Effect of chronic sciatic nerve lesion on the neurogenic inflammatory response in intact and acutely injured denervated rat skin

Abstract

A supersensitivity to the neuropeptide substance P (SP) has been shown to develop in post-terminal membranes of many denervated tissues. This study examined changes in the sensitivity of post-terminal vascular receptors to SP and calcitonin gene-related peptide (CGRP) in rat skin microvasculature following sciatic nerve section. In anaesthetised rats, 0.5 cm of sciatic nerve in the right mid-thigh region was removed. Two weeks later, SP (100 microM) and sodium nitroprusside (SNP, 1 mM), a direct smooth muscle vasodilator, were introduced into denervated intact footpad skin, via the electrophoresis technique. Laser doppler flowmeter was used to record changes in relative blood flow in the rat hind footpad. The results showed a significant increase in SP response over controls and slight increase in smooth muscle reactivity as determined by an increase in the vascular response to SNP. In another set of experiments, the sensitivity of post-terminal receptors was examined over a 4 weeks period in an acutely injured footpad skin of sciatic nerve lesioned rats. A vacuum-induced blister was raised on the hind footpad and SP, CGRP (each at 1 microM) or SNP (100 microM) were superfused over the blister base. In nerve lesioned rats, using the acutely injured footpad skin model, the results showed a reduction in the vascular responses to SP, CGRP and SNP. The response to SP continued to decrease over time reaching 22% of control values by 4 weeks. Responses to SNP and CGRP were reduced to 53% and 45% respectively by 2 weeks and then improved to 75% of control values by 4 weeks. Possible contributions of sympathetic efferents and the saphenous nerve to these reduced responses in acutely injured skin of nerve lesioned rats were examined using guanethidine (50 mg/kg i.p.) or sectioned saphenous nerve respectively. These procedures did not significantly modify the reduced vascular responses in the blister base of lesioned rats. Possible activation of endogenous opioids and/or the release of endothelin due to blister induction in nerve lesioned rats was examined using naloxone and the endothelin receptor antagonist, BQ-123, respectively. Treatment with naloxone increased SP response in lesioned rats to 41% of control value with no change in smooth muscle reactivity. BQ-123 significantly increased the responses to SP and SNP to 51% and 100% of their own control values respectively. It is concluded that supersensitivity of post-terminal vascular receptors develops in intact skin following chronic nerve lesion. On the other hand, acute injury of the denervated skin area induces activation of endogenous inhibitory modulatory mechanisms that masks this supersensitivity.

B1 and B2 antagonists and bradykinin-induced blood flow in rat skin inflammation

“…Alternatively, other factors (e. g. endogenous opioids) could have contributed to the reduction in the vascular response to BK as they are known to inhibit sensory nerve activity [26]. It has been suggested that the opioid system is activated during blister induction in rats with chronic nerve injury [27]. Our current results suggest that the B 2 receptor is the major receptor involved in regulating BK-induced vasodilatation under this experimental condition.…”

Topical Combinations Aimed at Treating Microvascular Dysfunction Reduce Allodynia in Rat Models of CRPS-I and Neuropathic Pain

“…It has previously been shown that CCI rats, and rats with sciatic nerve lesions, exhibit enhanced xanthine oxidase in sciatic nerve 47 and reduced vasodilatory responses to either the neuropeptides substance P and CGRP or the nitric oxide donor sodium nitroprusside applied at the base of a skin blister on the foot pad 2,3,47 . These findings indicate that nerve injury can induce endoneurial oxidative stress and diminished vascular reactivity in hind paw skin.…”

“…Recent parallel studies by other groups suggest that microvascular dysfunction and the resulting production of reactive oxygen and nitrogen species may contribute to neuropathic pain (including chronic constriction injury (CCI) of the sciatic nerve 2,3,31 , painful diabetic neuropathy (PDN) 21,24,42,45,48,74 and chemotherapy-induced painful neuropathy (CIPN) 20,22,49,50 . Therefore, it is expected that treatments aimed at enhancing tissue oxygenation by reducing arterial vasospasm and capillary slow-flow/no-reflow will also relieve allodynia in animal models of nerve constriction, PDN and CIPN.…”

Modulation of peripheral inflammation by locally administered hemorphin-7

“…To investigate the possibility that opioid receptors could be activated by endogenous hemorphins or endogenous opioids based on their availability, we examined the effect of hemorphin-7 on the vascular response to SP in a model where the involvement of opioids has previously been established, namely, a model of acute injury induced in a denervated skin site due to chronic nerve lesion [3]. The results showed that the vascular response to SP perfused over a denervated skin site is significantly reduced compared to the responses obtained in the acute injury model.…”

“…Using a blister model of inflammation, we have previously reported that the decrease in the peripheral inflammatory response in chronic inflammatory conditions e.g. chronic nerve injury conditions [3] can be partially reversed by the opioid antagonist naloxone. Our previous study therefore suggests that endogenous opioids are activated under chronic inflammatory conditions.…”