Nociceptor 569879 217152172 2008-06-04T20:49:21Z Zfaulkes 2088397 Added non-mammalian section. A '''nociceptor''' is a [[sensory receptor]] that sends signals that cause the perception of [[pain]] in response to potentially damaging stimulus. Nociceptors are the [[nerve]] endings responsible for [[nociception]], one of the two types of persistent pain (the other, [[neuropathic pain]], occurs when nerves in the [[central nervous system|central]] or [[peripheral nervous system]] are not functioning properly). Nociceptors are silent receptors and do not sense normal stimuli. Only when activated by a threatening stimulus do they invoke a [[reflex]]. ==History== Nociceptors were discovered by [[Charles Scott Sherrington]] in 1906. At the time it was believed that animals were mechanical devices that transformed sensory stimuli into motor responses. That transitioned into more specific research where it was determined that different types of stimulation to a receptive field led to different responses. One of these stimuli had an intensity and quality sufficient to trigger autonomic reflex withdrawal, and pain. Sherrington used many different styles of experiments to discover that this pain was a nociceptive reaction and was sensed through specific receptors called nociceptors.<ref>{{cite journal |author=Levine DN |title=Sherrington's "The Integrative action of the nervous system": a centennial appraisal |journal=J. Neurol. Sci. |volume=253 |issue=1-2 |pages=1–6 |year=2007 |month=February |pmid=17223135 |doi=10.1016/j.jns.2006.12.002 |url=}}</ref> ==Location== In mammals, nociceptors are sensory [[neuron]]s that are found in any area of the body that can sense pain either externally or internally. External examples are in [[Biological tissue|tissue]]s such as [[skin]] ([[cutaneous nociceptor]]s), [[cornea]] and [[mucosa]]. Internal nociceptors are in a variety of organs, such as the [[muscle]], [[joint]], [[Urinary bladder|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 nerve|trigeminal]] ganglia.<ref name = Jessell>{{cite book |author=Jessell, Thomas M.; Kandel, Eric R.; Schwartz, James H. |title=Principles of neural science |publisher=Appleton & Lange |location=Norwalk, CT |year=1991 |pages= 472-9|isbn=0-8385-8034-3 |oclc= |doi= |accessdate=}}</ref> 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 with the dendrites wherever a receptive field is found. ==Development== Nociceptors develop from [[neural crest]] stem cells. The neural crest is responsible for a large part of early development in vertebrates. More specifically it is responsible for neuronal development. The neural crest stem cells form the [[neural tube]] and nociceptors grow from the dorsal part of this tube. They form late during neurogenesis. If they were formed early they would be either [[proprioceptors]] or low-threshold [[mechanoreceptors]]. Those are non-pain sensing receptors, so the development of nociceptors late in neurogeneis allows for their different sensing capabilities. All embryonic nociceptors express the TrkA nerve growth factor (NGF). However, transcription factors that determine the type of nociceptor remain unclear.<ref name = Woolf>{{cite journal |author=Woolf CJ, Ma Q |title=Nociceptors--noxious stimulus detectors |journal=Neuron |volume=55 |issue=3 |pages=353–64 |year=2007 |month=August |pmid=17678850 |doi=10.1016/j.neuron.2007.07.016 |url=}}</ref> Following sensory neurogenesis, differentiation occurs and two different types of nociceptors are formed. They are classified as either peptidergic or nonpeptidergic nociceptors. These two sets of receptors express distinct repertoires of ion channels and receptors. With their specialization, it allows the receptors to innvervate different peripheral and central targets. This differentiation occurs in both perinatal and postnatal periods. The nonpeptidergic nociceptors switch off the TrkA nerve growth factor 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.<ref name = Woolf/> ==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 potential]] is induced and driven towards the 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 reach by either chemical, thermal, or mechanical environments are the nociceptors triggered. 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 have thereby earned the more poetic title of sleeping or silent nociceptors. Nociceptors have two different types of axons. The first are the [[A delta fiber|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.