Nociceptor
Encyclopedia
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
.
in 1906. In earlier centuries, scientists believed that animals were like mechanical devices that transformed the energy of sensory stimuli into motor responses. Sherrington used many different styles of experiments to demonstrate that different types of stimulation to a nerve's receptive field led to different responses. Some intense stimuli trigger reflex withdrawal, autonomic responses and pain. The specific receptors for these intense stimuli were called nociceptors.
s that are found in any area of the body that can sense pain either externally or internally. External examples are in tissue
s such as skin
(cutaneous nociceptors), cornea
and mucosa. Internal nociceptors are in a variety of organs, such as the muscle
, joint
, bladder
, gut
and continuing along the digestive tract. The cell bodies of these neurons are located in either the dorsal root ganglia or the trigeminal
ganglia. The trigeminal ganglia are specialized nerves for the face, whereas the dorsal root ganglia associate with the rest of the body. The axons extend into the peripheral nervous system and terminate in branches to form receptive fields.
stem cells. The neural crest is responsible for a large part of early development in vertebrates. More specifically it is responsible for development of the peripheral nervous system. The neural crest stem cells split off from the neural tube as it closes, and nociceptors grow from the dorsal part of this neural crest tissue. They form late during neurogenesis. Earlier forming cells from this region can become non-pain sensing receptors; either proprioceptors or low-threshold mechanoreceptors. All neurons derived from neural crest, including embryonic nociceptors, express the TrkA which is a receptor to nerve growth factor (NGF). However, transcription factors that determine the type of nociceptor remain unclear.
Following sensory neurogenesis, differentiation occurs and two different types of nociceptors are formed. They are classified as either peptidergic or nonpeptidergic nociceptors. The sets of receptors express distinct repertoires of ion channels and receptors. With their specialization, it allows the receptors to innervate different peripheral and central targets. This differentiation occurs in both perinatal and postnatal periods. The nonpeptidergic nociceptors switch off the TrkA and begin expressing Ret. Ret is a transmembrane signaling component which allows for the expression of another growth factor—glial cell-derived growth factor (GDNF). This transition is assisted by Runx1 which has proven to be vital in the development of nonpeptidergic nociceptors. On the contrary, the peptidergic nociceptors continue to use TrkA and they express a completely different type of growth factor. Currently there is a lot of research being done to determine more specifically what creates the differences between nociceptors.
is induced and driven towards the central nervous system
(CNS). This leads to the train of events that allows for the conscious awareness of pain. The sensory specificity of nociceptors is established by the high threshold only to particular features of stimuli. Only when the high threshold has been reached by either chemical, thermal, or mechanical environments are the nociceptors triggered. The majority of nociceptors are classified by which of the environmental modalities they respond to. Some nociceptors respond to more than one of these modalities and are consequently designated polymodal. Other nociceptors respond to none of these modalities (although they may respond to stimulation under conditions of inflammation) and are referred to as sleeping or silent nociceptors.
Nociceptors have two different types of axons. The first are the Aδ fiber
axons. They are myelinated and can allow an action potential to travel at a rate of about 20 meters/second towards the CNS. The other type is the more slowly conducting C fiber axons. These only conduct at speeds of around 2 meters/second. This is due to the light or non-myelination of the axon. As a result, pain comes in two phases. The first phase is mediated by the fast-conducting Aδ fibers and the second part due to (Polymodal) C fibers. The pain associated with the Aδ fibers can be associated to an initial extremely sharp pain. The second phase is a more prolonged and slightly less intense feeling of pain as a result of the damage. If there is massive or prolonged input to a C fiber, there is a progressive build up in the spinal cord dorsal horn; this phenomenon is similar to tetanus
in muscles but is called wind-up
. If wind-up occurs there is a probability of increased sensitivity to pain.
, and it has a threshold that coincides with the heat pain temperature of 42 °C. Other temperature in the warm–hot range is mediated by more than one TRP channel. Each of these channels express a particular C-terminal domain that corresponds to the warm–hot sensitivity. The interactions between all these channels and how the temperature level is determined to be above the pain threshold are unknown at this time. The cool stimuli are sensed by TRPM8
channels. Its C-terminal domain differs from the heat sensitive TRPs. Although this channel corresponds to cool stimuli, it is still unknown whether it also contributes in the detection of intense cold. An interesting finding related to cold stimuli is that tactile sensibility and motor function deteriorate while pain perception persists.
