Mechanism of Axon Reflex Vasodilation
Axon reflex vasodilation occurs when stimulation of nociceptive C-fiber nerve endings triggers antidromic conduction along adjacent axon branches, causing the release of vasoactive neuropeptides—primarily calcitonin gene-related peptide (CGRP) and substance P—which directly induce local vasodilation and increased vascular permeability. 1
The Neurophysiological Pathway
The axon reflex operates through a peripheral mechanism that bypasses the central nervous system entirely:
Initial stimulation of C-fiber nociceptive nerve endings by thermal, chemical, or mechanical stimuli triggers both orthodromic conduction (toward the spinal cord) and antidromic conduction (backward along adjacent nerve branches). 1
Antidromic impulses travel to neighboring terminal branches of the same sensory neuron, creating a local circuit without requiring central processing. 1, 2
Neuropeptide release occurs from these adjacent C-fiber terminals, specifically releasing CGRP, substance P, neurokinin A, and potentially histamine. 1
Key Vasoactive Mediators
The vasodilation results from specific neuropeptide actions:
CGRP functions as the most potent endogenous vasodilator in this response, mediating the late-phase vasodilation through CGRP-1 receptor activation, as demonstrated by significant inhibition with CGRP(8-37) antagonist. 2
Substance P contributes additional vasodilation and markedly increases vascular permeability, leading to plasma extravasation and edema formation. 1, 3
The combined effect of these neuropeptides produces the characteristic spreading erythema (flare) that extends well beyond the initial site of stimulation. 1, 2
Fiber Type Specificity
Recent evidence clarifies which C-fiber subtypes mediate this response:
Mechano-insensitive C-nociceptors, rather than polymodal (mechano-heat responsive) C-nociceptors, primarily mediate the axon reflex flare in human skin. 4
In guinea pigs, C-fibers arising from jugular ganglia that express substance P and CGRP are responsible for axon reflex-mediated responses including bronchospasm, mucus secretion, vasodilation, and edema. 1
Heat-evoked axon reflex vasodilation is triggered by heat-sensitive nociceptors at thresholds around 39.4-39.6°C, which matches the lower range of C-fiber nociceptor heat thresholds but occurs even without conscious pain perception. 5
Clinical Significance
The axon reflex serves as a diagnostic tool for small fiber function:
The flare response reflects intact small fiber C-nociceptive function and neurovascular responsiveness, making it useful for detecting small fiber neuropathy. 1, 2
Reduced flare responses correlate with diabetic neuropathy severity, with the test showing 87.5% sensitivity and 88.2% specificity for detecting diabetic autonomic neuropathy. 1, 2
In spinal cord injury patients, axon reflex vasodilation remains present below the lesion but is significantly diminished by 39% compared to controls, despite the reflex being independent of central connections. 6
Species Differences: Critical Caveat
A major pitfall is extrapolating animal data to humans regarding the clinical importance of axon reflexes:
In guinea pigs and rats, neuropeptide-dependent axon reflexes play a prominent role in airway responses to inflammation, with the majority of C-fiber terminals containing substance P, neurokinin A, and CGRP. 1
In humans, axon reflexes are unlikely to play a major role in airway physiology due to the paucity of neuropeptide-containing sensory nerves in human airway mucosa, contrasting sharply with rodent models. 1
Human C-fibers may release non-peptide transmitters like ATP through axonal reflexes, but the clinical significance remains under investigation. 1
Inflammatory Contribution
The axon reflex mechanism can be modulated by local inflammation: