A new rat model for thrombus-induced ischemic pain (TIIP); development of bilateral mechanical allodynia.
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% FeCl(2) onto the surface of the femoral artery for 20min. 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-FeCl(2) 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 ET(A) (endothelin-A) receptor antagonist, at day 3 selectively blocked ipsilateral pain, indicating that ET(A) receptor activity mediated TIIP. Spinal GFAP expression was significantly increased by FeCl(2) 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.
Seo
Hyoung-Sig
HS
Department of Veterinary Physiology, College of Veterinary Medicine and BK21 program for Veterinary Science, Seoul National University, San 56-1, Sillim-dong, Gwanak-gu, Seoul, South Korea Department of Physiology, College of Medicine and Research Institute for Medical Sciences, Chungnam National University, Daejeon, South Korea Department of Pharmacology, Institute for Medical Science, Chonbuk National University Medical School, Jeonju, South Korea Department of Veterinary Physiology, College of Veterinary Medicine and Biotherapy Human Resources Center, Chonnam National University, Gwangju, South Korea Department of Neuroscience and Cell Biology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1069, USA Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA.
Kim
Hyun-Woo
HW
Roh
Dae-Hyun
DH
Yoon
Seo-Yeon
SY
Kwon
Young-Bae
YB
Han
Ho-Jae
HJ
Chung
Jin Mo
JM
Beitz
Alvin J
AJ
Lee
Jang-Hern
JH
D000818:Animals; D001253:Astrocytes / Q000737:chemistry; D015415:Biomarkers; D004195:Disease Models, Animal; D005263:Femoral Artery / Q000187:drug effects; D005296:Ferrous Compounds / Q000633:toxicity; D005911:Gliosis / Q000209:etiology; D006493:Heparin / Q000627:therapeutic use; D006614:Hindlimb / Q000098:blood supply*; D006358:Hot Temperature / Q000009:adverse effects; D006930:Hyperalgesia / Q000209:etiology / Q000503:physiopathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis; D007511:Ischemia / Q000209:etiology / Q000503:physiopathology*; D008297:Male; D016877:Oxidants / Q000633:toxicity; D010812:Physical Stimulation / Q000009:adverse effects; D020671:Posterior Horn Cells / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000473:pathology / Q000503:physiopathology; D013927:Thrombosis / Q000139:chemically induced / Q000150:complications* / Q000473:pathology / Q000517:prevention & control; D014110:Touch; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis
D015415:Biomarkers; D005296:Ferrous Compounds; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016877:Oxidants; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D006493:Heparin; C029451:ferrous chloride