. Other chemical stimulants are environmental irritants like acrolein
, a World War I
chemical weapon and a component of cigarette smoke. Besides from these external stimulants, chemical nociceptors have the capacity to detect endogenous ligands, and certain fatty acid amines that arise from changes in internal tissues. Like in thermal nociceptors, TRPV1 can detect chemicals like capsaicin and spider toxins.
nociceptive fibers (those that send information to, rather than from the brain) travel back to the spinal cord
where they form synapses in its dorsal horn. This nociceptive fiber (located in the periphery) is a first order neuron. The cells
in the dorsal horn are divided into physiologically distinct layers called laminae. Different fiber types form synapses
in different layers, and use either glutamate or substance P
as the neurotransmitter. Aδ fibers form synapses in laminae I and V, C fibers connect with neurons in lamina II, Aβ fibers connect with lamina I, III, & V. After reaching the specific lamina within the spinal cord, the first order nociceptive project to second order neurons and cross the midline. The second order neurons then send their information via two pathways to the thalamus
: the dorsal column medial-lemniscal system and the anterolateral system
. The first is reserved more for regular non-painful sensation, while the lateral is reserved for pain sensation. Upon reaching the thalamus, the information is processed in the ventral posterior nucleus and sent to the cerebral cortex
in the brain. As there is an ascending pathway to the brain that initiates the conscious realization of pain, there also is a descending pathway which modulates pain sensory. The brain can request the release of specific hormones or chemicals that can have analgesic effects which can reduce or inhibit pain sensation. The area of the brain that stimulates the release of these hormones is the hypothalamus
.
This effect of descending inhibition can be shown by electrically stimulating the periaqueductal grey area of the midbrain. The periaqueductal grey in turn projects to other areas involved in pain regulation, such as the nucleus raphe magnus
(which also receives similar afferents from the nucleus reticularis paragigantocellularis (NPG). In turn the nucleus raphe magnus projects to the substantia gelatinosa
region of the dorsal horn and mediates the sensation of spinothalamic inputs. The periaqueductal grey also contains opioid receptors which explains one of the mechanisms by which opioids such as morphine
and diacetylmorphine exhibit an analgesic effect.
. Inflammation is one common cause that results in the sensitization of nociceptors. Normally hyperalgesia ceases when inflammation goes down, however, sometimes genetic defects and/or repeated injury can result in allodynia
: a completely non-noxious stimulus like light touch causes extreme pain. Allodynia can also be caused when a nociceptor is damaged in the peripheral nerves. This can result in deafferentation, which means the development of different central processes from the surviving afferent nerve. With this situation, surviving dorsal root axons of the nociceptors can make contact with the spinal cord, thus changing the normal input.
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...
that responds to potentially damaging stimuli by sending nerve signals to the spinal cord and brain. This process, called nociception
Nociception
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...
, usually causes the perception of pain
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."...
.
History
Nociceptors were discovered by Charles Scott SherringtonCharles Scott Sherrington
Sir Charles Scott Sherrington, OM, GBE, PRS was an English neurophysiologist, histologist, bacteriologist, and a pathologist, Nobel laureate and president of the Royal Society in the early 1920s...
in 1906. In earlier centuries, scientists believed that animals were like mechanical devices that transformed the energy of sensory stimuli into motor responses. Sherrington used many different styles of experiments to demonstrate that different types of stimulation to a nerve's receptive field led to different responses. Some intense stimuli trigger reflex withdrawal, autonomic responses and pain. The specific receptors for these intense stimuli were called nociceptors.
Location
In mammals, nociceptors are sensory neuronNeuron
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 that are found in any area of the body that can sense pain either externally or internally. External examples are in tissue
Biological tissue
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
s such as skin
Skin
-Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat...
