A new rat model for thrombus-induced ischemic pain (TIIP); development of bilateral mechanical allodynia

Hyoung Sig Seo, Hyun Woo Kim, Dae Hyun Roh, Seo Yeon Yoon, Young Bae Kwon, Ho Jae Han, Jin Chung, Alvin J. Beitz, Jang Hern Lee

Research output: Contribution to journalArticle

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Abstract

Patients with peripheral arterial disease (PAD) commonly suffer from ischemic pain associated with severe thrombosis. However, the pathophysiology of peripheral ischemic pain is not fully understood due to the lack of an adequate animal model. In this study, we developed a new rodent model of thrombus-induced ischemic pain (TIIP) to investigate the neuronal mechanisms underlying ischemic pain. Ischemia was induced by application of 20% FeCl2 onto the surface of the femoral artery for 20 min. Induction of peripheral ischemia was confirmed by measurement of the concentration of Evans blue and by increases in the ischemia-specific markers, hypoxia-inducible factor-1 alpha and vascular endothelial growth factor in the ipsilateral plantar muscles. Ischemic pain, as indicated by the presence of mechanical allodynia, developed bilaterally and peaked at days 3-9 post-FeCl2 application and gradually decreased through day 31. Systemic heparin pretreatment dose dependently suppressed ischemic pain, suggesting that thrombosis-induced ischemia might be a key factor in TIIP. Intraplantar injection of BMS-182874, an ETA (endothelin-A) receptor antagonist, at day 3 selectively blocked ipsilateral pain, indicating that ETA receptor activity mediated TIIP. Spinal GFAP expression was significantly increased by FeCl2 and intrathecal injection of carbenoxolone (an astrocyte gap junction decoupler) at day 3 significantly reduced TIIP, suggesting that spinal astrocyte activation plays an important role. However, the anti-inflammatory agent, ibuprofen, did not affect TIIP. In conclusion, we have developed a novel animal model of TIIP that should be useful in investigating the pathophysiological mechanisms that underlie human peripheral ischemic pain.

Original languageEnglish (US)
Pages (from-to)520-532
Number of pages13
JournalPain
Volume139
Issue number3
DOIs
StatePublished - Oct 31 2008

Fingerprint

Hyperalgesia
Thrombosis
Pain
Ischemia
Astrocytes
Animal Models
Carbenoxolone
Endothelin A Receptors
Hypoxia-Inducible Factor 1
Spinal Injections
Evans Blue
Ibuprofen
Peripheral Arterial Disease
Gap Junctions
Femoral Artery
Vascular Endothelial Growth Factor A
Heparin
Rodentia
Anti-Inflammatory Agents

Keywords

  • Arterial thrombus
  • Ferrous chloride
  • Mechanical allodynia
  • Peripheral arterial disease
  • Peripheral ischemia

ASJC Scopus subject areas

  • Clinical Neurology
  • Anesthesiology and Pain Medicine
  • Neurology
  • Pharmacology

Cite this

Seo, H. S., Kim, H. W., Roh, D. H., Yoon, S. Y., Kwon, Y. B., Han, H. J., ... Lee, J. H. (2008). A new rat model for thrombus-induced ischemic pain (TIIP); development of bilateral mechanical allodynia. Pain, 139(3), 520-532. https://doi.org/10.1016/j.pain.2008.06.011

A new rat model for thrombus-induced ischemic pain (TIIP); development of bilateral mechanical allodynia. / Seo, Hyoung Sig; Kim, Hyun Woo; Roh, Dae Hyun; Yoon, Seo Yeon; Kwon, Young Bae; Han, Ho Jae; Chung, Jin; Beitz, Alvin J.; Lee, Jang Hern.

In: Pain, Vol. 139, No. 3, 31.10.2008, p. 520-532.

Research output: Contribution to journalArticle

Seo, HS, Kim, HW, Roh, DH, Yoon, SY, Kwon, YB, Han, HJ, Chung, J, Beitz, AJ & Lee, JH 2008, 'A new rat model for thrombus-induced ischemic pain (TIIP); development of bilateral mechanical allodynia', Pain, vol. 139, no. 3, pp. 520-532. https://doi.org/10.1016/j.pain.2008.06.011
Seo, Hyoung Sig ; Kim, Hyun Woo ; Roh, Dae Hyun ; Yoon, Seo Yeon ; Kwon, Young Bae ; Han, Ho Jae ; Chung, Jin ; Beitz, Alvin J. ; Lee, Jang Hern. / A new rat model for thrombus-induced ischemic pain (TIIP); development of bilateral mechanical allodynia. In: Pain. 2008 ; Vol. 139, No. 3. pp. 520-532.
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abstract = "Patients with peripheral arterial disease (PAD) commonly suffer from ischemic pain associated with severe thrombosis. However, the pathophysiology of peripheral ischemic pain is not fully understood due to the lack of an adequate animal model. In this study, we developed a new rodent model of thrombus-induced ischemic pain (TIIP) to investigate the neuronal mechanisms underlying ischemic pain. Ischemia was induced by application of 20{\%} FeCl2 onto the surface of the femoral artery for 20 min. Induction of peripheral ischemia was confirmed by measurement of the concentration of Evans blue and by increases in the ischemia-specific markers, hypoxia-inducible factor-1 alpha and vascular endothelial growth factor in the ipsilateral plantar muscles. Ischemic pain, as indicated by the presence of mechanical allodynia, developed bilaterally and peaked at days 3-9 post-FeCl2 application and gradually decreased through day 31. Systemic heparin pretreatment dose dependently suppressed ischemic pain, suggesting that thrombosis-induced ischemia might be a key factor in TIIP. Intraplantar injection of BMS-182874, an ETA (endothelin-A) receptor antagonist, at day 3 selectively blocked ipsilateral pain, indicating that ETA receptor activity mediated TIIP. Spinal GFAP expression was significantly increased by FeCl2 and intrathecal injection of carbenoxolone (an astrocyte gap junction decoupler) at day 3 significantly reduced TIIP, suggesting that spinal astrocyte activation plays an important role. However, the anti-inflammatory agent, ibuprofen, did not affect TIIP. In conclusion, we have developed a novel animal model of TIIP that should be useful in investigating the pathophysiological mechanisms that underlie human peripheral ischemic pain.",
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