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ANALGESIA

Activation of Extracellular Signal-Regulated Kinase in Sciatic Nerve Contributes to Neuropathic Pain After Partial Sciatic Nerve Ligation in Mice

From the Department of Pharmacology, Wakayama Medical University, Wakayama City, Wakayama, Japan.

Address correspondence and reprint requests to Shiroh Kishioka, MD, PhD, Department of Pharmacology, Wakayama Medical University, 811-1 Kimiidera, Wakayama City, Wakayama 641-0012, Japan. Address e-mail to kishioka{at}wakayama-med.ac.jp.

Abstract

BACKGROUND: The mitogen-activated protein kinase family plays an important role in several types of pain. However, the detailed role of phosphorylated extracellular signal-regulated kinase (pERK) in the region of injured peripheral nerve is poorly understood. In this study, we investigated whether pERK in injured sciatic nerve contributes to neuropathic pain induced by partial sciatic nerve ligation (PSL) in mice.

METHODS: Mice received PSL; pERK1/2 (p44/42) in sciatic nerve was measured by both Western blotting and immunohistochemistry. U0126 (an ERK kinase inhibitor) was injected twice, an intraneural injection (20 nmol/2 µL) 30 min before PSL, and a perineural injection (20 nmol/10 µL) on Day 1 after PSL. Thermal hyperalgesia and tactile allodynia induced by PSL were evaluated by the thermal paw withdrawal test and the von Frey test, respectively.

RESULTS: As measured by Western blotting, in sham-operated mice, the levels of pERK1/2 in sciatic nerve were constant and the same as those in naive mice across Days 1-14. In PSL-operated mice, a significant increase in pERK1/2 was observed on Day 1 after PSL and persisted until Day 3. As measured by immunohistochemistry, immunoreactivity of pERK1/2 in PSL-operated sciatic nerve was markedly increased in comparison with that in sham-operated sciatic nerve on Day 1 after PSL. In the sciatic nerve on Day 1 after PSL, as indicated by double immunostaining, the increased immunoreactivity of pERK1/2 was colocalized with glial fibrillary acidic protein (GFAP), a marker of Schwann cells, but not F4/80, a marker of macrophages. PSL-induced thermal hyperalgesia was significantly attenuated by treatment with U0126 on Days 3, 7, and 14 after PSL. The PSL-induced tactile allodynia was also significantly attenuated by treatment with U0126 on Days 7 and 14 after PSL.

CONCLUSION: Activation of ERK in Schwann cells of the injured peripheral nervous system may play an important role in the development of neuropathic pain. Our results suggest that pERK itself and ERK-related mediators are potential therapeutic targets for the treatment of neuropathic pain.