(cutaneous nociceptors), cornea
Cornea
The cornea is the transparent front part of the eye that covers the iris, pupil, and anterior chamber. Together with the lens, the cornea refracts light, with the cornea accounting for approximately two-thirds of the eye's total optical power. In humans, the refractive power of the cornea is...
and mucosa. Internal nociceptors are in a variety of organs, such as the muscle
Muscle
Muscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
, joint
Joint
A joint is the location at which two or more bones make contact. They are constructed to allow movement and provide mechanical support, and are classified structurally and functionally.-Classification:...
, bladder
Urinary bladder
The urinary bladder is the organ that collects urine excreted by the kidneys before disposal by urination. A hollow muscular, and distensible organ, the bladder sits on the pelvic floor...
, gut
Gut (zoology)
In zoology, the gut, also known as the alimentary canal or alimentary tract, is a tube by which bilaterian animals transfer food to the digestion organs. In large bilaterians the gut generally also has an exit, the anus, by which the animal disposes of solid wastes...
and continuing along the digestive tract. The cell bodies of these neurons are located in either the dorsal root ganglia or the trigeminal
Trigeminal nerve
The trigeminal nerve contains both sensory and motor fibres. It is responsible for sensation in the face and certain motor functions such as biting, chewing, and swallowing. Sensory information from the face and body is processed by parallel pathways in the central nervous system...
ganglia. The trigeminal ganglia are specialized nerves for the face, whereas the dorsal root ganglia associate with the rest of the body. The axons extend into the peripheral nervous system and terminate in branches to form receptive fields.
Development
Nociceptors develop from neural crestNeural crest
Neural crest cells are a transient, multipotent, migratory cell population unique to vertebrates that gives rise to a diverse cell lineage including melanocytes, craniofacial cartilage and bone, smooth muscle, peripheral and enteric neurons and glia....
stem cells. The neural crest is responsible for a large part of early development in vertebrates. More specifically it is responsible for development of the peripheral nervous system. The neural crest stem cells split off from the neural tube as it closes, and nociceptors grow from the dorsal part of this neural crest tissue. They form late during neurogenesis. Earlier forming cells from this region can become non-pain sensing receptors; either proprioceptors or low-threshold mechanoreceptors. All neurons derived from neural crest, including embryonic nociceptors, express the TrkA which is a receptor to nerve growth factor (NGF). However, transcription factors that determine the type of nociceptor remain unclear.
Following sensory neurogenesis, differentiation occurs and two different types of nociceptors are formed. They are classified as either peptidergic or nonpeptidergic nociceptors. The sets of receptors express distinct repertoires of ion channels and receptors. With their specialization, it allows the receptors to innervate different peripheral and central targets. This differentiation occurs in both perinatal and postnatal periods. The nonpeptidergic nociceptors switch off the TrkA and begin expressing Ret. Ret is a transmembrane signaling component which allows for the expression of another growth factor—glial cell-derived growth factor (GDNF). This transition is assisted by Runx1 which has proven to be vital in the development of nonpeptidergic nociceptors. On the contrary, the peptidergic nociceptors continue to use TrkA and they express a completely different type of growth factor. Currently there is a lot of research being done to determine more specifically what creates the differences between nociceptors.
Types and functions
The peripheral terminal of the mature nociceptor is where the noxious stimuli are detected and transduced into electrical energy. When the electrical energy reaches a threshold value, an action potentialAction 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...
is induced and driven towards 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...
(CNS). This leads to the train of events that allows for the conscious awareness of pain. The sensory specificity of nociceptors is established by the high threshold only to particular features of stimuli. Only when the high threshold has been reached by either chemical, thermal, or mechanical environments are the nociceptors triggered. The majority of nociceptors are classified by which of the environmental modalities they respond to. Some nociceptors respond to more than one of these modalities and are consequently designated polymodal. Other nociceptors respond to none of these modalities (although they may respond to stimulation under conditions of inflammation) and are referred to as sleeping or silent nociceptors.
