Allodynia is a condition in which

pain Pain is a distressing feeling often caused by intense or damaging Stimulus (physiology), stimuli. The International Association for the Study of Pain defines pain as "an unpleasant sense, sensory and emotional experience associated with, or res ...

is caused by a stimulus that does not normally elicit pain. For example,

sunburn Sunburn is a form of radiation burn that affects living tissue, such as skin, that results from an overexposure to ultraviolet (UV) radiation, usually from the Sun. Common symptoms in humans and other animals include red or reddish skin tha ...

can cause temporary allodynia, so that usually painless stimuli, such as wearing clothing or running cold or warm water over it, can be very painful. It is different from

hyperalgesia Hyperalgesia ( or ; ''hyper'' from Greek ὑπέρ (''huper'') 'over' + ''-algesia'' from Greek ἄλγος (algos) 'pain') is an abnormally increased sensitivity to pain, which may be caused by damage to nociceptors or peripheral nerves and ...

, an exaggerated response from a normally painful stimulus. The term comes .

Types

There are different kinds or types of allodynia: * Mechanical allodynia (also known as tactile allodynia) ** Static mechanical allodynia – pain in response when touched ** Dynamic mechanical allodynia – pain in response to stroking lightly * 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 *

complex regional pain syndrome Complex regional pain syndrome (CRPS type 1 and type 2), sometimes referred to by the hyponyms reflex sympathetic dystrophy (RSD) or reflex neurovascular dystrophy (RND), is a rare and severe form of neuroinflammatory and dysautonomic disorder ...

fibromyalgia Fibromyalgia (FM) is a functional somatic syndrome with symptoms of widespread chronic pain, accompanied by fatigue, sleep disturbance including awakening unrefreshed, and Cognitive deficit, cognitive symptoms. Other symptoms can include he ...

migraine Migraine (, ) is a complex neurological disorder characterized by episodes of moderate-to-severe headache, most often unilateral and generally associated with nausea, and light and sound sensitivity. Other characterizing symptoms may includ ...

neuropathies Peripheral neuropathy, often shortened to neuropathy, refers to damage or disease affecting the nerves. Damage to nerves may impair sensation, movement, gland function, and/or organ function depending on which nerve fibers are affected. Neuropa ...

Landerholm, A. (2010). Neuropathic pain: Somatosensory Functions related to Spontaneous Ongoing Pain, Mechanical Allodynia and Pain Relief. Thesis. Stockholm: Karolinska Institutet http://diss.kib.ki.se/2010/978-91-7457-025-0/thesis.pdf *

postherpetic neuralgia Postherpetic neuralgia (PHN) is neuropathic pain that occurs due to damage to a peripheral nerve caused by the reactivation of the varicella zoster virus ( herpes zoster, also known as shingles). PHN is defined as pain in a dermatomal distributi ...

. Allodynia may also be caused by some populations of

stem cell In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can change into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type of cell ...

s used to treat nerve damage including

spinal cord injury A spinal cord injury (SCI) is damage to the spinal cord that causes temporary or permanent changes in its function. It is a destructive neurological and pathological state that causes major motor, sensory and autonomic dysfunctions. Symptoms of ...

Pathophysiology

Cellular level

Mechanoreceptors can influence the output of nociceptors by making connections with the same

interneuron Interneurons (also called internuncial neurons, association neurons, connector neurons, or intermediate neurons) are neurons that are not specifically motor neurons or sensory neurons. Interneurons are the central nodes of neural circuits, enab ...

s, the activation of which can reduce or 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 is the study of disease. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when used in the context of modern medical treatme ...

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 reported 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 are a type of glia, glial cell located throughout the brain and spinal cord of the central nervous system (CNS). Microglia account for about around 5–10% of cells found within the brain. As the resident macrophage cells, they act as t ...

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 The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to bacteria, as well as Tumor immunology, cancer cells, Parasitic worm, parasitic ...

cells such as

monocyte Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and monocyte-derived dendritic cells. As a part of the vertebrate innate immune system monocytes also ...

macrophage Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...

s and

T lymphocytes T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes A lymphocyte is a type of white blood cell (leukoc ...

Molecular level

There is a substantial body of evidence that the so-called

sensitization Sensitization is a non-associative learning process in which repeated administration of a stimulation, stimulus results in the progressive amplification of a response. Sensitization often is characterized by an enhancement of response to a whole ...

of the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

contributes to the emergence 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. 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 Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In addit ...

s and other

molecule A molecule is a group of two or more atoms that are held together by Force, attractive forces known as chemical bonds; depending on context, the term may or may not include ions that satisfy this criterion. In quantum physics, organic chemi ...

s important in the inflammatory response. An 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 The ventral posterolateral nucleus (VPL) is one of the subdivisions of the ventral posterior nucleus in the ventral nuclear group of the thalamus. It relays sensory information from the second-order neurons of the neospinothalamic tract and me ...

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 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 Prostaglandins (PG) are a group of physiology, physiologically active lipid compounds called eicosanoids that have diverse hormone-like effects in animals. Prostaglandins have been found in almost every Tissue (biology), tissue in humans and ot ...

E₂ (PGE₂) by

cyclooxygenase Cyclooxygenase (COX), officially known as prostaglandin-endoperoxide synthase (PTGS), is an enzyme (specifically, a family of isozymes, ) that is responsible for biosynthesis of prostanoids, including thromboxane and prostaglandins such a ...

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 spinal cord level differs from that in the thalamus.

