Department of Anatomy and Cell Biology, Oklahoma State University Center for Health Sciences, 1111 West 17th Street, Tulsa, OK 74107, USA.
Neuroscience. 2011 Oct 13;193:452-65. doi: 10.1016/j.neuroscience.2011.06.069. Epub 2011 Jul 28.
Nerve growth factor (NGF) antagonism has long been proposed as a chronic pain treatment. In 2010, the FDA suspended clinical trials using tanezumab, a humanized monoclonal anti-NGF antibody, to treat osteoarthritis due to worsening joint damage in 16 patients. Increased physical activity in the absence of acute pain which normally prevents self-harm was purported as a potential cause. Such an adverse effect is consistent with an extension of tanezumab's primary mechanism of action by decreasing pain sensitivity below baseline levels. In animal inflammatory pain models, NGF antagonism decreases intraepidermal nerve fiber (IENF) density and attenuates increases in expression of nociception-related proteins, such as calcitonin gene-related peptide (CGRP) and substance P (SP). Little is known of the effects of NGF antagonism in noninflamed animals and the hypoalgesia that ensues. In the current study, we immunized rats with NGF or cytochrome C (cytC) and examined (1) nocifensive behaviors with thermal latencies, mechanical thresholds, the hot plate test, and the tail flick test, (2) IENF density, and (3) expression of CGRP, SP, voltage-gated sodium channel 1.8 (Nav1.8), and glutaminase in subpopulations of dorsal root ganglion (DRG) neurons separated by size and isolectin B4 (IB4) labeling. Rats with high anti-NGF titers had delayed responses on the hot plate test but no other behavioral abnormalities. Delayed hot plate responses correlated with lower IENF density. CGRP and SP expression was decreased principally in medium (400-800 μm(2)) and small neurons (<400 μm(2)), respectively, regardless of IB4 labeling. Expression of Nav1.8 was only decreased in small and medium IB4 negative neurons. NGF immunization appears to result in a more profound antagonism of NGF than tanezumab therapy, but we hypothesize that decreases in IENF density and nociception-related protein expression are potential mechanisms for tanezumab-induced hypoalgesia.
神经生长因子 (NGF) 拮抗剂一直被提议作为慢性疼痛治疗方法。2010 年，由于 16 名患者的关节损伤恶化，美国食品和药物管理局暂停了使用人源化单克隆抗 NGF 抗体 tanezumab 治疗骨关节炎的临床试验。据称，缺乏通常可防止自残的急性疼痛而增加的身体活动是潜在原因。这种不良反应与 tanezumab 通过将疼痛敏感性降低至基线以下而扩展其主要作用机制一致。在动物炎症性疼痛模型中，NGF 拮抗剂减少表皮内神经纤维 (IENF) 密度，并减弱伤害感受相关蛋白（如降钙素基因相关肽 (CGRP) 和 P 物质 (SP)）表达的增加。对于非炎症动物和随之而来的低痛觉，人们知之甚少。在当前的研究中，我们用 NGF 或细胞色素 C (cytC) 免疫大鼠，并检查了 (1) 热潜伏期、机械阈值、热板试验和尾巴拍打试验的伤害性行为，(2) IENF 密度，以及 (3) 大小和异硫氰酸荧光素 B4 (IB4) 标记的背根神经节 (DRG) 神经元亚群中 CGRP、SP、电压门控钠通道 1.8 (Nav1.8) 和谷氨酰胺酶的表达。具有高抗 NGF 滴度的大鼠在热板试验中反应延迟，但没有其他行为异常。热板试验的延迟反应与 IENF 密度降低相关。CGRP 和 SP 的表达分别主要在中（400-800 μm2）和小神经元（<400 μm2）中减少，而与 IB4 标记无关。Nav1.8 的表达仅在小和中 IB4 阴性神经元中减少。NGF 免疫似乎导致比 tanezumab 治疗更严重的 NGF 拮抗作用，但我们假设 IENF 密度和伤害感受相关蛋白表达的降低是 tanezumab 引起的低痛觉的潜在机制。
