The Axon Reflex Mechanism in the Histamine Flare Test
The axon reflex is the fundamental neurophysiological mechanism that produces the flare response in the histamine flare test—when histamine stimulates C-fiber nociceptive nerve endings, it triggers antidromic conduction along adjacent nerve branches that release vasoactive neuropeptides (primarily CGRP and substance P), causing the characteristic spreading vasodilation that defines the flare. 1
The Neurogenic Pathway
The axon reflex operates through a specific sequence of events that distinguishes it from simple histamine diffusion:
Histamine acts on H1 receptors on C-fiber nerve terminals, initiating the neurogenic response rather than causing direct vascular effects at distant sites 1
Stimulation produces bidirectional nerve conduction: orthodromic signals travel toward the spinal cord (perceived as itch), while antidromic signals travel backward along adjacent axon branches 2
Antidromic stimulation triggers neuropeptide release from neighboring C-fiber terminals, specifically calcitonin gene-related peptide (CGRP) and substance P 2, 1
CGRP functions as the most potent endogenous vasodilator in this response, producing the spreading erythema that extends well beyond the site of histamine injection 1
Critical Evidence Against Histamine Diffusion
A pivotal microdialysis study definitively demonstrated that the flare is neurogenic, not due to histamine spread:
No increased histamine levels were detected in the flare zone with any provocative agent, despite large histamine concentrations at the injection site (337-1293 nM) 3
Histamine diffusion within even the wheal was poor, with levels at 2.3 mm from injection being only 4-22% of those at 1 mm, and virtually undetectable at 3.7 mm 3
High histamine concentrations (100-1000 nM) are required to produce visible vascular effects, far exceeding any levels found in the flare zone 3
Clinical Utility for Small Fiber Assessment
The histamine flare test serves as a functional assessment of small C-fiber integrity:
The flare reflects intact small fiber C-nociceptive function and neurovascular responsiveness, making it particularly valuable for detecting small fiber neuropathy 1
Reduced flare responses correlate with diabetic neuropathy severity, as measured by Neurological Impairment Score and other validated measures 2, 4
The test demonstrates 87.5% sensitivity and 88.2% specificity for detecting diabetic autonomic neuropathy when assessing the complete neurovascular response 1
Flare area is significantly reduced in diabetic patients with neuropathy compared to those without neuropathy and healthy controls, with reductions proportional to disease severity 4, 5, 6
Methodological Considerations
Laser Doppler imaging (LDI) provides objective quantification of both flare area and blood flow intensity, offering superior reliability over visual assessment alone 4, 5
Electrical stimulation can also induce axon reflex flare, with increased electrical thresholds indicating C-fiber dysfunction in diabetic small fiber neuropathy 4
The response is attenuated in diabetes even before clinical neuropathy develops, suggesting early small fiber involvement that precedes detectable changes on standard nerve conduction studies 6
Important Caveats
The axon reflex mechanism appears species-specific—while well-established in guinea pigs and rats, evidence suggests it may be less prominent or absent in human airways, though it is clearly functional in human skin 2
The test cannot distinguish between painful and painless neuropathy, as both conditions show similar reductions in flare response 6
Baseline sympathetic tone may influence results, particularly in conditions like spinal cord injury where increased sympathetic vasoconstriction may counteract the axon reflex vasodilation 7