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Introduction
The axon reflex (or the flare response) is a reflex stimulation in the peripheral nerves of the body. Generally, a reflex is a unit reaction in nervous integration, making up the building blocks of the overall signaling in the nervous system. The axon reflex differs from the spinal cord reflex in that the signal starts in the middle of the axon and transmits directly to the effector organ skipping both an integration center and a chemical synapse. Neurons are made up of axons, dendrites, and cell bodies and function as the most basic, singular unit of nervous tissue. Axons project from the cell body and make connections to other neurons, muscles, and glands. Axons facilitate intercellular communication through electrical signaling. The electrical signal flows to adjacent neurons to activate local muscle tissues and arterioles innervated by that neuron. The impulse is limited to a single bifurcated axon and does not cause a general response to surrounding tissue.



The axon reflex arc is distinct from the spinal cord reflex arc. In the spinal cord reflex pathway the afferent neuron transmits information to spinal cord interneurons. These interneurons act as integrating centers, or a group of neurons that collectively process and make sense of inbound stimuli, to stimulate effector neurons. These effector neurons transmit a response to the original tissue the reflex arose from. The axon reflex effects only the locally innervated cells of the single neuron where the signal starts. The axon reflex pathway does not include an integration center or synapse that relay communication between neurons in the spinal cord reflex concentrating the effect of axon reflex on a single neuron and surrounding tissue.

Research and discovery
The axon reflex was discovered by Kovalevskiy and Sokovnin, two Russian scientists who described the axon reflex as a new type of peripheral (or local) reflex. Axon reflexes differ in that the electrical signal starts in the middle of the axon and transmit immediately skipping both an integration center and a chemical synapse. After its initial discovery, Langley defined this stimulation pathway as “axon reflex”. Langley researched the hair movement on cats as they were exposed to cold temperature. He concluded that the primary neuronal stimulation did not end after the first synapse but rather was involved in branching connections to multiple neurons resulting in rising of the cat hair in surrounding areas.

Later, Sir Thomas Lewis discovered that mechanical abrasion to the skin produces a red line and wheal pattern. Lewis believed that the skin’s response was due to the dilation of neighboring blood vessels that were triggered by the nervous system. The result of axon reflex stimulation is vasodilation. Vasodilation causes dilation of arterioles in the affected area. There was no real evidence against the idea of this flare impulse response due to sensory stimulators. There was also no real evidence explaining the branching of nerves from the center of an axon rather than a cell body and no evidence explaining which chemical agents were responsible for the goosebump, red line, and dilated blood vessel symptoms.

Janscó-Gabor and Szolcsányi later demonstrated that when irritant chemicals and electrical stimulants are applied to the skin, cutaneous nocireceptor afferents are stimulated and pass signals to neighboring tissues resulting in extravasation. This response is similar to Lewis’s as both rely on an intact sensory nerve supply and affect neighboring tissues.

Physiology
The location of stretch and heat stimulation one one branch of a nerve, results in an impulse that moves to the point of division of the nerve where the impulse reflects down the other branch to the effector organ. The location of the stimulation determines which effector organ is stimulated. Axon reflexes stimulate numerous effector organs including the endocrine, vascular and circulatory systems. Physiologically, the axon reflex helps to maintain homeostasis in animals. The axon reflex responds to changes in external conditions and regulates the internal environment so that it remains stable and relatively constant. The axon reflex is known to respond to changes in temperature, chemical concentration, and air contents. Axon reflex mediated mechanisms include itching, inflammation, pain, asthma, and dermal circulation.

Vasodilation
Itching, or nociception is a reflex that often evokes a scratching desire. The compound capsaicin can be used to deplete the chemicals in the axon reflex nerve endings and reduce the symptoms of itching and pain. Inflammation is the body’s response to tissue damage due to the trauma of an infection, physical injury or toxin. When these sensory receptors increase, the result is the axon reflex becomes stimulated and is responsible for many of the necessary inflammatory chemicals as inflammation alters the chemistry of the traumatized region. Axon reflex regulates vasodilation, or blood flow to particular tissues. Axon reflex aids in conduction of the neuromuscular junction in order to allow muscles to contract in the shortest amount of time possible.



