Editing Nociception

{{Short description|How an organism receives and responds to painful stimuli}}

In [[physiology]], '''nociception''' {{IPA|/ˌnəʊsɪˈsɛpʃ(ə)n/}}, also '''nocioception'''; {{ety|la|nocere|to [[harm]]/hurt}}) is the [[Somatosensory system|sensory nervous system]]'s process of encoding [[Noxious stimulus|noxious stimuli]]. It deals with a series of events and processes required for an organism to receive a [[pain]]ful stimulus, convert it to a molecular signal, and recognize and characterize the signal to trigger an appropriate defensive response. 

In nociception, intense chemical (e.g., [[capsaicin]] present in [[chili pepper]] or [[cayenne pepper]]), mechanical (e.g., cutting, crushing), or thermal (heat and cold) stimulation of [[sensory neuron]]s called [[nociceptor]]s produces a signal that travels along a chain of [[nerve fiber]]s to the [[brain]].<ref>{{cite book |chapter-url=https://books.google.com/books?id=1RGIDl4OP0IC&pg=RA3-PA403 |chapter=Chronic Pain Management |first1=Russell K. |last1=Portenoy |first2=Michael J. |last2=Brennan |title=Handbook of Neurorehabilitation |editor1-first=David C. |editor1-last=Good |editor2-first=James R. |editor2-last=Couch |publisher=Informa Healthcare |year=1994 |isbn=978-0-8247-8822-3 |access-date=2017-09-06 |archive-date=2020-10-24 |archive-url=https://web.archive.org/web/20201024000456/https://books.google.com/books?id=1RGIDl4OP0IC&pg=RA3-PA403 |url-status=live }}</ref> Nociception triggers a variety of physiological and behavioral responses to protect the organism against an aggression, and usually results in a subjective experience, or [[perception]], of pain in [[Sentience|sentient]] beings.<ref name="Bayne">{{cite book |last1=Bayne |first1=Kathryn |chapter=Assessing Pain and Distress: A Veterinary Behaviorist's Perspective |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK99551/ |pages=13–21 |title=Definition of Pain and Distress and Reporting Requirements for Laboratory Animals: Proceedings of the Workshop Held June 22, 2000 |date=2000 |publisher=National Academies Press |isbn=978-0-309-17128-1 |access-date=May 17, 2020 |archive-date=September 13, 2019 |archive-url=https://web.archive.org/web/20190913000715/https://www.ncbi.nlm.nih.gov/books/NBK99551/ |url-status=live }}</ref>

==Detection of noxious stimuli==
[[File:Nociceptive pain.jpg|thumb|upright=2|Mechanism of nociception via [[sensory afferents]]]]
Potentially damaging mechanical, thermal, and chemical stimuli are detected by nerve endings called nociceptors, which are found in the [[skin]], on internal surfaces such as the [[periosteum]], [[joint]] surfaces, and in some internal [[organ (anatomy)|organ]]s. Some nociceptors are unspecialized [[free nerve ending]]s that have their cell bodies outside the [[spinal column]] in [[dorsal root ganglia]].<ref>{{cite book |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK10965/ |chapter=Nociceptors |last=Purves |first=D. |title=Neuroscience |editor1-first=MA. |editor1-last=Sunderland |publisher=Sinauer Associates |year=2001 |access-date=2017-09-06 |archive-date=2020-08-14 |archive-url=https://web.archive.org/web/20200814091452/https://www.ncbi.nlm.nih.gov/books/NBK10965/ |url-status=live }}</ref> Others are specialised structures in the skin such as nociceptive [[Schwann cells]].<ref>{{Cite journal|last1=Doan|first1=Ryan A.|last2=Monk|first2=Kelly R.|date=16 August 2019|title=Glia in the skin activate pain responses|journal=Science|volume=365|issue=6454|pages=641–642|doi=10.1126/science.aay6144|issn=1095-9203|pmid=31416950|bibcode=2019Sci...365..641D|s2cid=201015745}}</ref> Nociceptors are categorized according to the [[axon]]s which travel from the receptors to the [[spinal cord]] or brain. After nerve injury, it is possible for touch fibers that normally carry non-noxious stimuli to be perceived as noxious.<ref>{{Cite journal|last1=Dhandapani|first1=Rahul|last2=Arokiaraj|first2=Cynthia Mary|last3=Taberner|first3=Francisco J.|last4=Pacifico|first4=Paola|last5=Raja|first5=Sruthi|last6=Nocchi|first6=Linda|last7=Portulano|first7=Carla|last8=Franciosa|first8=Federica|last9=Maffei|first9=Mariano|last10=Hussain|first10=Ahmad Fawzi|last11=de Castro Reis|first11=Fernanda|date=2018-04-24|title=Control of mechanical pain hypersensitivity in mice through ligand-targeted photoablation of TrkB-positive sensory neurons|journal=Nature Communications|language=en|volume=9|issue=1|page=1640|doi=10.1038/s41467-018-04049-3|pmid=29691410|pmc=5915601|bibcode=2018NatCo...9.1640D|issn=2041-1723|doi-access=free}}</ref>

