Xiao W H, Yu A L, Sorkin L S
Department of Anesthesiology, University of California, San Diego, USA.
Pain. 1997 Jan;69(1-2):145-51. doi: 10.1016/s0304-3959(96)03280-0.
An animal model showing mechanical allodynia following systemic bolus injection of a human/mouse chimeric monoclonal antibody to the GD2 ganglioside (ch14.18) has been established (e.g. pain behavior generated by a light tactile stimulus). This is of clinical relevance since ch14.18 is a promising experimental treatment for pediatric neuroblastoma. The present study examined the hypothesis that allodynic effects of the anti-GD2 antibody are mediated by actions on cutaneous nerve fibers. After determining the basal magnitude of the mechanical stimulus required to produce withdrawal, ch14.18, a murine form of the anti-GD2 antibody of IgG2a isotype (14G2a), a control murine anti-melanoma antibody of IgG2a isotype (9.2.27) or saline was injected through a previously implanted jugular cannula. The experimenter was blinded to the syringe contents. Withdrawal threshold was tested at 15 min intervals for 1 h. After administration of either ch14.18 or 14G2a mechanical allodynia typically started within the first 15 min and persisted throughout the hour of behavioral testing. In the control antibody group, a modest change in tactile withdrawal threshold was observed at the 60 min time point only. Rats were then anesthetized with pentobarbital and prepared for single fiber recordings from the sural nerve. Fibers were classified based on conduction velocity, as A beta (> 25 m/s), A delta (2-25 m/s) or C (< 2 m/s). Background activity (BA) was observed in a significant number of A delta (12/61) and C (32/42) fibers in both anti-GD2 treated groups compared to the anti-melanoma antibody (1/17 A delta and 2/10 C fibers) and saline (0/26 A delta and 0/19 C fibers) treated groups. Mean mechanical threshold for A delta fibers in all three antibody treated groups was significantly reduced compared to the saline control; this was not observed for C-fibers in any group. Intravenous bolus injection (15 mg/kg) and infusion of lidocaine (plasma level 0.3-2.2 micrograms/ml) both reduced anti-GD2 associated BA. These data demonstrate that mechanical-allodynia could be produced by action(s) of the anti-GD2 antibody (direct or indirect) on peripheral nerves and suggest intravenous lidocaine as part of the analgesic regimen accompanying anti-GD2 antibody treatment.
已建立一种动物模型，该模型在全身推注针对GD2神经节苷脂的人/鼠嵌合单克隆抗体（ch14.18）后会出现机械性异常性疼痛（例如由轻触觉刺激产生的疼痛行为）。这具有临床相关性，因为ch14.18是一种有前景的小儿神经母细胞瘤实验性治疗药物。本研究检验了抗GD2抗体的异常性疼痛效应是通过对皮肤神经纤维的作用介导的这一假设。在确定产生退缩所需的机械刺激的基础强度后，通过先前植入的颈静脉插管注射ch14.18（IgG2a同种型抗GD2抗体的鼠形式，即14G2a）、IgG2a同种型的对照鼠抗黑色素瘤抗体（9.2.27）或生理盐水。实验者对注射器内容物不知情。以15分钟的间隔测试退缩阈值，持续1小时。给予ch14.18或14G2a后，机械性异常性疼痛通常在最初15分钟内开始，并在整个行为测试小时内持续存在。在对照抗体组中，仅在60分钟时间点观察到触觉退缩阈值有适度变化。然后用戊巴比妥麻醉大鼠，并准备从腓肠神经进行单纤维记录。根据传导速度将纤维分类为Aβ（>25 m/s）、Aδ（2 - 25 m/s）或C（<2 m/s）。与抗黑色素瘤抗体治疗组（1/17条Aδ纤维和2/10条C纤维）和生理盐水治疗组（0/26条Aδ纤维和0/19条C纤维）相比，在两个抗GD2治疗组中，大量的Aδ（12/61）和C（32/42）纤维观察到背景活动（BA）。与生理盐水对照组相比，所有三个抗体治疗组中Aδ纤维的平均机械阈值均显著降低；在任何组的C纤维中均未观察到这种情况。静脉推注（15 mg/kg）和输注利多卡因（血浆水平0.3 - 2.2微克/毫升）均降低了与抗GD2相关的BA。这些数据表明，抗GD2抗体（直接或间接）对周围神经的作用可产生机械性异常性疼痛，并提示静脉注射利多卡因作为抗GD2抗体治疗伴随的镇痛方案的一部分。
