Free radicals contribute to the reduction in peripheral vascular responses and the maintenance of thermal hyperalgesia in rats with chronic constriction injury

Abstract

We previously reported that the time frame and the extent of the changes in the peripheral neurogenic inflammatory response in the skin area, innervated by an injured nerve, coincide with those of pain behaviours. We raised the possibility that common factors might operate to modulate neuropathic pain and peripheral neurogenic processes in rats with chronic constriction nerve injury (CCI). In the present study we examined the role of free radicals in modulating the neurogenic vascular response and thermal hyperalgesia in rats with CCI of the sciatic nerve. Free radicals, via an interaction with nitric oxide (NO) to form peroxynitrite, have previously been implicated in the maintenance of thermal hyperalgesia in CCI rats. In this study, we induced CCI of the sciatic nerve and the activity of xanthine oxidase (XO), which catalyzes the formation of superoxide anions, was measured in the injured nerve. In addition, we examined the effect of antioxidants on thermal hyperalgesia and on the neurogenic vascular response to substance P (SP) perfused over the base of a blister induced on the hind footpad skin which is innervated by the injured sciatic nerve. Compared with the sham operated group, CCI rats had a significantly higher XO activity in the injured sciatic nerve and significantly reduced thermal threshold and peripheral neurogenic vascular response to SP. Treatment with antioxidants, superoxide dismutase (SOD) or tirilazad significantly improved the neurogenic vascular response while tirilazad treatment significantly alleviated thermal hyperalgesia. The results therefore, suggest that free radicals are elevated in CCI animals and that they contribute to the maintenance of thermal hyperalgesia and the reduction in peripheral microvascular blood flow in the area innervated by the injured nerve. We raise the possibility that common mechanisms may govern the changes in neuropathic pain and in the peripheral neurogenic vascular responses in tissues innervated by the injured nerve.