An investigation into the mechanism of capsaicin‐induced oedema in rabbit skin

Abstract

1 Oedema formation induced by intradermal capsaicin has been studied in rabbit skin. The effect of the anti-inflammatory steroid dexamethasone and also of a range of known inhibitors of oedema formation have been investigated in order to elucidate mechanisms involved in capsaicin-induced oedema formation. 2 Oedema formation, in response to intradermally-injected test agents, was measured by the local extravascular accumulation of intravenously injected '25I-labelled albumin. In separate experiments skin blood flow was assessed by the clearance of intradermally-injected 33xenon. 3 Oedema formation induced by intradermal histamine (3 nmol) and bradykinin (1 nmol), when in the presence of vasodilator doses of calcitonin gene-related peptide (CGRP) (3 pmol) or prostaglandin El, (PGEI) (lOpmol), was significantly inhibited (P<0.01) in rabbits pretreated with intravenous dexamethasone (3 mg kg-', -4 h). In contrast dexamethasone had no effect on capsaicin (3 tmol)-induced oedema formation or, on capsaicin (30-100nmol)-induced blood flow.4 Oedema formation observed in response to intradermal capsaicin (3 ftmol) was significantly inhibited (P<0.01) when the selective capsaicin antagonist, ruthenium red (3 nmol) was co-injected. This suggests that the mechanism of capsaicin-induced oedema involves activation of sensory nerves. However, oedema was not inhibited when capsaicin was co-injected with the neurokinin NKI receptor antagonist, RP67580 (10 nmol), the NK2 antagonist SR48960 (10 nmol) or the CGRP antagonist CGRP8-37 (300 pmol).5 Oedema formation induced by capsaicin was not inhibited when co-injected with the histamine HI receptor antagonist, mepyramine (3 nmol), the PAF antagonist, WEB 2086 (100 nmol), the bradykinin B2 receptor antagonist, Hoel4O (1 nmol), or the cyclo-oxygenase inhibitor, indomethacin (10 nmol), suggesting that these mediators do not play a major role in the capsaicin-induced response. 6 Histological analysis of capsaicin-treated skin sites revealed undamaged, intact microvessels and lack of haemorrhage. Further, co-injection of capsaicin with the hydrogen peroxide remover, catalase (2,200 u), had no effect on oedema formation. This suggests that capsaicin does not induce oedema formation secondary to free radical-induced damage. 7 These results indicate that capsaicin-induced oedema in rabbit skin involves activation of sensory nerves. However, the oedema is not inhibited by pretreatment with the anti-inflammatory steroid, dexamethasone. Further the mechanisms which lead to the oedema formation observed after intradermal capsaicin remain unknown.

Reproducibility of the capsaicin‐induced dermal blood flow response as assessed by laser Doppler perfusion imaging

“…In rats and rabbits, CGRP has been identified as one of the major mediators of capsaicin‐induced vasodilation [46, 47]. This was confirmed by Hershey et al.…”

“…In rats and rabbits, CGRP has been identified as one of the major mediators of capsaicin-induced vasodilation [46,47]. This was confirmed by Hershey et al, who developed and validated a non-invasive pharmacodynamic model using capsaicin in rats and nonhuman primates to assess CGRP antagonist activity in vivo [26].…”

The Mammalian Tachykinin Ligand-Receptor System: An Emerging Target for Central Neurological Disorders

“…Neurogenic inflammation is a neurally elicited reaction that involves vasodilation, increased microvascular permeability, protein extravasation, and tissue swelling. Studies of peripheral nerves have shown that neurogenic inflammation is the result of stimulation of C-fibers, which express several neuropeptides, including SP and NKA [71, 72]. Trauma-induced, uncontrolled edema formation in the CNS elevates intracranial pressure, which can cause disruption of cerebral blood flow.…”

A Substance P Antagonist Reduces Axonal Injury and Improves Neurologic Outcome When Administered Up to 12 Hours after Traumatic Brain Injury

“…It is caused by the release of neuropeptides from sensory neurons, and several neuropeptides have been identified as playing a role, including substance P (SP) and calcitonin gene-related peptide (CGRP). SP is thought to enhance plasma protein extravasation, as well as leukocyte adhesion to endothelial cells in postcapillary venules, while CGRP is thought to be associated with the vasodilation of arterioles (Newbold and Brain, 1995). It is well known that cerebral blood vessels are surrounded by a dense supply of sensory neurons, and that the release of neuropeptides around the cerebral vasculature will initiate neurogenic inflammation.…”