<ref>{{cite book |author=Williams, S. J.; Purves, Dale |title=Neuroscience |publisher=Sinauer Associates |location=Sunderland, Mass |year=2001 |pages= |isbn=0-87893-742-0 |oclc= |doi= |accessdate=}}</ref> 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 from the damage. If there is massive or prolonged input to a C fiber there is 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.<ref name = Fields>{{cite journal |author=Fields HL, Rowbotham M, Baron R |title=Postherpetic neuralgia: irritable nociceptors and deafferentation |journal=Neurobiol. Dis. |volume=5 |issue=4 |pages=209–27 |year=1998 |month=October |pmid=9848092 |doi=10.1006/nbdi.1998.0204 |url=}}</ref> ===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 TRPV1, 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 TRMP8 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. Many times these mechanical nociceptors 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 [[Capsaicin]]. 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.<ref name = Woolf/> ===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.<ref name = Jessell/> ==Pathway== [[Afferent nerve|Afferent]] 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 [[cell (biology)|cells]] in the dorsal horn are divided into physiologically distinct layers called laminae. Different fiber types form [[chemical synapse|synapses]] in different layers. 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.<ref name = Jessell/> 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. area of the brain that can release some of these hormones is the [[hypothalamus]].<ref>{{cite web | url = http://www.macalester.edu/psychology/whathap/UBNRP/Audition/site/pain%20pathway.html | title = Pain Pathway | accessdate = 2008-06-02 }}</ref> 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 invovled 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. ==Sensitivity== Nociceptor neuron sensitivity is modulated by a large variety of mediators in the extracellular space.<ref>{{cite journal |author=Hucho T, Levine JD |title=Signaling pathways in sensitization: toward a nociceptor cell biology |journal=Neuron |volume=55 |issue=3 |pages=365–76 |year=2007 |month=August |pmid=17678851 |doi=10.1016/j.neuron.2007.07.008 |url=}}</ref> 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 [[hyperalgesia]]. 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.<ref name = Fields/> ==Nociceptors in non-mammalian animals== Nociception has been documented in non-mammalian animals, including fishes<ref>Sneddon, L. U., V. A. Braithwaite, and M. J. Gentle. 2003. Do fishes have nociceptors? Evidence for the evolution of a vertebrate sensory system. ''Proceedings of the Royal Society of London. Series B. Biological sciences'' '''270''': 1115-1121. http://dx.doi.org/10.1098/rspb.2003.2349</ref> and a wide range of invertebrates, including leeches<ref>Pastor, J., B. Soria, and C. Belmonte. 1996. Properties of the nociceptive neurons of the leech segmental ganglion. Journal of Neurophysiology 75: 2268-2279. http://jn.physiology.org/cgi/content/abstract/75/6/2268</ref>, nematode worms<ref>Wittenburg, N., and R. Baumeister. 1999. Thermal avoidance in ''Caenorhabditis elegans'': an approach to the study of nociception. Proceedings of the National Academy of Sciences of the United States of America 96: 10477-10482. http://www.pnas.org/cgi/content/abstract/96/18/10477</ref>, sea slugs<ref>Illich, P. A., and E. T. Walters. 1997. Mechanosensory neurons innervating ''Aplysia'' siphon encode noxious stimuli and display nociceptive sensitization. The Journal of Neuroscience 17: 459-469. http://www.jneurosci.org/cgi/content/abstract/17/1/459</ref>, and fruit flies<ref>Tracey, J., W. Daniel, R. I. Wilson, G. Laurent, and S. Benzer. 2003. ''painless'', a ''Drosophila'' gene essential for nociception. Cell 113: 261-273. http://dx.doi.org/10.1016/S0092-8674(03)00272-1</ref>. Although these neurons may have different pathways and relationships to the central nervous system than mammalian nociceptors, nociceptive neurons in non-mammals often fire in response to similar stimuli as mammals, such as high temperature (40 degrees C or more), low pH, capsaicin, and tissue damage. ==Terminology== Due to historical understandings of pain, nociceptors are also called pain receptors. This usage is not consistent with the modern definition of pain as a subjective experience. == See also == * [[TRPC]] ion channel * [[Piperidine]] from [[black pepper]] ==References== {{reflist}} {{somatosensory system}} {{Sensory system}} {{pain}} [[Category:Sensory receptors]] [[Category:Nociception]] [[de:Nozizeptor]] [[nl:Nociceptor]] [[pl:Nocyceptor]] [[sl:Nociceptor]] [[pt:Nociceptor]]