Paul and Carole Stark Neurosciences Research Institute, Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA.
Channels (Austin). 2011 Sep-Oct;5(5):449-56. doi: 10.4161/chan.5.5.17363. Epub 2011 Sep 1.
The N-type voltage-gated calcium channel (Cav 2.2) has gained immense prominence in the treatment of chronic pain. While decreased channel function is ultimately anti-nociceptive, directly targeting the channel can lead to multiple adverse side effects. Targeting modulators of channel activity may facilitate improved analgesic properties associated with channel block and a broader therapeutic window. A novel interaction between Cav 2.2 and collapsin response mediator protein 2 (CRMP-2) positively regulates channel function by increasing surface trafficking. We recently identified a CRMP-2 peptide (TAT-CBD3), which effectively blocks this interaction, reduces or completely reverses pain behavior in a number of inflammatory and neuropathic models. Importantly, TAT-CBD3 did not produce many of the typical side effects often observed with Cav 2.2 inhibitors. Notably chronic pain mechanisms offer unique challenges as they often encompass a mix of both neuropathic and inflammatory elements, whereby inflammation likely causes damage to the neuron leading to neuropathic pain, and neuronal injury may produce inflammatory reactions. To this end, we sought to further disseminate the ability of TAT-CBD3 to alter behavioral outcomes in two additional rodent pain models. While we observed that TAT-CBD3 reversed mechanical hypersensitivity associated with a model of chronic inflammatory pain due to lysophosphotidylcholine-induced sciatic nerve focal demyelination (LPC), injury to the tibial nerve (TNI) failed to respond to drug treatment. Moreover, a single amino acid mutation within the CBD3 sequence demonstrated amplified Cav 2.2 binding and dramatically increased efficacy in an animal model of migraine. Taken together, TAT-CBD3 potentially represents a novel class of therapeutics targeting channel regulation as opposed to the channel itself.
N 型电压门控钙通道（Cav2.2）在慢性疼痛治疗中备受关注。虽然通道功能降低最终具有抗伤害感受作用，但直接靶向通道可能导致多种不良反应。靶向通道活性调节剂可能有助于改善与通道阻断相关的镇痛特性，并扩大治疗窗口。Cav2.2 与 collapsin 反应介质蛋白 2（CRMP-2）之间的新相互作用通过增加表面转运来正向调节通道功能。我们最近发现了一种 CRMP-2 肽（TAT-CBD3），它可以有效阻断这种相互作用，在多种炎症和神经病理性模型中减轻或完全逆转疼痛行为。重要的是，TAT-CBD3 没有产生 Cav2.2 抑制剂通常观察到的许多典型副作用。值得注意的是，慢性疼痛机制带来了独特的挑战，因为它们通常包含神经病理性和炎症性元素的混合，其中炎症可能导致神经元损伤，从而导致神经病理性疼痛，而神经元损伤可能产生炎症反应。为此，我们试图在另外两种啮齿动物疼痛模型中进一步传播 TAT-CBD3 改变行为结果的能力。虽然我们观察到 TAT-CBD3 逆转了由于溶血磷脂酰胆碱诱导的坐骨神经局灶性脱髓鞘（LPC）引起的慢性炎症性疼痛模型中的机械性超敏反应，但对胫骨神经（TNI）的损伤对药物治疗没有反应。此外，CBD3 序列中的单个氨基酸突变显示出与偏头痛动物模型中 Cav2.2 结合的增强和效力的显著增加。总之，TAT-CBD3 可能代表了一种新型的针对通道调节而不是通道本身的治疗药物。