Nociceptors have two different types of axons. The first are the Aδ fiber
A delta fiber
A delta fibers, or Aδ fibers, are a type of sensory fiber.They are associated with cold and pressure, and as nociceptors stimulation of them is interpreted as fast/first pain information....
axons. They are myelinated and can allow an action potential to travel at a rate of about 20 meters/second towards the CNS. The other type is the more slowly conducting C fiber axons. These only conduct at speeds of around 2 meters/second. This is due to the light or non-myelination of the axon. As a result, pain comes in two phases. The first phase is mediated by the fast-conducting Aδ fibers and the second part due to (Polymodal) C fibers. The pain associated with the Aδ fibers can be associated to an initial extremely sharp pain. The second phase is a more prolonged and slightly less intense feeling of pain as a result of the damage. If there is massive or prolonged input to a C fiber, there is a progressive build up in the spinal cord dorsal horn; this phenomenon is similar to tetanus
Tetanus
Tetanus is a medical condition characterized by a prolonged contraction of skeletal muscle fibers. The primary symptoms are caused by tetanospasmin, a neurotoxin produced by the Gram-positive, rod-shaped, obligate anaerobic bacterium Clostridium tetani...
in muscles but is called wind-up
Pain wind-up
Pain wind-up is central pain sensitization caused by repeated painful stimulation of peripheral nerves at sufficient intensity to stimulate group C nerve fibers, leading to progressively increasing electrical response in the corresponding spinal posterior horn neurons...
. If wind-up occurs there is a probability of increased sensitivity to pain.
Thermal
Thermal nociceptors are activated by noxious heat or cold at various temperatures. There are specific nociceptor transducers that are responsible for how and if the specific nerve ending responds to the thermal stimulus. The first to be discovered was TRPV1TRPV1
The transient receptor potential cation channel subfamily V member 1 ', also known as the capsaicin receptor and the vanilloid receptor 1, is a protein that, in humans, is encoded by the TRPV1 gene...
, and it has a threshold that coincides with the heat pain temperature of 42 °C. Other temperature in the warm–hot range is mediated by more than one TRP channel. Each of these channels express a particular C-terminal domain that corresponds to the warm–hot sensitivity. The interactions between all these channels and how the temperature level is determined to be above the pain threshold are unknown at this time. The cool stimuli are sensed by TRPM8
TRPM8
Transient receptor potential cation channel subfamily M member 8 , also known as the cold and menthol receptor 1 , is a protein that in humans is encoded by the TRPM8 gene.-Function:...
channels. Its C-terminal domain differs from the heat sensitive TRPs. Although this channel corresponds to cool stimuli, it is still unknown whether it also contributes in the detection of intense cold. An interesting finding related to cold stimuli is that tactile sensibility and motor function deteriorate while pain perception persists.
Mechanical
Mechanical nociceptors respond to excess pressure or mechanical deformation. They also respond to incisions that break the skin surface. The reaction to the stimulus is processed as pain by the cortex, just like chemical and thermal responses. These mechanical nociceptors frequently have polymodal characteristics. So it is possible that some of the transducers for thermal stimuli are the same for mechanical stimuli. The same is true for chemical stimuli, since TRPA1 appears to detect both mechanical and chemical changes.Chemical
Chemical nociceptors have TRP channels that respond to a wide variety of spices commonly used in cooking. The one that sees the most response and is very widely tested is CapsaicinCapsaicin
Capsaicin 2CHCH=CH4CONHCH2C6H3-4--3- ) is the active component of chili peppers, which are plants belonging to the genus Capsicum. It is an irritant for mammals, including humans, and produces a sensation of burning in any tissue with which it comes into contact...
. Other chemical stimulants are environmental irritants like acrolein
Acrolein
Acrolein is the simplest unsaturated aldehyde. It is produced widely but is most often immediately reacted with other products due to its instability and toxicity...
, a World War I
World War I
World War I , which was predominantly called the World War or the Great War from its occurrence until 1939, and the First World War or World War I thereafter, was a major war centred in Europe that began on 28 July 1914 and lasted until 11 November 1918...
chemical weapon and a component of cigarette smoke. Besides from these external stimulants, chemical nociceptors have the capacity to detect endogenous ligands, and certain fatty acid amines that arise from changes in internal tissues. Like in thermal nociceptors, TRPV1 can detect chemicals like capsaicin and spider toxins.
