| Allodynia | |
|---|---|
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| Specialty | Neurology |
Allodynia is a condition in which pain is caused by a stimulus that does not normally elicit pain. [1] For example, sunburn 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, an exaggerated response from a normally painful stimulus. The term comes from Ancient Greek άλλος (állos) 'other',and οδύνη (odúnē) 'pain'.
There are different kinds or types of allodynia:
Allodynia is a clinical feature of many painful conditions, such as neuropathies, [4] 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. [5]
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.[ citation needed ]
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 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. [6]
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 [7] [8] A different study reports the appearance of descending fibers at the injury site. [9] 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. [10] The same effect is achieved in the spinal cord by the recruitment of immune system cells such as monocytes/macrophages and T lymphocytes. [11]
There is a strong body of evidence that the so-called sensitization of the central nervous system 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 chemokines and other molecules important in the inflammatory response.[ citation needed ]
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 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. [10] In any case, CCL21 binds to C-C chemokine receptor type 7 and chemokine receptor CXCR3 receptors on microglia in the thalamus. [12] The physiologic response to the binding is probably the production of prostaglandin E2 (PGE2) by cyclooxygenase 2 (COX-2). [13] Activated microglia making PGE2 can then sensitize nociceptive neurons as manifested by their lowered threshold to pain. [14]
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. [15] 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). [11] 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. [16] Another outcome of the increased TNF-alpha is the release of PGE2, with a mechanism and effect similar to the ones in the thalamus. [17]
Numerous compounds alleviate the pain from allodynia. Some are specific for certain types of allodynia while others are general. They include: [18]
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. [19]
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. [20]
In physiology, nociception, also nocioception; from Latin nocere 'to harm/hurt') is the sensory nervous system's process of encoding noxious stimuli. It deals with a series of events and processes required for an organism to receive a painful stimulus, convert it to a molecular signal, and recognize and characterize the signal to trigger an appropriate defensive response.
The grey column refers to a somewhat ridge-shaped mass of grey matter in the spinal cord. This presents as three columns: the anterior grey column, the posterior grey column, and the lateral grey column, all of which are visible in cross-section of the spinal cord.
A mechanoreceptor, also called mechanoceptor, is a sensory receptor that responds to mechanical pressure or distortion. Mechanoreceptors are innervated by sensory neurons that convert mechanical pressure into electrical signals that, in animals, are sent to the central nervous system.
A nociceptor is a sensory neuron that responds to damaging or potentially damaging stimuli by sending "possible threat" signals to the spinal cord and the brain. The brain creates the sensation of pain to direct attention to the body part, so the threat can be mitigated; this process is called nociception.
The dorsal column–medial lemniscus pathway (DCML) is a sensory pathway of the central nervous system that conveys sensations of fine touch, vibration, two-point discrimination, and proprioception from the skin and joints. It transmits information from the body to the primary somatosensory cortex in the postcentral gyrus of the parietal lobe of the brain. The pathway receives information from sensory receptors throughout the body, and carries this in nerve tracts in the white matter of the dorsal column of the spinal cord to the medulla, where it is continued in the medial lemniscus, on to the thalamus and relayed from there through the internal capsule and transmitted to the somatosensory cortex. The name dorsal-column medial lemniscus comes from the two structures that carry the sensory information: the dorsal columns of the spinal cord, and the medial lemniscus in the brainstem.
Sensory neurons, also known as afferent neurons, are neurons in the nervous system, that convert a specific type of stimulus, via their receptors, into action potentials or graded receptor potentials. This process is called sensory transduction. The cell bodies of the sensory neurons are located in the dorsal ganglia of the spinal cord.
Hyperalgesia is an abnormally increased sensitivity to pain, which may be caused by damage to nociceptors or peripheral nerves and can cause hypersensitivity to stimulus. Prostaglandins E and F are largely responsible for sensitizing the nociceptors. Temporary increased sensitivity to pain also occurs as part of sickness behavior, the evolved response to infection.
A dorsal root ganglion is a cluster of neurons in a dorsal root of a spinal nerve. The cell bodies of sensory neurons known as first-order neurons are located in the dorsal root ganglia.
Neuropathic pain is pain caused by a lesion or disease of the somatosensory nervous system. Neuropathic pain may be associated with abnormal sensations called dysesthesia or pain from normally non-painful stimuli (allodynia). It may have continuous and/or episodic (paroxysmal) components. The latter resemble stabbings or electric shocks. Common qualities include burning or coldness, "pins and needles" sensations, numbness and itching.
The neuroimmune system is a system of structures and processes involving the biochemical and electrophysiological interactions between the nervous system and immune system which protect neurons from pathogens. It serves to protect neurons against disease by maintaining selectively permeable barriers, mediating neuroinflammation and wound healing in damaged neurons, and mobilizing host defenses against pathogens.
