Mechanism of Flare Response in Histamine Flare Test
The flare response in the histamine flare test is mediated by a neurogenic axon reflex mechanism, where histamine stimulates C-fiber nociceptive nerve endings, triggering antidromic conduction along adjacent nerve branches that release vasoactive neuropeptides—primarily calcitonin gene-related peptide (CGRP) and substance P—which cause the surrounding vasodilation, not by direct histamine diffusion. 1
The Axon Reflex Pathway
The flare mechanism operates through a specific neuroanatomical pathway:
Histamine stimulates C-fiber nociceptive nerve endings in the dermis, initiating both orthodromic conduction toward the spinal cord and antidromic conduction to adjacent axon branches 1
Antidromic stimulation triggers neuropeptide release from neighboring C-fiber terminals, specifically CGRP and substance P, which act as the primary vasodilatory mediators 1
CGRP functions as the most potent endogenous vasodilator in this response, causing the characteristic spreading erythema that defines the flare 1
Substance P contributes additional effects including increased vascular permeability and further vasodilation 1
Critical Evidence Against Direct Histamine Diffusion
Multiple lines of evidence demonstrate that histamine itself does not mediate the flare through direct diffusion:
Microdialysis studies show no elevated histamine levels in the flare zone, despite high concentrations at the injection site (337-1293 nM centrally versus undetectable levels in the surrounding flare) 2
Histamine diffusion within tissue is extremely limited, with levels dropping to 4-22% at just 2.3 mm from the injection site and 0.2-3.7% at 3.7 mm 2
H1-receptor antagonists (terfenadine) do not block the flare response to capsaicin-induced axon reflexes, despite effectively blocking responses to exogenous histamine by >60% 3
The flare requires relatively high histamine concentrations (100-1000 nM) to initiate, but these levels are only present at the central injection site, not in the surrounding flare area 2
Receptor-Specific Mechanisms
The response involves distinct receptor pathways:
Histamine acts primarily through H1 receptors to initiate the nerve stimulation that triggers the axon reflex 1, 4
CGRP-1 receptor activation mediates the late-phase vasodilation, as demonstrated by significant inhibition with CGRP(8-37) antagonist 1
H1 and H2 receptors both contribute to direct vascular effects at the central wheal site, but only H1 receptors mediate the neurogenic component 5
Clinical Implications for Testing
Understanding this mechanism is essential for proper test interpretation:
The flare reflects intact small fiber C-nociceptive function and neurovascular responsiveness, making it a useful test for small fiber neuropathy 1
Reduced flare responses correlate with diabetic neuropathy severity and other conditions affecting small sensory nerve fibers 1
The test has 87.5% sensitivity and 88.2% specificity for detecting diabetic autonomic neuropathy when assessing the complete neurovascular response 1
Important Caveats
Substance P does release histamine from dermal mast cells (plasma histamine increases from 0.17 to 1.26 ng/mL after substance P injection), but this released histamine does not contribute to the flare vasodilation itself 3
The wheal (central raised area) is mediated by direct histamine effects on vascular permeability through H1 receptors, distinct from the flare mechanism 4, 5, 2
Tissue concentrations of at least 100-1000 nM histamine are required to produce visible vascular effects, which only occur at the injection site 2