Allodynia
Encyclopedia
Allodynia is a pain
due to a stimulus
which does not normally provoke pain. Temperature or physical stimuli can provoke allodynia, and it often occurs after injury to a site. Allodynia is different from hyperalgesia
, an extreme reaction to a stimulus which is normally painful.
, postherpetic neuralgia
, fibromyalgia
, and migraine
. Allodynia may also be caused by some populations of stem cell
s used to treat nerve damage
including spinal cord injury
. One of the etiology of static mechanical allodynia is A-beta fibers lesions: Static mechanical allodynia is a paradoxical painful hypoaesthesia.
and mechanical sensation are the cells responsible for allodynia. In healthy individuals, nociceptor
s sense information about cell stress or damage and temperature at the skin and transmit it to the spinal cord
. The cell bodies
of these neuron
s lie in dorsal root ganglia
, important structures located on both sides of the spinal cord. The axon
s 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 interneuron
s, 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.
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. 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 monocyte
s/macrophage
s and T lymphocytes
.
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 chemokine
s and other molecule
s 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. In any case, CCL21 binds to C-C chemokine receptor type 7
and chemokine receptor CXCR3
receptors
on microglia
in the thalamus. The physiologic response to the binding is probably the production of prostaglandin
E2 (PGE2) by cyclooxygenase
2 (COX-2). Activated microglia making PGE2 can then sensitize nociceptive neurons as manifested by their lowered threshold to pain.
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. Macrophage
s and lymphocyte
s infiltrate the spinal cord, for example, because of injury, and release TNF-alpha and other pro-inflammatory molecules. 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
). This mechanism also explains the perpetuation of sensitization and thus allodynia. TNF-alpha might also increase the number of AMPA receptor
s, and decrease the numbers of GABA receptor
s on the membrane of nociceptors, both of which could change the nociceptors in a way that allows for their easier activation. Another outcome of the increased TNF-alpha is the release of PGE2, with a mechanism and effect similar to the ones in the thalamus.
(PAG) area of the midbrain.
The body possesses an additional mechanism to control pain: the release of endogenous
opioid
s, especially at the level of the PAG. There are neurons that release enkephalin
s, endorphin
s, and dynorphin
s at the PAG, and in this way modulate its ability to modulate pain perception. Other neurons can release their endogenous opioids at the source of the pain, as well. If this occurs, the transmission of pain information from the nociceptors to the secondary neurons is blocked, and no pain is felt. Unfortunately, these endogenous mechanisms are often damaged and nonfunctional in people suffering from allodynia, so the application of pharmaceuticals is needed.
Dynamic mechanical allodynia - compounds targeting different ion channel
s; opioids
Static mechanical allodynia - sodium channel blockers, opioids
Cold allodynia
The list of compounds that can be used to treat allodynia is even longer than this. For example, many non-steroidal anti-inflammatory drug
s, 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 thermoreceptor
s to stimuli.
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 neurotransmitter
s or the enzyme
s that remove neurotransmitters not bound to receptors.
YM-230888 is a compound that can bind to one of the metabotropic receptor
s, preventing glutamate from binding and the transmission of the signal. This compound can also overcome the blood-brain barrier
, allowing it to be useful in the thalamus.
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.
Pain
Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...
due to a stimulus
Stimulus (physiology)
In physiology, a stimulus is a detectable change in the internal or external environment. The ability of an organism or organ to respond to external stimuli is called sensitivity....
which does not normally provoke pain. Temperature or physical stimuli can provoke allodynia, and it often occurs after injury to a site. Allodynia is different from hyperalgesia
Hyperalgesia
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.-Types:...
, an extreme 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
- Dynamic mechanical allodynia – pain in response to brushing
- Thermal (hot or cold) allodynia – pain from normally mild skin temperatures in the affected area
Causes
Allodynia is a clinical feature of many painful conditions, such as neuropathies, complex regional pain syndromeComplex regional pain syndrome
Complex regional pain syndrome is a chronic progressive disease characterized by severe pain, swelling and changes in the skin. It often affects an arm or a leg and may spread to another part of the body.Though treatment is often unsatisfactory, early multimodal therapy can cause dramatic...