The chemokine ligand 1 (CXCL1) is a small peptide belonging to the CXC chemokine family that acts as a chemoattractant for several immune cells, especially neutrophils or other non-hematopoietic cells to the site of injury or infection and plays an important role in regulation of immune and inflammatory responses. It was previously called GRO1 oncogene, GROα, neutrophil-activating protein 3 (NAP-3) and melanoma growth stimulating activity, alpha (MGSA-α). CXCL1 was first cloned from a cDNA library of genes induced by platelet-derived growth factor (PDGF) stimulation of BALB/c-3T3 murine embryonic fibroblasts and named "KC" for its location in the nitrocellulose colony hybridization assay. This designation is sometimes erroneously believed to be an acronym and defined as "keratinocytes-derived chemokine". Rat CXCL1 was first reported when NRK-52E cells were stimulated with interleukin-1β (IL-1β) and lipopolysaccharide (LPS) to generate a cytokine that was chemotactic for rat neutrophils, cytokine-induced neutrophil chemoattractant (CINC). In humans, this protein is encoded by the gene Cxcl1 and is located on human chromosome 4 among genes for other CXC chemokines.
Group C nerve fibers are one of three classes of nerve fiber in the central nervous system (CNS) and peripheral nervous system (PNS). The C group fibers are unmyelinated and have a small diameter and low conduction velocity, whereas Groups A and B are myelinated. Group C fibers include postganglionic fibers in the autonomic nervous system (ANS), and nerve fibers at the dorsal roots. These fibers carry sensory information.
Mechanosensation is the transduction of mechanical stimuli into neural signals. Mechanosensation provides the basis for the senses of light touch, hearing, proprioception, and pain. Mechanoreceptors found in the skin, called cutaneous mechanoreceptors, are responsible for the sense of touch. Tiny cells in the inner ear, called hair cells, are responsible for hearing and balance. States of neuropathic pain, such as hyperalgesia and allodynia, are also directly related to mechanosensation. A wide array of elements are involved in the process of mechanosensation, many of which are still not fully understood.
The rostral ventromedial medulla (RVM), or ventromedial nucleus of the spinal cord, is a group of neurons located close to the midline on the floor of the medulla oblongata. The rostral ventromedial medulla sends descending inhibitory and excitatory fibers to the dorsal horn spinal cord neurons. There are 3 categories of neurons in the RVM: on-cells, off-cells, and neutral cells. They are characterized by their response to nociceptive input. Off-cells show a transitory decrease in firing rate right before a nociceptive reflex, and are theorized to be inhibitory. Activation of off-cells, either by morphine or by any other means, results in antinociception. On-cells show a burst of activity immediately preceding nociceptive input, and are theorized to be contributing to the excitatory drive. Neutral cells show no response to nociceptive input.
Group A nerve fibers are one of the three classes of nerve fiber as generally classified by Erlanger and Gasser. The other two classes are the group B nerve fibers, and the group C nerve fibers. Group A are heavily myelinated, group B are moderately myelinated, and group C are unmyelinated.
Edward Roy Perl was an American neuroscientist whose research focused on neural mechanisms of and circuitry involved in somatic sensation, principally nociception. Work in his laboratory in the late 1960s established the existence of unique nociceptors. Perl was one of the founding members of the Society for Neuroscience and served as its first president. He was a Sarah Graham Kenan Professor of Cell Biology & Physiology and a member of the UNC Neuroscience Center at the University of North Carolina School of Medicine.
C tactile afferents are nerve receptors in mammalian skin that generally respond to nonpainful stimulation such as light touch. For this reason they are classified as ‘low-threshold mechanoreceptors’. As group C nerve fibers, they are unmyelinated and have slow conduction velocities. They are mostly associated with the sensation of pleasant touch, though they may also mediate some forms of pain. CT afferents were discovered by Åke Vallbo using the technique of microneurography.
Microglia are the primary immune cells of the central nervous system, similar to peripheral macrophages. They respond to pathogens and injury by changing morphology and migrating to the site of infection/injury, where they destroy pathogens and remove damaged cells.
Presynaptic inhibition is a phenomenon in which an inhibitory neuron provides synaptic input to the axon of another neuron to make it less likely to fire an action potential. Presynaptic inhibition occurs when an inhibitory neurotransmitter, like GABA, acts on GABA receptors on the axon terminal. Or when endocannabinoids act as retrograde messengers by binding to presynaptic CB1 receptors, thereby indirectly modulating GABA and the excitability of dopamine neurons by reducing it and other presynaptic released neurotransmitters. Presynaptic inhibition is ubiquitous among sensory neurons.
Sandra M. Garraway is a Canadian-American neuroscientist and assistant professor of physiology in the Department of Physiology at Emory University School of Medicine in Atlanta, Georgia. Garraway is the director of the Emory Multiplex Immunoassay Core (EMIC) where she assists researchers from both academia and industry to perform, analyze, and interpret their multiplexed immunoassays. Garraway studies the neural mechanisms of spinal nociceptive pain after spinal cord injury and as a postdoctoral researcher she discovered roles for both BDNF and ERK2 in pain sensitization and developed novel siRNA technology to inhibit ERK2 as a treatment for pain.