Nociceptive pain consists of an adaptive alarm system.<ref>{{Cite journal|last1=Woolf|first1=Clifford J.|last2=Ma|first2=Qiufu|date=2007-08-02|title=Nociceptors--noxious stimulus detectors|journal=Neuron|volume=55|issue=3|pages=353–364|doi=10.1016/j.neuron.2007.07.016|issn=0896-6273|pmid=17678850|s2cid=13576368 |doi-access=free}}</ref> Nociceptors have a certain threshold; that is, they require a minimum intensity of stimulation before they trigger a signal. Once this threshold is reached, a signal is passed along the neuron's axon into the spinal cord.

Nociceptive threshold testing deliberately applies a noxious stimulus to a human or animal subject to study pain. In animals, the technique is often used to study the efficacy of [[analgesic drugs]] and to establish dosing levels and periods of effect. After establishing a baseline, the drug under test is given, and the elevation in threshold is recorded at specified times. The threshold should return to the baseline (pretreatment) value when the drug wears off. In some conditions, the excitation of pain fibers increases as the pain stimulus continues, leading to a condition called [[hyperalgesia]].

==Theory==
{{main|Pain theories}}

==Consequences==
Nociception can also cause generalized [[Autonomic nervous system|autonomic responses]] before or without reaching consciousness to cause [[pallor]], [[sweating]], [[tachycardia]], [[hypertension]], [[lightheadedness]], [[nausea]], and [[fainting]].<ref>{{cite journal |last1=Feinstein |first1=B. |last2=Langton |first2=J. N. K. |last3=Jameson |first3=R. M. |last4=Schiller |first4=F. |title=Experiments on pain referred from deep somatic tissues |journal=The Journal of Bone & Joint Surgery |date=October 1954 |volume=36 |issue=5 |pages=981–997 |doi=10.2106/00004623-195436050-00007 |pmid=13211692 }}</ref>

== System overview ==
[[File:Comprehensive List of Relevant Pathways for the Nociceptive, Proprioceptive, Thermoceptive, and Chemoceptive Systems.png|thumb|upright=1.2|This diagram linearly (unless otherwise mentioned) tracks the projections of all known structures that allow for pain, proprioception, thermoception, and chemoception to their relevant endpoints in the human brain.
Click to enlarge.
]]
This overview discusses [[proprioception]], [[thermoception]], chemoception, and nociception, as they are all integrally connected.

=== Mechanical ===
{{See also|Neuropathic pain}}
Proprioception is determined by using standard mechanoreceptors (especially [[ruffini corpuscle]]s (stretch) and [[transient receptor potential channel]]s (TRP channels). Proprioception is completely covered within the [[somatosensory system]], as the brain processes them together.