, postherpetic neuralgia
Postherpetic neuralgia
Postherpetic neuralgia is a neuralgia caused by the varicella zoster virus. Typically, the neuralgia is confined to a dermatomic area of the skin and follows an outbreak of herpes zoster in that same dermatomic area...
, fibromyalgia
Fibromyalgia
Fibromyalgia is a medical disorder characterized by chronic widespread pain and allodynia, a heightened and painful response to pressure. It is an example of a diagnosis of exclusion...
, and migraine
Migraine
Migraine is a chronic neurological disorder characterized by moderate to severe headaches, and nausea...
. Allodynia may also be caused by some populations of stem cell
Stem cell
This article is about the cell type. For the medical therapy, see Stem Cell TreatmentsStem cells are biological cells found in all multicellular organisms, that can divide and differentiate into diverse specialized cell types and can self-renew to produce more stem cells...
s used to treat nerve damage
Nerve Damage
Nerve Damage is a compilation album by Groove Metal band Skinlab, released in 2004. It is a 2CD collection of rare and unreleased material, including a live set, demos, remixes, alternate mixes, and two new tracks.-Disc 1:# "Losing All" – 4:04...
including spinal cord injury
Spinal cord injury
A spinal cord injury refers to any injury to the spinal cord that is caused by trauma instead of disease. Depending on where the spinal cord and nerve roots are damaged, the symptoms can vary widely, from pain to paralysis to incontinence...
. One of the etiology of static mechanical allodynia is A-beta fibers lesions: Static mechanical allodynia is a paradoxical painful hypoaesthesia.
Cellular level
The cell types involved in nociceptionNociception
Nociception is defined as "the neural processes of encoding and processing noxious stimuli." It is the afferent activity produced in the peripheral and central nervous system by stimuli that have the potential to damage tissue...
and mechanical sensation are the cells responsible for allodynia. In healthy individuals, nociceptor
Nociceptor
A nociceptor is a sensory receptor that responds to potentially damaging stimuli by sending nerve signals to the spinal cord and brain. This process, called nociception, usually causes the perception of pain.-History:...
s sense information about cell stress or damage and temperature at the skin and transmit it to the spinal cord
Spinal cord
The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...
. The cell bodies
Soma
Soma , or Haoma , from Proto-Indo-Iranian *sauma-, was a ritual drink of importance among the early Indo-Iranians, and the subsequent Vedic and greater Persian cultures. It is frequently mentioned in the Rigveda, whose Soma Mandala contains 114 hymns, many praising its energizing qualities...
of these neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s lie in dorsal root ganglia
Dorsal root ganglion
In anatomy and neuroscience, a dorsal root ganglion is a nodule on a dorsal root that contains cell bodies of neurons in afferent spinal nerves.-Unique unipolar structure:...
, important structures located on both sides of the spinal cord. The axon
Axon
An axon is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma....
s 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
Thalamus
The thalamus is a midline paired symmetrical structure within the brains of vertebrates, including humans. It is situated between the cerebral cortex and midbrain, both in terms of location and neurological connections...
. From there, the information is carried through one or more neurons to the somatosensory cortex
Postcentral gyrus
The lateral postcentral gyrus is a prominent structure in the parietal lobe of the human brain and an important landmark. It is the location of primary somatosensory cortex, the main sensory receptive area for the sense of touch...
of the brain
Human brain
The human brain has the same general structure as the brains of other mammals, but is over three times larger than the brain of a typical mammal with an equivalent body size. Estimates for the number of neurons in the human brain range from 80 to 120 billion...
. 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 interneuron
Interneuron
An interneuron is a multipolar neuron which connects afferent neurons and efferent neurons in neural pathways...
s, 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.
Both of these mechanisms for pain modulation have been implicated in the pathology
Pathology
Pathology is the precise study and diagnosis of disease. The word pathology is from Ancient Greek , pathos, "feeling, suffering"; and , -logia, "the study of". Pathologization, to pathologize, refers to the process of defining a condition or behavior as pathological, e.g. pathological gambling....
