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Evaluation of Pain Behavior and Calcitonin Gene-Related Peptide Immunoreactive Sensory Nerve Fibers in the Spinal Dorsal Horn After Sciatic Nerve Compression and Application of Nucleus Pulposus in Rats

Kimura, Seiji MD; Sakuma, Yoshihiro MD; Suzuki, Miyako MD, PhD; Orita, Sumihisa MD, PhD; Yamauchi, Kazuyo MD, PhD; Inoue, Gen MD, PhD; Aoki, Yasuchika MD, PhD; Ishikawa, Tetsuhiro MD, PhD; Miyagi, Masayuki MD, PhD; Kamoda, Hiroto MD, PhD; Kubota, Go MD; Oikawa, Yasuhiro MD; Inage, Kazuhide MD; Sainoh, Takeshi MD; Sato, Jun MD; Nakamura, Junichi MD, PhD; Toyone, Tomoaki MD, PhD; Takahashi, Kazuhisa MD, PhD; Ohtori, Seiji MD, PhD

doi: 10.1097/BRS.0000000000000180
Basic Science

Study Design. Animal study.

Objective. To evaluate pain behavior and neuropeptide changes in the spinal dorsal horn after sciatic nerve compression and application of nucleus pulposus (NP) in rats.

Summary of Background Data. The pathomechanisms of lumbar disc herniation pain have not been fully elucidated. Pain-associated neuropeptides, including substance P and calcitonin gene-related peptide (CGRP), are produced in dorsal root ganglion neurons and transported to spinal dorsal horn nerve terminals where they function in pain transmission. However, changes in CGRP-immunoreactive (IR) sensory nerve terminals have not been reported in models of disc herniation. This study evaluated pain-related behavior and changes in CGRP-IR terminals in the spinal dorsal horn after combined sciatic nerve compression and NP application.

Methods. Five groups of rats underwent either sciatic nerve compression with NP (n = 20), application of NP only (n = 20), nerve compression only (n = 20), and sham operation with neither compression nor NP (n = 20) or no operation (controls, n = 20). Mechanical hyperalgesia was measured every second day for 3 weeks. CGRP-IR terminals in each spinal dorsal horn lamina were examined 7 and 14 days postsurgery. Pain behavior and CGRP immunoreactivity were compared among the 5 groups.

Results. Mechanical hyperalgesia was found in the NP only, nerve compression only, and the NP with nerve compression groups (P ≤ 0.05). CGRP-IR nerve terminals in the superficial laminae (I and II) and the deep laminae (III–VI) significantly increased in the NP only, nerve compression only, and NP with nerve compression groups compared with control and sham groups (P ≤ 0.05). Significant mechanical hyperalgesia and increased CGRP-IR nerve terminals were found in the NP with nerve compression group compared with the NP only and nerve compression only groups (P ≤ 0.05).

Conclusion. Our results indicate that nerve compression plus NP application produces the most pain-related behavior. CGRP-IR nerve terminals increased in laminae I and II that transmit pain and in laminae III to VI that transmit proprioception. Findings suggest that nerve compression plus NP application induces changes in CGRP expression in the superficial and deep laminae, and these changes are partly responsible for disc herniation pain.

Level of Evidence: N/A

Sciatic nerve compression combined with nucleus pulposus (NP) application in a rat model resulted in increased pain behavior and calcitonin gene-related peptide–immunoreactive nerve terminals in both the superficial and deep spinal laminae. These changes in calcitonin gene-related peptide expression are hypothesized to be related to disc herniation pain.

From the Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.

Address correspondence and reprint requests to Seiji Ohtori, MD, PhD, Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan; E-mail:

Acknowledgment date: September 16, 2013. Revision date: November 11, 2013. Acceptance date: November 20, 2013.

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

No funds were received in support of this work.

No relevant financial activities outside the submitted work.

© 2014 by Lippincott Williams & Wilkins