*Co-corresponding authors:

William R. Lariviere

Department of Anesthesiology

University of Pittsburgh School of Medicine

A1305 Scaife Hall, 3550 Terrace St.

Pittsburgh, PA, 15261, USA

Tel: 412-383-9904

Fax: 412-648-9587

lariwr@upmc.edu

Jun Chen

Pain Research Center

Institute of Neuroscience
The Fourth Military Medical University
17 West Chang-le Road

Xi'an 710032  P.R. China
Tel: 86-29-83374559
Fax: 86-29-83246270
junchen@fmmu.edu.cn

Correlations between edema and the immediate and prolonged painful consequences of inflammation: therapeutic implications?

William R. LARIVIERE1,2*, Elissa J. CHESLER2,3, Zhen LI4, Gang-Wei SHANG4, Ya-Ning CHEN4, Yao-Qing YU4, Zhuo-Min LU4, Ying CHANG4,5, Ceng LUO4,

Kai-Cheng LI4, Jun CHEN4,5*

1 Department of Anesthesiology, University of Pittsburgh School of Medicine, A1305 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA, 15261, USA;

2 Department of Psychology and Neuroscience Program, University of Illinois, Urbana-Champaign, IL, USA;

3 Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, 855 Monroe Avenue Room 515, Memphis, TN, 38163, USA;

4 Pain Research Center, Institute of Neuroscience, Fourth Military Medical University, Xi’an, P.R. China;

5 Institute for Biomedical Sciences of Pain, Capital University of Medical Sciences, Beijing, P.R. China.

Abstract：

The precise relationship between the degree of pain and the degree of inflammation in the individual remains debated. A quantitative analysis simultaneously applied to the immediate and prolonged painful consequences of inflammation has not yet been done. Thus, the correlations between edema, nociception and hypersensitivity following an inflammatory insult were assessed in rodents. To better understand the therapeutic value of modifying specific aspects of inflammation, the effects of an anti-inflammatory drug were compared to the results. Inbred strains of mice and outbred rats received an intraplantar injection of honeybee venom and the between-group and within-group correlations were calculated for spontaneous nociceptive measures, thermal and mechanical hypersensitivity, and edema and temperature. The effect of indomethacin on the pain and inflammation measures was examined. Edema correlated with spontaneous flinching, licking and lifting of the injected paw (p ￡ 0.003), and not with thermal or mechanical hypersensitivity. Indomethacin affected edema and spontaneous nociception dose-dependently, and affected hypersensitivity only at the highest dose tested (p < 0.05). These results suggest that edema may contribute only to immediate spontaneous nociceptive responses to an inflammatory insult, and not to the more clinically relevant prolonged hypersensitivity. This analysis represents a method for determining which inflammatory processes are the most promising therapeutic targets against the multiple painful consequences of inflammation.

Key words: 

Correlation Study, inflammation, pain, Nociception Test, hyperalgesia 

炎症状态下水肿与即早期和持续期痛行为之间的相关性分析：治疗意义探讨

William R. LARIVIERE1,2 *, Elissa J. CHESLER2,3, 李   震4, 尚刚伟4, 陈亚宁4, 于耀清4, 吕卓敏4, 常   莹4,5, 罗   层4,5, 李开诚4, 陈  军4,5 *

1美国匹兹堡大学医学院麻醉系;2美国伊利诺斯大学Urbana-Champaign分校心理学与神经科学系; 3美国田纳西大学卫生科学中心解剖学与神经生物学系; 4第四军医大学神经科学研究所疼痛研究中心，西安710032; 5首都医科大学疼痛生物医学研究所，北京100054

摘要：迄今，有关个体的疼痛程度和炎症程度之间的精确关系一直存在争论，主要原因是缺乏能够同时反映多种痛（尤其是可鉴别疼痛即早期和持续期）的炎症模型以及定量方法的合理应用。因此，本研究在啮齿类动物评价了外周皮下组织致炎后炎症水肿与伤害性反应以及疼敏之间的相关性。为了更好地认识炎症特异性特征在治疗中的价值，我们对非甾体类抗炎药的作用效果也进行了评价。将一个剂量的蜜蜂毒（0.05 mg/0.025 ml）注入12个近交系（129P3/J, A/J, AKR/J, BALB/cJ, C3H/HeJ, C57BL/6J, C57BL/10J, C58/J, CBA/J, DBA/2J, RIIIS/J and SM/J）小鼠或6个剂量的蜜蜂毒（0.001, 0.005, 0.01, 0.05, 0.1, and 0.2 mg/0.05 ml）远交系（Sprague-Dawley）大鼠的一侧足底皮下，分别检测自发伤害性反应、热和机械性痛敏，以及炎症的水肿和局部皮温，然后对组间和组内数据进行相关性分析。此外，观察非甾体类抗炎药吲哚美辛对痛和炎症的作用效果。结果发现：（1）炎症水肿程度与注射侧自发缩足反射次数、舔足抬足时间等伤害性反射程度呈高度正相关（p £ 0.003），而与热或机械性痛敏的程度没有相关性；（2）吲哚美辛(0.5, 2.5, and 2.5 mg/kg, i.p., 稀释于60%二甲基桠枫)可以剂量依赖性地抑制炎症水肿和自发伤害性反应,但是对热或机械性痛敏却只有在最高剂量下才有作用。这些结果提示炎症水肿过程可能只参与动物受炎症刺激而引起的即早自发伤害性反应过程，而不参与与临床更加密切相关的痛敏过程。这个分析结果为确定抗炎治疗有益于缓解多种炎性痛中的哪个靶表证提供了一个有用的分析方法。

关键词：相关分析，炎症，疼痛，伤害性感受，痛超敏