In dermal circulation, the axon reflex controls the vasodilation in response to stimuli, and can thus control the temperature and circulation in the tissues more easily. Small nerve fibers called thermoreceptors are sensitive to temperature and can act as sensors that initiate axon reflex mediated vasodilation. Neuromuscular diseases can be predicted early by the presence of abnormal muscle fiber reflexes and corresponding twitches. This arises because axons can generate their own action potentials when hyperexcited from the original stimulus; this is known as a fasciculation potential in the muscle fiber. Fasciculations are prominent features in amyotrophic lateral sclerosis amyotrophic lateral sclerosis (ALS) and could be evidence of abnormal axon reflex with further experimental investigation.

Asthma
In asthma, the axon reflex induces the release of various neuropeptides, which can cause the smooth muscle in the airway to contract, and a similar mechanism happens in allergies. They are also responsible for the loss of body heat in the extremities, or the hunters test. One clinical test that can be taken on a person is the QSART Test, or the Quantitative Sudomotor Axon Reflex Testing, which stimulates the autonomic nervous system of an individual by stimulating sweat glands through the promotion of axon reflexes. The skin is stimulated with electricity to promote this. This allows for the assessment of the type and severity of autonomic nervous disorders and peripheral neuropathies.

Sweat response
Humans and primates use the sudomotor function to thermoregulate and regulate body temperature. The sudomotor function is mainly a result of the sympathetic nervous system with negligible influences from the parasympathetic nervous system. Heat sensitive receptors are present in the skin, viscera, and spinal cord where they receive information from the outside to the thermoregulatory center in the hypothalamus. A sweat response stimulates M3 muscarinic receptors on sweat glands. The sweat response also stimulates a sudomotor axon reflex where cholinergic agents bind to the nicotinic receptors on the sudomotor nerve terminals evoking an impulse that travels opposite a normal impulse, toward the soma. At the soma of the postganglionic sympathetic sudomotor neuron the impulse branches and travels orthodromically away from the soma. Finally, as this impulse reaches other sweat glands, it causes an indirect axon-reflex sweat response. Sudomotor axon reflexes can be peripherally amplified by acetylcholine. Acetylcholine activates sudomotor fibers and primary afferent nociceptors triggering axon reflexes for both. However with nerve damage (neuropathy) there is still some increase in axon reflex sweating.

Mechanisms
Cutaneous receptors or sensory receptors on the skin detect changes temperature (thermoreceptors) and pain (nociceptors). These cutaneous receptors initiate an impulse via the main axon to the spinal cord. The axon reflex is the spread of this impulse from the main axon to nearby blood vessels in the stimulated area of the skin. These impulses in the affected area release chemical agents that cause blood vessels to dilate and leak, causing the skin to sweat. A thermoreceptor in vasodilation will trigger an impulse that flows to a chemical synapse to oppose release of ACh at the junction. This trigger will allow periocytes to relax along the arterioles and capillaries, therefore allowing more blood flow and effectively triggering vasodilation. As this action opposes contraction, it would be an inhibitory signaling reflex.

This mechanism of vasodilation is supported by previous research. The vasomotor response effectiveness can be explained by the value of Tau (the time constant of the blood circulation over that area experiences effect from a sensor). In general, the value of Tau is negligibly affected among temperatures of 39C and higher, whereas temperatures below 39C will exhibit a significant variance in the value of Tau. The original signal for vasodilation to occur is from the skin experiencing a gain of temperature from heat exposure, approaching a threshold (around 40C). The cooling phase of Tau will depend on body mechanics and that individual’s ability to radiate heat from the body.