Iwakura Nahoko, Ohtori Seiji, Orita Sumihisa, Yamashita Masaomi, Takahashi Kazuhisa, Kuniyoshi Kazuki
Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.
J Hand Surg Am. 2010 Feb;35(2):267-73. doi: 10.1016/j.jhsa.2009.10.030. Epub 2010 Jan 8.
Nerve growth factor (NGF), via the high-affinity receptor, tyrosine kinase A, has been widely reported as a mediator of pain caused by inflammation. A clinical trial has suggested that anti-NGF antibody is effective for pain caused by osteoarthritis of the knee. However, adverse events such as headache (8.9%), upper respiratory tract infection (7.3%), and paresthesia (6.8%) were reported. We hypothesized that inhibition of the low-affinity NGF receptor, p75 neurotrophin receptor (p75NTR), is also effective for joint pain and may reduce side effects. This study examined suppression of pain behavior and expression of pain-inducing neuropeptides such as calcitonin gene-related peptide (CGRP) and p75NTR in dorsal root ganglia neurons by a p75NTR inhibitory antibody in a rat model of wrist joint inflammatory pain.
We injected complete Freund's adjuvant (CFA) into the wrist joint of rats and used this as a model of inflammatory pain. We applied 10 microL of saline (CFA + saline group; n = 20) or 1, 10, or 50 microL of a p75NTR inhibitory antibody (CFA + p75NTR inhibitory antibody group; n = 40) directly to the inflamed joint in the rats. Mechanical hyperalgesia was measured for 2 weeks using von Frey filaments. We assessed CGRP and p75NTR expression in C8 dorsal root ganglia immunochemically. Adverse events such as loss of weight and/or appetite, constipation, and infection were examined.
p75NTR inhibitory antibody reduced mechanical hyperalgesia caused by CFA (p<.05 vs controls) in the rat model (p<.01 vs saline), without any adverse events. We found that 10 and 50 microL of a p75NTR inhibitory antibody were more effective for pain, without a significant difference between doses. CGRP and p75NTR immunoreactivity was upregulated in the CFA + saline groups compared with a control group (p<.01). However, direct p75NTR inhibitory antibody application decreased CGRP and p75NTR expression after wrist inflammation (p<.01).
p75NTR inhibition may be a therapeutic target for inflamed joint pain treatment with reduced adverse events.
神经生长因子（NGF）通过高亲和力受体酪氨酸激酶A，已被广泛报道为炎症性疼痛的介质。一项临床试验表明，抗NGF抗体对膝关节骨关节炎引起的疼痛有效。然而，有报道称出现了诸如头痛（8.9%）、上呼吸道感染（7.3%）和感觉异常（6.8%）等不良事件。我们推测，抑制低亲和力NGF受体p75神经营养因子受体（p75NTR）对关节疼痛也有效，且可能减少副作用。本研究在大鼠腕关节炎性疼痛模型中，检测了p75NTR抑制性抗体对背根神经节神经元疼痛行为的抑制作用以及降钙素基因相关肽（CGRP）和p75NTR等致痛神经肽的表达。
我们将完全弗氏佐剂（CFA）注射到大鼠腕关节，以此作为炎性疼痛模型。我们将10微升生理盐水（CFA + 生理盐水组；n = 20）或1、10或50微升p75NTR抑制性抗体（CFA + p75NTR抑制性抗体组；n = 40）直接应用于大鼠的发炎关节。使用von Frey细丝测量机械性痛觉过敏2周。我们通过免疫化学方法评估C8背根神经节中CGRP和p75NTR的表达。检查了体重和/或食欲丧失、便秘和感染等不良事件。
在大鼠模型中，p75NTR抑制性抗体减轻了CFA引起的机械性痛觉过敏（与对照组相比，p <.05；与生理盐水组相比，p <.01），且未出现任何不良事件。我们发现10微升和50微升p75NTR抑制性抗体对疼痛更有效，不同剂量之间无显著差异。与对照组相比，CFA + 生理盐水组中CGRP和p75NTR免疫反应性上调（p <.01）。然而，直接应用p75NTR抑制性抗体可降低腕关节炎症后CGRP和p75NTR的表达（p <.01）。
抑制p75NTR可能是治疗发炎关节疼痛且减少不良事件的治疗靶点。
