Histamine-induced edema in the rat paw--effect of capsaicin denervation and a CGRP receptor antagonist.

Histamine is known to cause edema and excitation of small-diameter primary afferent neurons. In the present study we wanted to investigate to which extent afferent neurons participate in histamine-induced edema and, subsequently, determine possible inhibitory effects of a tachykinin NK1 receptor and CGRP receptor antagonist on the histamine response. Intraplantar injection of histamine (0.5 mumol) into the rat hind paw caused a 34% increase of paw volume. In capsaicin-denervated rats, this effect of histamine was nearly abolished. The calcitonin gene-related peptide (CGRP) receptor antagonist CGRP-(8-37), but not the tachykinin NK1 receptor antagonist SR140333, caused significant inhibition of the edema response. Further indication that CGRP can promote the histamine action was obtained in capsaicin-denervated rats, where co-injection of CGRP (0.3 pmol) increased the edema response to intraplantar histamine. In additional experiments, plasma protein extravasation in the paw skin was evaluated after close arterial infusion of histamine. Also in these experiments CGRP-(8-37), but not SR140333, significantly reduced the histamine effect. The observation that in the rat hind paw a CGRP receptor antagonist, but not a tachykinin NK1 receptor antagonist, attenuates histamine-induced vascular leakage raises the possibility that in some tissues CGRP receptor antagonists may be superior to tachykinin NK1 receptor antagonists in reducing histamine-induced neurogenic inflammatory responses.