-803467 for the MIA-treated group suggests an increased role of Nav1.7 and 1.8 within nociceptive pathways in the arthritic condition, located at peripheral and central sites. These findings demonstrate the importance of, and add to, the mechanistic understanding of these channels in osteoarthritic pain.
传统上不推荐使用电压门控钠通道阻滞剂来治疗骨关节炎（OA）疼痛，但鉴于OA发展后存在较大的外周驱动因素，使用它们是有理论依据的。我们利用碘乙酸钠（MIA）诱导的OA大鼠模型，通过体内电生理学方法，分别评估Nav1.7和Nav1.8选择性拮抗剂ProTxII和A-803467对施加于外周感受野的电、机械和热刺激所诱发的脊髓背角神经元活动的影响。这些研究能够考察这些通道在阈上刺激中的作用，而阈上刺激并不适用于行为阈值测量。仅在MIA大鼠中，脊髓注射ProTxII可显著降低机械点状刺激（von Frey（vF）8 - 60g）和有害热刺激（45和48°C）所诱发的神经元反应。脊髓注射后，A-803467可显著抑制vF 8 - 60g和48°C热刺激所诱发的神经元反应；全身给药后，可显著抑制刷擦、vF 26 - 60g和40 - 48°C刺激所诱发的反应；在MIA组中，足底注射后，可显著抑制电诱发的Aδ纤维、C纤维、后放电、输入和易化反应以及刷擦、vF 8 - 60g和45 - 48°C诱发的神经元反应。相比之下，A-803467对假手术组的影响极小，包括脊髓注射后抑制vF 60g和45°C热刺激所诱发的神经元反应，全身给药后无影响，仅在足底注射后抑制对45°C热刺激的诱发反应。ProTxII和A-803467对MIA治疗组的选择性抑制作用表明，在关节炎状态下，Nav1.7和1.8在伤害性感受通路中的作用增强，其作用位点位于外周和中枢。这些发现证明了这些通道在骨关节炎疼痛中的重要性，并加深了对其作用机制的理解。
