Chronic post-ischemia pain (CPIP): a novel animal model of complex regional pain syndrome-Type I (CRPS-I; reflex sympathetic dystrophy) produced by prolonged hindpaw ischemia and reperfusion in the rat

Abstract

A neuropathic-like pain syndrome was produced in rats following prolonged hindpaw ischemia and reperfusion, creating an animal model of complex regional pain syndrome-Type I (CRPS-I; reflex sympathetic dystrophy) that we call chronic post-ischemia pain (CPIP). The method involves placing a tourniquet (a tight fitting O-ring) on one hindlimb of an anesthetized rat just proximal to the ankle joint for 3 h, and removing it to allow reperfusion prior to termination of the anesthesia. Rats exhibit hyperemia and edema/plasma extravasation of the ischemic hindpaw for a period of 2-4 h after reperfusion. Hyperalgesia to noxious mechanical stimulation (pin prick) and cold (acetone exposure), as well as mechanical allodynia to innocuous mechanical stimulation (von Frey hairs), are evident in the affected hindpaw as early as 8 h after reperfusion, and extend for at least 4 weeks in approximately 70% of the rats. The rats also exhibit spontaneous pain behaviors (hindpaw shaking, licking and favoring), and spread of hyperalgesia/allodynia to the uninjured contralateral hindpaw. Light-microscopic examination of the tibial nerve taken from the region just proximal to the tourniquet reveals no signs of nerve damage. Consistent with the hypothesis that the generation of free radicals may be partly responsible for CRPS-I and CPIP, two free radical scavengers, N-acetyl-L-cysteine (NAC) and 4-hydroxy-2,2,6,6-tetramethylpiperydine-1-oxyl (Tempol), were able to reduce signs of mechanical allodynia in this model.

Update on the pathogenesis of complex regional pain syndrome: Role of oxidative stress

“…34 Furthermore, Coderre et al detected elevated levels of malondialdehyde in the hind paw muscles of the rat and have shown that the animal's pain hypersensitivity is reduced by free radical scavengers and antioxidant therapy. 35,36 Taken together with the previous data, we observed that oxidative stress occurs mainly in CRPS I. Although previous clinical studies have indicated the presence of oxidative stress in CRPS I patients, it has been difficult to prove whether it is a cause or a consequence of CRPS I.…”

“…[30][31][32][33] It has been speculated that free radical generation by the mitochondrial respiratory chain contributes to the pathophysiology of CRPS I. [34][35][36] Eisenberg et al demonstrated significant increases in malondialdehyde, lactic dehydrogenase, and antioxidants (peroxidase, superoxide dismutase, uric acid) in the serum and especially the saliva of CRPS I patients compared to healthy controls. 34 Furthermore, Coderre et al detected elevated levels of malondialdehyde in the hind paw muscles of the rat and have shown that the animal's pain hypersensitivity is reduced by free radical scavengers and antioxidant therapy.…”

Sympathetic Vasoconstrictor Antagonism and Vasodilatation Relieve Mechanical Allodynia in Rats With Chronic Postischemia Pain

“…Chronic postischemia pain was generated after exposure to prolonged hind paw ischemia and reperfusion as described in Coderre et al 14 Briefly, rats were anesthetized over a 3-to 4-hour period with a bolus (40 mg/kg, i.p.) and chronic intraperitoneal infusion of sodium pentobarbital for 2 hours (13 mg/h for the first hour, 6.5 mg/h for the second hour).…”

Role of NFκB in an Animal Model of Complex Regional Pain Syndrome–type I (CRPS-I)

“…CPIP rats display several features that resemble human CRPS, including edema, hyperemia, and the development of mechanical and cold allodynia without direct nerve injury. 14 The CPIP model has therefore been proposed as animal model for CRPS type-I. The aim of the present study was investigate the involvement of NFkB in CPIP, and potentially the pathogenesis of CRPS, by measuring NFkB levels and assessing the antiallodynic effect of NFkB inhibition by PDTC in rats after IR injury.…”