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. 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
Microglia
Microglia are a type of glial cell that are the resident macrophages of the brain and spinal cord, and thus act as the first and main form of active immune defense in the central nervous system . Microglia constitute 20% of the total glial cell population within the brain...
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
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
cells such as monocyte
Monocyte
Monocytes are a type of white blood cell and are part of the innate immune system of vertebrates including all mammals , birds, reptiles, and fish. Monocytes play multiple roles in immune function...
s/macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
s and T lymphocytes
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
.
Molecular level
There is a strong body of evidence that the so called sensitizationSensitization
Sensitization is an example of non-associative learning in which the progressive amplification of a response follows repeated administrations of a stimulus. An everyday example of this mechanism is the repeated tonic stimulation of peripheral nerves that will occur if a person rubs his arm...
of the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
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 chemokine
Chemokine
Chemokines are a family of small cytokines, or proteins secreted by cells. Their name is derived from their ability to induce directed chemotaxis in nearby responsive cells; they are chemotactic cytokines...
s and other molecule
Molecule
A molecule is an electrically neutral group of at least two atoms held together by covalent chemical bonds. Molecules are distinguished from ions by their electrical charge...
s important in the inflammatory
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
response.
A very important molecule in the thalamus appears to be cysteine-cysteine chemokine ligand 21
CCL21
Chemokine ligand 21 is a small cytokine belonging to the CC chemokine family. This chemokine is also known as 6Ckine , exodus-2, and secondary lymphoid-tissue chemokine . The gene for CCL21 is located on human chromosome 9...
(CCL21). The concentration of this chemokine is increased in the ventral posterolateral nucleus
Ventral posterolateral nucleus
The ventral posterolateral nucleus is a nucleus of the thalamus. Together with the ventral posteromedial nucleus , VPI and VMpo, it constitutes the ventral posterior nucleus.-Input and output:...
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. In any case, CCL21 binds to C-C chemokine receptor type 7
C-C chemokine receptor type 7
C-C chemokine receptor type 7 is a protein that in humans is encoded by the CCR7 gene.CCR7 has also recently been designated CD197 .-Further reading:...
and chemokine receptor CXCR3
CXCR3
Chemokine receptor CXCR3 is a Gαi protein-coupled receptor in the CXC chemokine receptor family. Other names for CXCR3 are G protein-coupled receptor 9 and CD183...
receptors
Sensory receptor
In a sensory system, a sensory receptor is a sensory nerve ending that responds to a stimulus in the internal or external environment of an organism...
on microglia
Microglia
Microglia are a type of glial cell that are the resident macrophages of the brain and spinal cord, and thus act as the first and main form of active immune defense in the central nervous system . Microglia constitute 20% of the total glial cell population within the brain...
in the thalamus. The physiologic response to the binding is probably the production of prostaglandin
Prostaglandin
A prostaglandin is any member of a group of lipid compounds that are derived enzymatically from fatty acids and have important functions in the animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring....
E2 (PGE2) by cyclooxygenase
Cyclooxygenase
Cyclooxygenase is an enzyme that is responsible for formation of important biological mediators called prostanoids, including prostaglandins, prostacyclin and thromboxane. Pharmacological inhibition of COX can provide relief from the symptoms of inflammation and pain...
2 (COX-2). Activated microglia making PGE2 can then sensitize nociceptive neurons as manifested by their lowered threshold to pain.
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. Macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
s and lymphocyte
Lymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...
s infiltrate the spinal cord, for example, because of injury, and release TNF-alpha and other pro-inflammatory molecules. TNF-alpha then binds to the TNF receptors expressed on nociceptors, activating the MAPK
Mitogen-activated protein kinase
Mitogen-activated protein kinases are serine/threonine-specific protein kinases that respond to extracellular stimuli and regulate various cellular activities, such as gene expression, mitosis, differentiation, proliferation, and cell survival/apoptosis.-Activation:MAP kinases are activated...
/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
Autocrine signalling
Autocrine signaling is a form of signalling in which a cell secretes a hormone or chemical messenger that binds to autocrine receptors on the same cell, leading to changes in the cell...
