No Useful Purpose

Allodynia is a particularly nasty and mysterious problem. One of the first things to get about allodynia is that it serves no useful purpose. Other types of pain serve to protect an injured area but there’s nothing protective about a condition that causes pain at the touch of clothing.

Neck-shoulder-pain-FibromyaWith about twenty percent of the population suffering from a chronically painful condition, pain has become a huge problem in our society. With the population aging and rates of diabetes – a major cause of allodynia – skyrocketing, pain will sure become an even bigger problem in the future.

In this blog we take a look at a recent overview of allodynia and see where we’re at with this perplexing condition.

Mechanical allodynia. Lolignier S, Eijkelkamp N, Wood JN. Pflugers Arch. 2015 Jan;467(1):133-9. doi: 10.1007/s00424-014-1532-0. Epub 2014 May 22.

Unfortunately it appears that allodynia, like other types of pain, appears to be caused by different factors in different people. Some sensory neurons may be involved in some people, and other sensory neurons in other people.  Sympathetic nervous system neurons, for instance, are clearly involved in triggering allodynia in some people but not in others.

Some people with bone cancer pain have a type of allodynia which does not appear to involve any of the normal pain mechanisms understood to produce pain. The cause of their allodynia is a complete mystery.

Do You Have Allodynia?

At least four different kinds of allodynia exist:

  • Tactile mechanical allodynia  – triggered by touch
  • Static mechanical allodynia – triggered by light pressure
  • Dynamic mechanical allodynia – triggered by brushing the skin
  • Thermal allodynia – triggered by cold or hot stimuli
touch allodynia and fibromyalgia

A simple touch can be excruciatingly painful in allodynia

Severe allodynia is painfully obvious to anyone who has it but if you have a more moderate case you might be unaware that it’s present. You can check for allodynia by applying a cotton pad or cold or warm compress to your skin. If you feel pain or tenderness, tingling or pins and needles or a burning sensation you may have allodynia.

A wide variety of conditions including neuropathies (from diabetes, B-vitamin deficiencies), migraine, fibromyalgia, demyelinating diseases and midbrain problems are associated with allodynia.

While much remains to be understood, and allodynia is still not getting the resources it should be, significant progress is being made in understanding its cause.

The Body

Any understanding of allodynia should probably begin at ion channels found in the sensory neurons in the skin that respond to touch.  Since the slightest touch is able to trigger allodynia in susceptible people researchers believe that stretch receptors which respond to very slight stretching of the cells of the skin are  involved.

The finding that a toxin called conotoxin NMB-1 that reduces electrical currents is able to reduce pain sensitivity without interfering with the ability to ascertain touch, indicates that electrical currents are involved. However, it’s not yet clear yet which ion channels this current is associated with.

“TRPA1 appears to dynamically respond to an amazingly wide range of diverse stimuli that include apparently unrelated modalities such as mechanical, chemical and thermal stimuli that activate somatosensory neurons.” Garrison – the Dynamic TRPAI Channel


The ion channels that register “stretch” are clearly affected in allodynia

The TRP1A channel is one possibility. This ion channel, which is found in many cell types, translates stimulation from environmental irritants, heat, cold and stretch into nervous system activity.  It is heavily involved, for instance, in producing pain signals in response to bacterial  infections. Removing the TRP1A ion channel from mice increases their tolerance of noxious stimuli dramatically. This channel also, interestingly enough, can affect blood vessel functioning.

A recent review of the TRPA1 channel unequivocally stated it’s involved in fibromyalgia and other persistent pain states. It’s not clear that TRP1A, however, is telling the sensory nerves to go banana’s every time the cells on the skin experience a slight stretch. It’s involved but it doesn’t appear to be the answer.

The Kv1.1 potassium channel, on the other hand, might be. It both responds to stretch and appears to put a damper on the type of electrical current involved in allodynia.  (Mice bred without these protective potassium channels invariably experience allodynia.)

Simply knocking out the ion channels could lead to an inability to detect sensation and result in further injury. A better approach might be to stop the pain at a different level. That brings us to immune system manipulation.

Immune Factors

A great deal of research has been focused on understanding how immune factors contribute to pain sensitization at the level of the sensory neurons. Little is knownm unfortunately, how they contribute to allodynia.

Researchers do know that injecting an intracellular messenger called cAMP that is often associated with inflammation can cause profound allodynia in laboratory animals. They also know that inducing allodynia in mice that are deficient in adenylate cyclase – an enzyme that produces cAMP – has proven to be difficult. cAMP, therefore, is definitely involved in allodynia.

The cAMP situation is confused, though, by the finding that a important byproduct of cAMP activation called PKA which plays a major role in  producing inflammation triggered pain is apparently not involved in allodynia.

unusual allodynia pathway

An unusual pain producing pathway is associated with allodynia

That was a surprise. Further studies, however, found evidence of an alternate cAMP activated pathway called epac in allodynia which is entirely distinct from the pain pathways associated with inflammation.

Further studies indicated that activation of the epac pathway sensitizes the sensory neurons involved in sensing touch. Then research indicated that this new pathway is  also associated with the production of proteins that regulate sensory neuron activity.

Researchers ability to reduce allodynia in mice by knocking down the levels of these proteins suggests that the epac pathway may be the real deal. An epac antagonist has recently been developed to fight cancer.

Epac does its work  not in the skin but at the dorsal root ganglia: a gathering place for pain and other signals that’s found just outside the spine.  Manipulating these channels could hold the key to reducing allodynia.

Central Sensitivity

Sensory neurons and the immune system are clearly implicated in allodynia. Studies suggest the dorsal root ganglia found just outside of  the spinal cord are effected as well, and so is the central nervous system.

Like other aberrant pain sensitization states allodynia may present something of a perfect storm which affects every pain processing aspect in the body and the brain in some way.

It’s clear that central nervous system sensitization is present in allodynia. It appears the microglia are involved and that raises the spectre of an dysregulated neuro-immune interface.

Calling microglial activation a possible “spin-off” from normal wound healing in the periphery, the authors presented a scenario in which a barrage of stimuli from the body sensitizes neurons in the dorsal horn of the spinal cord. That opens up ion channels called TRPVI which promptly shut down inhibitory pain pathways associated with GABA, providing the crucial step of increasing the level and intensity of pain signals sent to the thalamus. The stage is set for an enduring case of central sensitization.

Stopping Allodynia

Four strategies for stopping allodynia were put forth:

  1.  Blocking mediators such as BDNF, cytokines and nerve growth factor that sensitize the neurons in both the central nervous system and periphery.
  2. Blocking the activity of the ion channels that tell the nerves the cells are being touched (stretched). Thus far one channel – Piezo2- is a potential candidate but more surely play a role.
  3. Trying to turn down the electrical activity in the pain producing channels found in the sensory nerves. Some success with this is being found in animal studies.
  4. Dismantling the aberrant circuitry that has been linked to allodynia.



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