• M Bassirat, R D Helme, and Z Khalil.
• National Ageing Research Institute, North West Hospital, Parkville, Melbourne, Victoria, Australia.
• Inflamm. Res. 1996 Aug 1; 45 (8): 380-5.

AbstractA 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.

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