). This mechanism also explains the perpetuation of sensitization and thus allodynia. TNF-alpha might also increase the number of AMPA receptor
AMPA receptor
The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor is a non-NMDA-type ionotropic transmembrane receptor for glutamate that mediates fast synaptic transmission in the central nervous system . Its name is derived from its ability to be activated by the artificial glutamate analog AMPA...
s, and decrease the numbers of GABA receptor
GABA receptor
The GABA receptors are a class of receptors that respond to the neurotransmitter gamma-aminobutyric acid , the chief inhibitory neurotransmitter in the vertebrate central nervous system...
s on the membrane of nociceptors, both of which could change the nociceptors in a way that allows for their easier activation. Another outcome of the increased TNF-alpha is the release of PGE2, with a mechanism and effect similar to the ones in the thalamus.
Endogenous body mechanisms for reducing pain
As already mentioned, there are descending neurons that modulate the perception of pain. Many of these neurons originate in nuclei in the brainstem and pass through the periaqueductal grayPeriaqueductal gray
Periaqueductal gray is the gray matter located around the cerebral aqueduct within the tegmentum of the midbrain. It plays a role in the descending modulation of pain and in defensive behaviour...
(PAG) area of the midbrain.
The body possesses an additional mechanism to control pain: the release of endogenous
Endogenous
Endogenous substances are those that originate from within an organism, tissue, or cell. Endogenous retroviruses are caused by ancient infections of germ cells in humans, mammals and other vertebrates...
opioid
Opioid
An opioid is a psychoactive chemical that works by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract...
s, especially at the level of the PAG. There are neurons that release enkephalin
Enkephalin
An enkephalin is a pentapeptide involved in regulating nociception in the body. The enkephalins are termed endogenous ligands, or specifically endorphins, as they are internally derived and bind to the body's opioid receptors. Discovered in 1975, two forms of enkephalin were revealed, one...
s, endorphin
Endorphin
Endorphins are endogenous opioid peptides that function as neurotransmitters. They are produced by the pituitary gland and the hypothalamus in vertebrates during exercise, excitement, pain, consumption of spicy food, love and orgasm, and they resemble the opiates in their abilities to produce...
s, and dynorphin
Dynorphin
Dynorphins are a class of opioid peptides that arise from the precursor protein prodynorphin. When prodynorphin is cleaved during processing by proprotein convertase 2 , multiple active peptides are released: dynorphin A, dynorphin B, and α/β-neo-endorphin...
s at the PAG, and in this way modulate its ability to modulate pain perception. Other neurons can release their endogenous opioids at the source of the pain, as well. If this occurs, the transmission of pain information from the nociceptors to the secondary neurons is blocked, and no pain is felt. Unfortunately, these endogenous mechanisms are often damaged and nonfunctional in people suffering from allodynia, so the application of pharmaceuticals is needed.
Drugs
Numerous compounds alleviate the pain from allodynia. Some are specific for certain types of allodynia while others are general. They include:Dynamic mechanical allodynia - compounds targeting different ion channel
Ion channel
Ion channels are pore-forming proteins that help establish and control the small voltage gradient across the plasma membrane of cells by allowing the flow of ions down their electrochemical gradient. They are present in the membranes that surround all biological cells...
s; opioids
- MexiletineMexiletineMexiletine belongs to the Class IB anti-arrhythmic group of medicines. It is used to treat arrhythmias within the heart, or seriously irregular heartbeats. It slows conduction in the heart and makes the heart tissue less sensitive. Dizziness, heartburn, nausea, nervousness, trembling, unsteadiness...
- LidocaineLidocaineLidocaine , Xylocaine, or lignocaine is a common local anesthetic and antiarrhythmic drug. Lidocaine is used topically to relieve itching, burning and pain from skin inflammations, injected as a dental anesthetic or as a local anesthetic for minor surgery.- History :Lidocaine, the first amino...
(IV/topical) - TramadolTramadolTramadol hydrochloride is a centrally acting synthetic opioid analgesic used in treating moderate pain. The drug has a wide range of applications, including treatment for restless legs syndrome and fibromyalgia...