Thermoception refers to stimuli of moderate temperatures {{convert|24|&ndash;|28|C|F}}, as anything beyond that range is considered pain and moderated by nociceptors. TRP and potassium channels [TRPM (1-8), TRPV (1-6), TRAAK, and TREK] each respond to different temperatures (among other stimuli), which create action potentials in nerves that join the mechano (touch) system in the posterolateral tract. Thermoception, like proprioception, is then covered by the somatosensory system.<ref>{{cite book |last1=McCann |first1=Stephanie |title=Kaplan Medical Anatomy Flashcards: Clearly Labeled, Full-Color Cards |date=2017 |publisher=KAPLAN |isbn=978-1-5062-2353-7 }}{{page needed|date=May 2020}}</ref><ref>Albertine, Kurt. Barron's Anatomy Flash Cards{{page needed|date=May 2020}}</ref><ref>{{cite journal |last1=Hofmann |first1=Thomas |last2=Schaefer |first2=Michael |last3=Schultz |first3=Günter |last4=Gudermann |first4=Thomas |title=Subunit composition of mammalian transient receptor potential channels in living cells |journal=Proceedings of the National Academy of Sciences |date=28 May 2002 |volume=99 |issue=11 |pages=7461–7466 |doi=10.1073/pnas.102596199 |pmid=12032305 |pmc=124253 |bibcode=2002PNAS...99.7461H |doi-access=free }}</ref><ref>{{cite journal |last1=Noël |first1=Jacques |last2=Zimmermann |first2=Katharina |last3=Busserolles |first3=Jérome |last4=Deval |first4=Emanuel |last5=Alloui |first5=Abdelkrim |last6=Diochot |first6=Sylvie |last7=Guy |first7=Nicolas |last8=Borsotto |first8=Marc |last9=Reeh |first9=Peter |last10=Eschalier |first10=Alain |last11=Lazdunski |first11=Michel |title=The mechano-activated K+ channels TRAAK and TREK-1 control both warm and cold perception |journal=The EMBO Journal |date=12 March 2009 |volume=28 |issue=9 |pages=1308–1318 |doi=10.1038/emboj.2009.57 |pmid=19279663 |pmc=2683043 }}</ref><ref>{{cite journal |last1=Scholz |first1=Joachim |last2=Woolf |first2=Clifford J. |title=Can we conquer pain? |journal=Nature Neuroscience |date=November 2002 |volume=5 |issue=11 |pages=1062–1067 |doi=10.1038/nn942 |pmid=12403987 |s2cid=15781811 }}</ref>

TRP channels that detect noxious stimuli (mechanical, thermal, and chemical pain) relay that information to nociceptors that generate an action potential. Mechanical TRP channels react to depression of their cells (like touch), thermal TRPs change shape in different temperatures, and chemical TRPs act like [[taste bud]]s, signalling if their receptors bond to certain elements/chemicals.

