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Delayed Granulocyte Colony-Stimulating Factor Treatment in Rats Attenuates Mechanical Allodynia Induced by Chronic Constriction Injury of the Sciatic Nerve

Koda, Masao MD, PhD*; Furuya, Takeo MD, PhD*; Kato, Kei MD, PhD*; Mannoji, Chikato MD, PhD; Hashimoto, Masayuki MD, PhD; Inada, Taigo MD*; Kamiya, Koshiro MD*; Ota, Mitsutoshi MD*; Maki, Satoshi MD*; Okawa, Akihiko MD, PhD*; Takahashi, Kazuhisa MD, PhD*; Ishikawa, Tetsuhiro MD, PhD*; Yamazaki, Masashi MD, PhD§

doi: 10.1097/BRS.0000000000000108
Basic Science

Study Design. Animal experimental study with intervention.

Objective. The aim of this study was to elucidate therapeutic effects of delayed granulocyte colony-stimulating factor treatment for mechanical allodynia induced by chronic constriction injury (CCI) of the sciatic nerve in rats.

Summary of Background Data. Granulocyte colony-stimulating factor (G-CSF) is used clinically for patients with hematological disorders. Previous reports showed that immediate G-CSF attenuates neuropathic pain in CCI of the sciatic nerve. However, the acute treatment for neuropathic pain prior to accurate diagnosis is not realistic in clinical settings.

Methods. Adult, female Sprague-Dawley rats were subjected to the CCI model. This model induces mechanical allodynia on the ipsilateral hind paw within the first week after the injury. One week after CCI, rats received intraperitoneal G-CSF (15.0 μg/kg) for 5 consecutive days. Mechanical allodynia was assessed using the von Frey hair test. Immunohistochemistry for phosphorylated p38 mitogen-activated kinase (p-p38MAPK) and OX-42 (a marker for activated microglia) on tissue slides from a subset of rats 2 weeks after surgery. Western blot analyses were carried out to determine protein expression level of p-p38MAPK and interleukin-1 β on spinal cord homogenates 2 weeks after CCI.

Results. Results of the von Frey filament test showed that G-CSF significantly attenuates mechanical allodynia induced by the CCI model. Immunohistochemistry revealed that G-CSF reduced the number of p-p38MAPK–positive cells in the ipsilateral dorsal horn compared with that in the vehicle group rats. Immunofluorescent double staining revealed that p-p38MAPK–expressing cells in the spinal cord dorsal horn are mainly microglia. Western blot analysis indicated that G-CSF decreased the expression levels of both p-p38MAPK and interleukin-1 β in the ipsilateral dorsal horn compared with that in the vehicle group rats.

Conclusion. The present results indicate a beneficial effect of delayed G-CSF treatment in an animal model of peripheral nerve injury-induced neuropathic pain.

Level of Evidence: N/A

Effect of delayed granulocyte colony-stimulating factor (G-CSF) for peripheral neuropathic pain was assessed. Delayed G-CSF significantly attenuated mechanical allodynia, reduced the number of activated microglia and the expression of phosphorylated p38 mitogen-activated kinase and interleukin-1β in dorsal horn. The present results indicate a beneficial effect of delayed G-CSF treatment.

*Department of Orthopedic Surgery, Chiba Medical Center, Chiba, Japan

Graduate School of Medicine, Chiba University, Chiba Medical Center, Chiba, Japan

Chiba Aoba Municipal Hospital, Chiba Medical Center, Chiba, Japan; and

§Department of Orthopedic Surgery, University of Tsukuba, Ibaraki, Japan.

Address correspondence and reprint requests to Masao Koda, MD, PhD, Department of Orthopedic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba 260-8670, Japan; E-mail: masaokod@gmail.com

Acknowledgment date: May 16, 2013. Revision date: September 2, 2013. Acceptance date: October 14, 2013.

The manuscript submitted does not contain information about medical device(s)/drug(s).

Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Culture of Japan (16591473-00) funds were received in support of this work.

No relevant financial activities outside the submitted work.

© 2014 by Lippincott Williams & Wilkins