- MorphineMorphineMorphine is a potent opiate analgesic medication and is considered to be the prototypical opioid. It was first isolated in 1804 by Friedrich Sertürner, first distributed by same in 1817, and first commercially sold by Merck in 1827, which at the time was a single small chemists' shop. It was more...
(IV) - AlfentanilAlfentanilAlfentanil is a potent but short-acting synthetic opioid analgesic drug, used for anaesthesia in surgery. It is an analogue of fentanyl with around 1/4 the potency of fentanyl and around 1/3 of the duration of action, but with an onset of effects 4x faster than fentanyl...
(IV) - KetamineKetamineKetamine is a drug used in human and veterinary medicine. Its hydrochloride salt is sold as Ketanest, Ketaset, and Ketalar. Pharmacologically, ketamine is classified as an NMDA receptor antagonist...
(IV) - Methylprednisone (intrathecalIntrathecalIntrathecal is an adjective that refers to something introduced into or occurring in the space under the arachnoid membrane of the brain or spinal cord...
) - Adenosine
- GlycineGlycineGlycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...
antagonistReceptor antagonistA receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses... - DesipramineDesipramineDesipramine is a tricyclic antidepressant . It inhibits the reuptake of norepinephrine and to a lesser extent serotonin. It is used to treat depression, but not considered a first line treatment since the introduction of SSRI antidepressants...
- VenlafaxineVenlafaxineVenlafaxine is an antidepressant of the serotonin-norepinephrine reuptake inhibitor class. First introduced by Wyeth in 1993, now marketed by Pfizer, it is licensed for the treatment of major depressive disorder , as a treatment for generalized anxiety disorder, and comorbid indications in...
Static mechanical allodynia - sodium channel blockers, opioids
- Lidocaine (IV)
- Alfentanil (IV)
- Adenosine (IV)
- Ketamine (IV)
- Glycine antagonist
- Venlafaxine
Cold allodynia
- LamotrigineLamotrigineLamotrigine, marketed in the US and most of Europe as Lamictal by GlaxoSmithKline, is an anticonvulsant drug used in the treatment of epilepsy and bipolar disorder. It is also used as an adjunct in treating depression, though this is considered off-label usage...
- 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 drug
Non-steroidal anti-inflammatory drug
Nonsteroidal anti-inflammatory drugs, usually abbreviated to NSAIDs or NAIDs, but also referred to as nonsteroidal anti-inflammatory agents/analgesics or nonsteroidal Anti-inflammatory medicines , are drugs with analgesic and antipyretic effects and which have, in higher doses, anti-inflammatory...
s, such as naproxen
Naproxen
Naproxen sodium is a nonsteroidal anti-inflammatory drug commonly used for the reduction of pain, fever, inflammation and stiffness caused by conditions such as:...
, 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 thermoreceptor
Thermoreceptor
A thermoreceptor is a sensory receptor, or more accurately the receptive portion of a sensory neuron, that codes absolute and relative changes in temperature, primarily within the innocuous range...
s to stimuli.
Other compounds act on molecules important for the transmission of an action potential
Action potential
In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...
from one neuron to another. Examples of these include interfering with receptors for neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
s or the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s that remove neurotransmitters not bound to receptors.
YM-230888 is a compound that can bind to one of the metabotropic receptor
Metabotropic receptor
Metabotropic receptor is a subtype of membrane receptors at the surface or in vesicles of eukaryotic cells.In the nervous system, based on their structural and functional characteristics, neurotransmitter receptors can be classified into two broad categories: metabotropic and ionotropic receptors...
s, preventing glutamate from binding and the transmission of the signal. This compound can also overcome the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
, allowing it to be useful in the thalamus.
Endocannabinoids are molecules that can relieve pain by modulating nociceptive neurons. When anandamide
Anandamide
Anandamide, also known as N-arachidonoylethanolamide or AEA, is an endogenous cannabinoid neurotransmitter. The name is taken from the Sanskrit word ananda, which means "bliss, delight", and amide. It is synthesized from N-arachidonoyl phosphatidylethanolamine by multiple pathways...
, 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.