Sleeping/silent
Although each nociceptor can have a variety of possible threshold levels, some do not respond at all to chemical, thermal or mechanical stimuli unless injury actually has occurred. These are typically referred to as silent or sleeping nociceptors since their response comes only on the onset of inflammation to the surrounding tissue.Pathway
AfferentAfferent nerve
In the nervous system, afferent neurons , carry nerve impulses from receptors or sense organs towards the central nervous system. This term can also be used to describe relative connections between structures. Afferent neurons communicate with specialized interneurons...
nociceptive fibers (those that send information to, rather than from the brain) travel back 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...
where they form synapses in its dorsal horn. This nociceptive fiber (located in the periphery) is a first order neuron. The cells
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
in the dorsal horn are divided into physiologically distinct layers called laminae. Different fiber types form synapses
Chemical synapse
Chemical synapses are specialized junctions through which neurons signal to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous system. They are crucial to the biological computations that underlie...
in different layers, and use either glutamate or substance P
Substance P
In the field of neuroscience, substance P is a neuropeptide: an undecapeptide that functions as a neurotransmitter and as a neuromodulator. It belongs to the tachykinin neuropeptide family. Substance P and its closely related neuropeptide neurokinin A are produced from a polyprotein precursor...
as the neurotransmitter. Aδ fibers form synapses in laminae I and V, C fibers connect with neurons in lamina II, Aβ fibers connect with lamina I, III, & V. After reaching the specific lamina within the spinal cord, the first order nociceptive project to second order neurons and cross the midline. The second order neurons then send their information via two pathways to 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...
: the dorsal column medial-lemniscal system and the anterolateral system
Anterolateral system
In the nervous system, the anterolateral system is an ascending pathway that conveys pain, temperature , and crude touch from the periphery to the brain. It comprises three main pathways:-External links:*...
. The first is reserved more for regular non-painful sensation, while the lateral is reserved for pain sensation. Upon reaching the thalamus, the information is processed in the ventral posterior nucleus and sent to the cerebral cortex
Cerebral cortex
The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...
in the brain. As there is an ascending pathway to the brain that initiates the conscious realization of pain, there also is a descending pathway which modulates pain sensory. The brain can request the release of specific hormones or chemicals that can have analgesic effects which can reduce or inhibit pain sensation. The area of the brain that stimulates the release of these hormones is the hypothalamus
Hypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
.
This effect of descending inhibition can be shown by electrically stimulating the periaqueductal grey area of the midbrain. The periaqueductal grey in turn projects to other areas involved in pain regulation, such as the nucleus raphe magnus
Nucleus raphe magnus
The nucleus raphes magnus, located directly rostral to the nucleus raphes obscurus, is afferently stimulated from axons in the spinal cord and cerebellum....
(which also receives similar afferents from the nucleus reticularis paragigantocellularis (NPG). In turn the nucleus raphe magnus projects to the substantia gelatinosa
Substantia gelatinosa
Substantia gelatinosa can refer to:* Substantia gelatinosa of Rolando * Substantia gelatinosa centralisSubstantia gelatinosa is a structure involved in pain transmission....
region of the dorsal horn and mediates the sensation of spinothalamic inputs. The periaqueductal grey also contains opioid receptors which explains one of the mechanisms by which opioids such as morphine
Morphine
Morphine 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...
and diacetylmorphine exhibit an analgesic effect.
Sensitivity
Nociceptor neuron sensitivity is modulated by a large variety of mediators in the extracellular space. Peripheral sensitization represents a form of functional plasticity of the nociceptor. The nociceptor can change from being simply a noxious stimulus detector to a detector of non-noxious stimuli. The result is that low intensity stimuli from regular activity, initiates a painful sensation. This is commonly known as hyperalgesiaHyperalgesia
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:...
. Inflammation is one common cause that results in the sensitization of nociceptors. Normally hyperalgesia ceases when inflammation goes down, however, sometimes genetic defects and/or repeated injury can result in allodynia
Allodynia
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...
: a completely non-noxious stimulus like light touch causes extreme pain. Allodynia can also be caused when a nociceptor is damaged in the peripheral nerves. This can result in deafferentation, which means the development of different central processes from the surviving afferent nerve. With this situation, surviving dorsal root axons of the nociceptors can make contact with the spinal cord, thus changing the normal input.