=== Neural ===

* [[Nucleus proprius of spinal cord|Laminae 3-5]] make up [[nucleus proprius]] in spinal grey matter.
* [[Rexed lamina|Lamina 2]] makes up [[substantia gelatinosa of Rolando]], unmyelinated spinal grey matter. Substantia receives input from nucleus proprius and conveys intense, poorly localized pain.
* [[Marginal nucleus of spinal cord|Lamina 1]] primarily project to the [[parabrachial area]] and [[Periaqueductal gray|periaqueductal grey]], which begins the suppression of pain via neural and hormonal inhibition. Lamina 1 receive input from thermoreceptors via the <!--Paleospinothalamic tract redirects here-->[[posterolateral tract]]. Marginal nucleus of the spinal cord are the only unsuppressible pain signals.
* The [[parabrachial area]] integrates taste and pain info, then relays it. Parabrachial checks if the pain is being received in normal temperatures and if the [[gustatory system]] is active; if both are so the pain is assumed to be due to poison.
* [[Ao fiber]]s synapse on laminae 1 and 5 while [[Ab fiber|Ab]] synapses on 1, 3, 5, and C. [[C fiber]]s exclusively synapse on lamina 2.<ref>{{cite journal |last1=Braz |first1=Joao M. |last2=Nassar |first2=Mohammed A. |last3=Wood |first3=John N. |last4=Basbaum |first4=Allan I. |title=Parallel 'Pain' Pathways Arise from Subpopulations of Primary Afferent Nociceptor |journal=Neuron |date=September 2005 |volume=47 |issue=6 |pages=787–793 |doi=10.1016/j.neuron.2005.08.015 |pmid=16157274 |s2cid=2402859 |doi-access=free }}</ref><ref>{{cite book |last1=Brown |first1=A. G. |title=Organization in the Spinal Cord: The Anatomy and Physiology of Identified Neurones |date=2012 |publisher=Springer Science & Business Media |isbn=978-1-4471-1305-8 }}{{page needed|date=May 2020}}</ref>
* The [[amygdala]] and [[hippocampus]] create and encode the memory and emotion due to pain stimuli.
* The [[hypothalamus]] signals for the release of hormones that make pain suppression more effective; some of these are sex hormones.
* [[Periaqueductal grey]] (with hypothalamic hormone aid) hormonally signals [[reticular formation]]'s [[raphe nucleus|raphe nuclei]] to produce [[serotonin]] that inhibits laminae pain nuclei.<ref>{{cite journal |last1=van den Pol |first1=Anthony N. |title=Hypothalamic Hypocretin (Orexin): Robust Innervation of the Spinal Cord |journal=The Journal of Neuroscience |date=15 April 1999 |volume=19 |issue=8 |pages=3171–3182 |doi=10.1523/JNEUROSCI.19-08-03171.1999 |pmid=10191330 |pmc=6782271 |doi-access=free }}</ref>
* <!--Neospinothalamic tract redirects here-->
* [[Lateral spinothalamic tract]] aids in localization of pain.
* [[Spinoreticular tract|Spinoreticular]] and [[spinotectal tract]]s are merely relay tracts to the [[thalamus]] that aid in the perception of pain and alertness towards it. Fibers cross over (left becomes right) via the spinal [[anterior white commissure]].
* [[Lateral lemniscus]] is the first point of integration of sound and pain information.<ref>{{cite journal |last1=Bajo |first1=Victoria M. |last2=Merchán |first2=Miguel A. |last3=Malmierca |first3=Manuel S. |last4=Nodal |first4=Fernando R. |last5=Bjaalie |first5=Jan G. |title=Topographic organization of the dorsal nucleus of the lateral lemniscus in the cat |journal=The Journal of Comparative Neurology |date=10 May 1999 |volume=407 |issue=3 |pages=349–366 |doi=10.1002/(SICI)1096-9861(19990510)407:3<349::AID-CNE4>3.0.CO;2-5 |pmid=10320216 |s2cid=25724084 }}</ref>
* [[Inferior colliculus]] (IC) aids in sound orienting to pain stimuli.<ref>{{cite book |doi=10.1007/0-387-27083-3_2 |chapter=Neuronal Organization in the Inferior Colliculus |title=The Inferior Colliculus |year=2005 |last1=Oliver |first1=Douglas L. |pages=69–114 |isbn=0-387-22038-0 }}</ref>