Tumor necrosis factor-alpha Tumor necrosis factor (TNF), formerly known as TNF-α, is a chemical messenger produced by the immune system that induces inflammation. TNF is produced primarily by activated macrophages, and induces inflammation by binding to its receptors o ...

(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

lymphocyte A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include T cells (for cell-mediated and cytotoxic adaptive immunity), B cells (for humoral, antibody-driven adaptive immunity), an ...

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 A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of serine/threonine-specific protein kinases involved in directing cellular responses to a diverse array of stimuli, such as mitogens, osmotic stress, heat shock and proinflamm ...

/ 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 The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA receptor, AMPAR, or quisqualate receptor) is an ionotropic receptor, ionotropic glutamate receptor (iGluR) and predominantly sodium ion channel that mediates fast excitator ...

s 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. Another outcome of the increased TNF-alpha is the release of PGE₂, with a mechanism and effect similar to the ones in the thalamus.

Treatment

Medications

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 channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by Gating (electrophysiol ...

s; opioids * Mexiletine *

Lidocaine Lidocaine, also known as lignocaine and sold under the brand name Xylocaine among others, is a local anesthetic of the amino amide type. It is also used to treat ventricular tachycardia and ventricular fibrillation. When used for local anae ...

(IV/topical) *

Tramadol Tramadol, sold under the brand name Tramal among others, is an opioid analgesic, pain medication and a serotonin–norepinephrine reuptake inhibitor (SNRI) used to treat moderately severe pain. When taken by mouth in an immediate-release form ...

Morphine Morphine, formerly also called morphia, is an opiate that is found naturally in opium, a dark brown resin produced by drying the latex of opium poppies (''Papaver somniferum''). It is mainly used as an analgesic (pain medication). There are ...

(IV) * Alfentanil (IV) *

Ketamine Ketamine is a cyclohexanone-derived general anesthetic and NMDA receptor antagonist with analgesic and hallucinogenic properties, used medically for anesthesia, depression, and pain management. Ketamine exists as its S- (esketamine) a ...

(IV) * Methylprednisone ( intrathecal) *

Adenosine Adenosine (symbol A) is an organic compound that occurs widely in nature in the form of diverse derivatives. The molecule consists of an adenine attached to a ribose via a β-N9- glycosidic bond. Adenosine is one of the four nucleoside build ...

Glycine Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid. Glycine is one of the proteinogenic amino acids. It is encoded by all the codons starting with GG (G ...

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.Desipramine *

Venlafaxine Venlafaxine, sold under the brand name Effexor among others, is an antidepressant medication of the serotonin–norepinephrine reuptake inhibitor (SNRI) class. It is used to treat major depressive disorder, generalized anxiety disorder, pani ...

Pregabalin Pregabalin, sold under the brand name Lyrica among others, is an anticonvulsant, analgesic, and anxiolytic amino acid medication used to treat epilepsy, neuropathic pain, fibromyalgia, restless legs syndrome, opioid withdrawal, generalized anx ...

;Static mechanical allodynia –

sodium channel Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell (biology), cell's cell membrane, membrane. They belong to the Cation channel superfamily, superfamily of cation channels. Classific ...

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 drug Non-steroidal anti-inflammatory drugs (NSAID) are members of a therapeutic drug class which reduces pain, decreases inflammation, decreases fever, and prevents blood clots. Side effects depend on the specific drug, its dose and duration of ...

s, such as

naproxen Naproxen, sold under the brand name Aleve among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain, menstrual cramps, and inflammatory diseases such as rheumatoid arthritis, gout and fever. It is taken orally. It ...

, 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 A thermoreceptor is a non-specialised sense Cutaneous receptor, receptor, or more accurately the receptive portion of a sensory neuron, that codes absolute and relative changes in temperature, primarily within the innocuous range. In the mammalian ...

s to stimuli. Other compounds act on molecules important for the transmission of an

action potential An action potential (also known as a nerve impulse or "spike" when in a neuron) is a series of quick changes in voltage across a cell membrane. An action potential occurs when the membrane potential of a specific Cell (biology), cell rapidly ri ...

from one neuron to another. Examples of these include interfering with receptors for

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...

s or the

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

s that remove neurotransmitters not bound to receptors.

Endocannabinoid Cannabinoids () are several structural classes of compounds found primarily in the ''Cannabis'' plant or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoact ...

s are molecules that can relieve pain by modulating nociceptive neurons. When

anandamide Anandamide (ANA), also referred to as ''N''-arachidonoylethanolamine (AEA) is a fatty acid neurotransmitter belonging to the fatty acid derivative group known as N-acylethanolamine (NAE). Anandamide takes its name from the Sanskrit word ''ananda ...

, an

endocannabinoid Cannabinoids () are several structural classes of compounds found primarily in the ''Cannabis'' plant or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoact ...

, is released, pain sensation is reduced. Anandamide is later transported back to the neurons releasing it using transporter enzymes on the

plasma membrane The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...

, eventually disinhibiting pain perception. However, this re-uptake can be blocked by AM404, elongating the duration of pain inhibition.

Notable people

Howard Hughes Howard Robard Hughes Jr. (December 24, 1905 – April 5, 1976) was an American Aerospace engineering, aerospace engineer, business magnate, film producer, and investor. He was The World's Billionaires, one of the richest and most influential peo ...

is thought to have had allodynia in his later years; he seldom bathed, wore clothes, or cut his nails and hair, possibly due to the pain these typically normal actions would cause him.

References

{{pain Pain Symptoms and signs: Nervous system