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Metallothionein deficiency in the injured peripheral nerves of complex regional pain syndrome as revealed by proteomics

Oki, Gosukea,b; Wada, Takurob; Iba, Kosukeb; Aiki, Hikonob; Sasaki, Kouichib; Imai, Shin-ichia; Sohma, Hitoshia,c; Matsumoto, Kayoa; Yamaguchi, Mamia; Fujimiya, Minekod; Yamashita, Toshihikob; Kokai, Yasuoa,*

doi: 10.1016/j.pain.2011.11.008
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Summary This work, for the first time, revealed molecules central in intractable pain in complex regional pain syndrome (CRPS). Metallothionein, a very strong free radical scavenger and an anti-inflammatory mediator is lacked in the affected nerves of CRPS. This work may shed a light in pathology of this intractable algetic disorder and open a new paradigm in this difficult condition.

Complex regional pain syndrome (CRPS) is characterized by persistent and severe pain after trauma or surgery; however, its molecular mechanisms in the peripheral nervous system are poorly understood. Using proteomics, we investigated whether injured peripheral nerves of CRPS patients have altered protein profiles compared with control nerves. We obtained nerve samples from 3 patients with CRPS-2 who underwent resection of part of an injured peripheral nerve. Sural nerves from fresh cadavers with no history of trauma or neuropathic pain served as controls. Proteomic analysis showed that the number and functional distribution of proteins expressed in CRPS and control nerves was similar. Interestingly, metallothionein was absent in the injured nerves of CRPS-2, although it was readily detected in control nerves. Western blotting further confirmed the absence of metallothionein in CRPS-2 nerves, and immunohistochemistry corroborated the deficiency of metallothionein expression in injured nerves from 5 of 5 CRPS patients and 2 of 2 patients with painful neuromas. In contrast, all control nerves, including 5 sural nerves from fresh cadavers and 41 nerves obtained from surgically resected tumors, expressed MT. Furthermore, expression of S100 as a marker for Schwann cells, and neurofilament M as a marker of axons was comparable in both CRPS-2 and controls.

Metallothioneins are zinc-binding proteins that are probably involved in protection against injury and subsequent regeneration after CNS damage. Their absence from the injured peripheral nerves of patients with CRPS-2 suggests a potential pathogenic role in generating pain in the damaged peripheral nerves.

aDepartment of Biomedical Engineering, Sapporo Medical University School of Medicine, Sapporo, Japan

bDepartment of Orthopaedic Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan

cDepartment of Educational Development, Sapporo Medical University Center for Medical Education, Sapporo, Japan

dDepartment of Anatomy, Sapporo Medical University School of Medicine, Sapporo, Japan

*Corresponding author. Address: Department of Biomedical Engineering, Sapporo Medical University School of Medicine, S1W17, Chuo-ku, Sapporo 060-8556, Japan. Tel.: +81 11 611 2111x2520; fax: +81 615 2315.

E-mail: kokai@sapmed.ac.jp

Submitted July 6, 2011; revised October 5, 2011; accepted November 7, 2011.

© 2012 Lippincott Williams & Wilkins, Inc.
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