* [[Superior colliculus]] receives IC's input, integrates visual orienting info, and uses the balance topographical map to orient the body to the pain stimuli.<ref>{{cite journal |last1=Corneil |first1=Brian D. |last2=Olivier |first2=Etienne |last3=Munoz |first3=Douglas P. |title=Neck Muscle Responses to Stimulation of Monkey Superior Colliculus. I. Topography and Manipulation of Stimulation Parameters |journal=Journal of Neurophysiology |date=1 October 2002 |volume=88 |issue=4 |pages=1980–1999 |doi=10.1152/jn.2002.88.4.1980 |pmid=12364523 |s2cid=2969333 |doi-access=free }}</ref><ref>{{cite book |doi=10.1016/S0079-6123(05)51011-2 |chapter=The mammalian superior colliculus: Laminar structure and connections |title=Neuroanatomy of the Oculomotor System |series=Progress in Brain Research |year=2006 |last1=May |first1=Paul J. |volume=151 |pages=321–378 |pmid=16221594 |isbn=9780444516961 }}</ref>
* [[Inferior cerebellar peduncle]] integrates proprioceptive info and outputs to the [[vestibulocerebellum]]. The peduncle is not part of the lateral-spinothalamic-tract-pathway; the medulla receives the info and passes it onto the peduncle from elsewhere (see [[somatosensory system]]).
* The [[thalamus]] is where pain is thought to be brought into [[perception]]; it also aids in pain suppression and modulation, acting like a [[bouncer (doorman)|bouncer]], allowing certain intensities through to the cerebrum and rejecting others.<ref>{{cite journal |last1=Benevento |first1=Louis A. |last2=Standage |first2=Gregg P. |title=The organization of projections of the retinorecipient and nonretinorecipient nuclei of the pretectal complex and layers of the superior colliculus to the lateral pulvinar and medial pulvinar in the macaque monkey |journal=The Journal of Comparative Neurology |date=1 July 1983 |volume=217 |issue=3 |pages=307–336 |doi=10.1002/cne.902170307 |pmid=6886056 |s2cid=44794002 }}</ref>
* The [[somatosensory cortex]] decodes nociceptor info to determine the exact location of pain and is where proprioception is brought into consciousness; inferior cerebellar peduncle is all unconscious proprioception.
* [[Insular cortex|Insula]] judges the intensity of the pain and provides the ability to imagine pain.<ref>{{cite journal |last1=Sawamoto |first1=Nobukatsu |last2=Honda |first2=Manabu |last3=Okada |first3=Tomohisa |last4=Hanakawa |first4=Takashi |last5=Kanda |first5=Masutaro |last6=Fukuyama |first6=Hidenao |last7=Konishi |first7=Junji |last8=Shibasaki |first8=Hiroshi |title=Expectation of Pain Enhances Responses to Nonpainful Somatosensory Stimulation in the Anterior Cingulate Cortex and Parietal Operculum/Posterior Insula: an Event-Related Functional Magnetic Resonance Imaging Study |journal=The Journal of Neuroscience |date=1 October 2000 |volume=20 |issue=19 |pages=7438–7445 |doi=10.1523/JNEUROSCI.20-19-07438.2000 |pmid=11007903 |pmc=6772793 |doi-access=free }}</ref><ref>{{cite journal |last1=Menon |first1=Vinod |last2=Uddin |first2=Lucina Q. |title=Saliency, switching, attention and control: a network model of insula function |journal=Brain Structure and Function |date=29 May 2010 |volume=214 |issue=5–6 |pages=655–667 |doi=10.1007/s00429-010-0262-0 |pmid=20512370 |pmc=2899886 }}</ref>
* [[Cingulate cortex]] is presumed to be the memory hub for pain.<ref>{{cite journal |last1=Shackman |first1=Alexander J. |last2=Salomons |first2=Tim V. |last3=Slagter |first3=Heleen A. |last4=Fox |first4=Andrew S. |last5=Winter |first5=Jameel J. |last6=Davidson |first6=Richard J. |title=The integration of negative affect, pain and cognitive control in the cingulate cortex |journal=Nature Reviews Neuroscience |date=March 2011 |volume=12 |issue=3 |pages=154–167 |doi=10.1038/nrn2994 |pmid=21331082 |pmc=3044650 }}</ref>

