Allodynia & Hyperalgesia WHAT ?!?

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Allodynia & Hyperalgesia (painful skin conditions)

Allodynia refers to central pain sensitization (increased response of neurons) following painful, often repetitive, stimulation. Allodynia can lead to the triggering of a pain response from stimuli which do not normally provoke pain.

Temperature or physical stimuli can provoke allodynia, which may feel like a burning sensation, and it often occurs after injury to a site.

Allodynia is different from hyperalgesia, an extreme, exaggerated reaction to a stimulus which is normally painful.

Types

There are different kinds or types of allodynia:

• Mechanical allodynia (also known as tactile allodynia)
  • Static mechanical allodynia – pain in response to light touch/pressure^[3]
  • Dynamic mechanical allodynia – pain in response to stroking lightly^[4]
• Thermal (hot or cold) allodynia – pain from normally mild skin temperatures in the affected area
• Movement allodynia - pain triggered by normal movement of joints or muscles

Causes

Allodynia is a clinical feature of many painful conditions, such as neuropathies, complex regional pain syndrome, postherpetic neuralgia, fibromyalgia, and migraine. Allodynia may also be caused by some populations of stem cells used to treat nerve damage including spinal cord injury. Static mechanical allodynia is a paradoxical painful hypoaesthesia, one etiology of which is lesions of A-beta fibres

Pathophysiology

Cellular level

The cell types involved in nociception and mechanical sensation are the cells responsible for allodynia. In healthy individuals, nociceptors sense information about cell stress or damage and temperature at the skin and transmit it to the spinal cord. The cell bodies of these neurons lie in dorsal root ganglia, important structures located on both sides of the spinal cord.

The axons then pass through the dorsal horn to make connections with secondary neurons. The secondary neurons cross over to the other (contralateral) side of the spinal cord and reach nuclei of the thalamus. From there, the information is carried through one or more neurons to the somatosensory cortex of the brain.

Mechanoreceptors follow the same general pathway. However, they do not cross over at the level of the spinal cord, but at the lower medulla instead. In addition, they are grouped in tracts that are spatially distinct from the nociceptive tracts.

Despite this anatomical separation, mechanoreceptors can influence the output of nociceptors by making connections with the same interneurons, the activation of which can reduce or completely eliminate the sensation of pain.

Another way to modulate the transmission of pain information is via descending fibers from the brain. These fibers act through different interneurons to block the transmission of information from the nociceptors to secondary neurons.^[9]

Both of these mechanisms for pain modulation have been implicated in the pathology of allodynia. Several studies suggest that injury to the spinal cord might lead to loss and re-organization of the nociceptors, mechanoreceptors and interneurons, leading to the transmission of pain information by mechanoreceptors^.

A different study reports the appearance of descending fibers at the injury site.^[12] All of these changes ultimately affect the circuitry inside the spinal cord, and the altered balance of signals probably leads to the intense sensation of pain associated with allodynia.

Different cell types have also been linked to allodynia. For example, there are reports that microglia in the thalamus might contribute to allodynia by changing the properties of the secondary nociceptors.

The same effect is achieved in the spinal cord by the recruitment of immune system cells such as monocytes/macrophages and T lymphocytes.

 

Molecular level[edit]

There is a strong body of evidence that the so-called sensitization of the central nervous system contributes to the appearance of allodynia. Sensitization refers to the increased response of neurons following repetitive stimulation. In addition to repeated activity, the increased levels of certain compounds lead to sensitization, as well.

The work of many researchers has led to the elucidation of pathways that can result in neuronal sensitization both in the thalamus and dorsal horns. Both pathways depend on the production of chemokines and other molecules important in the inflammatory response.

A very important molecule in the thalamus appears to be cysteine-cysteine chemokine ligand 21 (CCL21). The concentration of this chemokine is increased in the ventral posterolateral nucleus of the thalamus where secondary nociceptive neurons make connections with other neurons. The source of CCL21 is not exactly known, but two possibilities exist. First, it might be made in primary nociceptive neurons and transported up to the thalamus.

Most likely, neurons intrinsic to the ventral posterolateral nucleus make at least some of it.^[13] In any case, CCL21 binds to C-C chemokine receptor type 7 and chemokine receptor CXCR3 receptors on microglia in the thalamus.^[15] The physiologic response to the binding is probably the production of prostaglandin E₂ (PGE₂) by cyclooxygenase 2 (COX-2).^[16] Activated microglia making PGE₂ can then sensitize nociceptive neurons as manifested by their lowered threshold to pain.^[17]

The mechanism responsible for sensitization of the central nervous system at the level of the spinal cord is different from the one in the thalamus. Tumor necrosis factor-alpha (TNF-alpha) and its receptor are the molecules that seem to be responsible for the sensitization of neurons in the dorsal horns of the spinal cord. Macrophages and lymphocytes infiltrate the spinal cord, for example, because of injury, and release TNF-alpha and other pro-inflammatory molecules.^[18]

TNF-alpha then binds to the TNF receptors expressed on nociceptors, activating the MAPK/NF-kappa B pathways. This leads to the production of more TNF-alpha, its release, and binding to the receptors on the cells that released it (autocrine signalling).^[14] This mechanism also explains the perpetuation of sensitization and thus allodynia. TNF-alpha might also increase the number of AMPA receptors, and decrease the numbers of GABA receptors on the membrane of nociceptors, both of which could change the nociceptors in a way that allows for their easier activation.^[19] Another outcome of the increased TNF-alpha is the release of PGE₂, with a mechanism and effect similar to the ones in the thalamus.^[20]

