A calcitonin gene‐related peptide (CGRP) antagonist (CGRP8–37) inhibits microvascular responses induced by CGRP and capsaicin in skin

1 The effect of the calcitonin gene‐related peptide (CGRP) antagonist CGRP8–37 on responses to CGRP and other mediators was investigated in rabbit dorsal skin. 2 Blood flow changes at intradermally‐injected sites were measured by a multiple site 133xenon clearance technique. CGRP8–37 had little effect on blood flow at doses up to 0.3 nmol/site, when injected alone, although a significant increase in blood flow was observed at the highest dose tested (1 nmol/site). 3 CGRP8–37 dose‐dependently inhibited the increased blood flow induced by human αCGRP and human βCGRP, but had no effect on equivalent vasodilator responses induced by vasoactive intestinal peptide (VIP) and prostaglandin E1 (PGE1). CGRP8–37 showed a preferential ability to inhibit αCGRP (IC50 0.04 nmol), when compared with βCGKP (IC50 ≥ 0.3 nmol). 4 Capsaicin, which selectively activates sensory nerves, caused a dose‐dependent increase in blood flow when injected intradermally into rabbit skin. The effects of capsaicin (0.01–0.1 μmol/site) were inhibited by CGRP8–37 (0.3 nmol/site), with a partial but significant attenuation of blood flow induced by the highest dose of capsaicin. 5 Oedema formation, induced by intradermal histamine injection (3 nmol/site), was measured in rabbit skin by the local accumulation of intravenously‐injected 125I‐labelled albumin. Vasodilator doses of CGRP, PGE1 and capsaicin potentiated, in a synergistic manner, oedema formation induced by histamine. CGRP8–37 totally inhibited the potentiating effect of CGRP, partially inhibited the synergistic effect of capsaicin, but did not affect PGE1‐induced responses. 6 The results suggest that capsaicin acts to release a rabbit form of CGRP in skin and that CGRP8–37 is a useful antagonist for investigating the potential of CGRP as a neurogenic mediator of inflammation.