==In non-mammals==

Nociception has been documented in other animals, including fish<ref>{{cite journal |last1=Sneddon |first1=L. U. |first2=V. A. |last2=Braithwaite |first3=M. J. |last3=Gentle |year=2003 |title=Do fishes have nociceptors? Evidence for the evolution of a vertebrate sensory system |journal=[[Proceedings of the Royal Society B]] |volume=270 |issue= 1520|pages=1115–1121 |doi=10.1098/rspb.2003.2349 |pmid=12816648 |pmc=1691351}}</ref> and a wide range of [[Pain in invertebrates|invertebrates]],<ref>{{cite journal |author=Jane A. Smith |title=A Question of Pain in Invertebrates |journal=Institute for Laboratory Animals Journal |volume=33 |issue=1–2 |year=1991 |url=http://www.abolitionist.com/darwinian-life/invertebrate-pain.html |access-date=2011-06-02 |archive-date=2011-10-08 |archive-url=https://web.archive.org/web/20111008212237/http://www.abolitionist.com/darwinian-life/invertebrate-pain.html |url-status=live }}</ref> including leeches,<ref>{{cite journal |last1=Pastor |first1=J. |first2=B. |last2=Soria |first3=C. |last3=Belmonte |year=1996 |title=Properties of the nociceptive neurons of the leech segmental ganglion |journal=Journal of Neurophysiology |volume=75 |issue=6 |pages=2268–2279 |doi= 10.1152/jn.1996.75.6.2268|pmid=8793740 }}</ref> nematode worms,<ref>{{cite journal |last1=Wittenburg |first1=N. |first2=R. |last2=Baumeister |year=1999 |title=Thermal avoidance in ''Caenorhabditis elegans'': an approach to the study of nociception |journal=[[Proceedings of the National Academy of Sciences|PNAS]] |volume=96 |issue=18 |pages=10477–10482 |doi=10.1073/pnas.96.18.10477 |pmid=10468634 |pmc=17914 |bibcode=1999PNAS...9610477W |doi-access=free }}</ref> sea slugs,<ref>{{cite journal |last1=Illich |first1=P. A. |first2=E. T. |last2=Walters |year=1997 |title=Mechanosensory neurons innervating ''Aplysia'' siphon encode noxious stimuli and display nociceptive sensitization |journal=Journal of Neuroscience |volume=17 |issue= 1|pages=459–469 |pmid=8987770 |pmc=6793714 |doi=10.1523/JNEUROSCI.17-01-00459.1997 }}</ref> and fruit flies.<ref>{{cite journal |last1=Tracey |first1=W.Daniel |last2=Wilson |first2=Rachel I |last3=Laurent |first3=Gilles |last4=Benzer |first4=Seymour |title=''painless'', a ''Drosophila'' Gene Essential for Nociception |journal=Cell |date=April 2003 |volume=113 |issue=2 |pages=261–273 |doi=10.1016/s0092-8674(03)00272-1 |pmid=12705873 |s2cid=1424315 |doi-access=free }}</ref> As in mammals, nociceptive neurons in these species are typically characterized by responding preferentially to high temperature (40&nbsp;°C or more), low pH, capsaicin, and tissue damage.

==History of term==
The term "nociception" was coined by [[Charles Scott Sherrington]] to distinguish the physiological process (nervous activity) from pain (a subjective experience).<ref>{{cite book |last=Sherrington |first=C. |title=The Integrative Action of the Nervous System |url=https://archive.org/details/integrativeacti00shergoog |location=Oxford |publisher=Oxford University Press |year=1906 }}{{page needed|date=May 2020}}</ref> It is derived from the Latin verb ''nocēre'', which means "to harm".

==See also==
* {{Annotated link|Electroreception}}
* {{Annotated link|Mechanoreceptor}}
* {{Annotated link|Thermoception}}
* {{Annotated link|Proprioception}}

==References==
{{reflist}}
{{Sensation and perception}}
{{pain}}

[[Category:Nociception| ]]
[[Category:Pain]]
[[Category:Sensory systems]]
[[Category:Acute pain]]