Treatment

Medications

Numerous compounds alleviate the pain from allodynia. Some are specific for certain types of allodynia while others are general. They include:^[21]

Dynamic mechanical allodynia - compounds targeting different ion channels; opioids

• Mexiletine
• Lidocaine (IV/topical)
• Tramadol
• Morphine (IV)
• Alfentanil (IV)
• Ketamine (IV)
• Methylprednisone (intrathecal)
• Adenosine
• Glycine antagonist
• Desipramine
• Venlafaxine
• Lyrica

Static mechanical allodynia - sodium channel blockers, opioids

• Lidocaine (IV)
• Alfentanil (IV)
• Adenosine (IV)
• Ketamine (IV)
• Glycine antagonist
• Venlafaxine
• Gabapentin (may also be helpful in cold and dynamic allodynias)

Cold allodynia

• Lamotrigine
• Lidocaine (IV)

The list of compounds that can be used to treat allodynia is even longer than this. For example, many non-steroidal anti-inflammatory drugs, such as naproxen, can inhibit COX-1 and/or COX-2, thus preventing the sensitization of the central nervous system. Another effect of naproxen is the reduction of the responsiveness of mechano- and thermoreceptors to stimuli.^[22]

Other compounds act on molecules important for the transmission of an action potential from one neuron to another. Examples of these include interfering with receptors for neurotransmitters or the enzymes that remove neurotransmitters not bound to receptors.

Endocannabinoids are molecules that can relieve pain by modulating nociceptive neurons. When anandamide, an endocannabinoid, is released, pain sensation is reduced. Anandamide is later transported back to the neurons releasing it using transporter enzymes on the plasma membrane, eventually disinhibiting pain perception. However, this re-uptake can be blocked by AM404, elongating the duration of pain inhibition.

Hyperalgesia

is an increased sensitivity to pain, which may be caused by damage to nociceptors or peripheral nerves. Temporary increased sensitivity to pain also occurs as part of sickness behavior, the evolved response to infection.^[1]

Types

Hyperalgesia can be experienced in focal, discrete areas, or as a more diffuse, body-wide form. Conditioning studies have established that it is possible to experience a learned hyperalgesia of the latter, diffuse form.

• The focal form is typically associated with injury, and is divided into two subtypes:

• Primary hyperalgesia describes pain sensitivity that occurs directly in the damaged tissues.
• Secondary hyperalgesia describes pain sensitivity that occurs in surrounding undamaged tissues.

Opioid-induced hyperalgesia may develop as a result of long-term opioid use in the treatment of chronic pain.^[2] Various studies of humans and animals have demonstrated that primary or secondary hyperalgesia can develop in response to both chronic and acute exposure to opioids. This side effect can be severe enough to warrant discontinuation of opioid treatment.

Causes

Hyperalgesia is induced by platelet-activating factor (PAF) which comes about in an inflammatory or an allergic response. This seems to occur via immune cells interacting with the peripheral nervous system and releasing pain-producing chemicals (cytokines and chemokines).^[3]

One unusual cause of focal hyperalgesia is platypus venom.^[4]

Long term opioid (e.g. heroin, morphine) users and those on high-dose opioid medications for the treatment of chronic pain, may experience hyperalgesia and experience pain out of proportion to physical findings, which is a common cause for loss of efficacy of these medications over time.^[2][5][6]

As it can be difficult to distinguish from tolerance, opioid-induced hyperalgesia is often compensated for by escalating the dose of opioid, potentially worsening the problem by further increasing sensitivity to pain.

Chronic hyperstimulation of opioid receptors results in altered homeostasis of pain signalling pathways in the body with several mechanisms of action involved. One major pathway being through stimulation of the nociceptin receptor,^[7][8][9] and blocking this receptor may therefore be a means of preventing the development of hyperalgesia.^[10]

Stimulation of nociceptive fibers in a pattern consistent with that from inflammation switches on a form of amplification in the spinal cord, long term potentiation.^[11] This occurs where the pain fibres synapse to pain pathway, the periaqueductal grey. Amplification in the spinal cord may be another way of producing hyperalgesia.

The release of proinflammatory cytokines such as Interleukin-1 by activated leukocytes triggered by lipopolysaccharides, endotoxins and other signals of infection also increases pain sensitivity as part of sickness behavior, the evolved response to illness.^[1][12][13]

Treatment

Hyperalgesia is similar to other sorts of pain associated with nerve irritation or damage such as allodynia and neuropathic pain, and consequently may respond to standard treatment for these conditions, using various drugs such as SSRI or tricyclic antidepressants,^[14][15]

 Non-steroidal anti-inflammatory drugs,^[16] glucocorticoids,^[17] gabapentin^[18] or pregabalin,^[19] NMDA antagonists,^[20][21][22] or atypical opioids such as tramadol.^[23] Where hyperalgesia has been produced by chronic high doses of opioids, reducing the dose may result in improved pain management.^[24]

However, as with other forms of nerve dysfunction associated pain, treatment of hyperalgesia can be clinically challenging, and finding a suitable drug or drug combination that is effective for a particular patient may require trial and error. The use of a transcutaneous electrical nerve stimulation device has been shown to alleviate hyperalgesia.

(All information on this page sourced from Wikipedia)