A comparative study of the ability of calcitonin gene-related peptide and adrenomedullin(13 - 52) to modulate microvascular but not thermal hyperalgesia responses.

Calcitonin gene-related peptide (CGRP), a neuropeptide, is a potent vasodilator. Adrenomedullin (ADM) is suggested to be produced by vascular cells in inflamed tissue. ADM shares some structural homology with CGRP. We have compared the ability of CGRP and ADM to modulate microvascular and thermal hyperalgesic responses in rat skin. Vasodilator activity was assessed by laser Doppler flowmetry, inflammatory oedema by the extravascular accumulation of intravenously-injected labelled albumin, and neutrophil accumulation by tissue myeloperoxidase, in dorsal skin. Hyperalgesia was assessed by a thermal hyperalgesimeter in paw skin. ADM (10-300 pmol) was 3 fold less potent than CGRP (3-100 pmol) as a direct vasodilator. CGRP (30 pmol) potentiated oedema formation induced by mediators of increased microvascular permeability, as expected (P<0.01). However, ADM (30-100 pmol) was without a potentiating effect, although ADM (300 pmol) was effective (P<0.01). By comparison ADM (100 pmol) potentiated neutrophil accumulation induced by interleukin-1beta (P<0.05), whereas CGRP (30 pmol) did not. No thermal hyperalgesia was observed to either CGRP or ADM, when given as single or repeated treatments. Thus despite a dilator activity neither CGRP nor ADM appears to mediate hyperalgesic activity in the periphery. However ADM, like CGRP, has the ability to potentiate inflammatory oedema formation and, in addition, ADM can potentiate neutrophil accumulation. ADM may, as suggested for CGRP, act as a modulator of the vascular phases of inflammation. The property of the two compounds of evoking differential microvascular responses and neutrophil accumulation may be due to differing mechanisms of action.