Biochemistry Of Pain

Biochemistry of Pain:LlAll syndromes ekurwadziwa ane chimiro chekuzvimba. Mbiri yekuvhiringidza inogona kusiyana kubva pamunhu kusvika pamunhu uye inogona zvakare kusiyana mumunhu mumwe panguva dzakasiyana. Kurapa kwemarwadzo syndromes ndeyekunzwisisa iyi yekuzvimba chimiro. Marwadzo syndromes anorapwa zvemishonga, ekuvhiya kana ese ari maviri. Chinangwa ndechekudzivirira / kudzvinyirira kugadzirwa kwevanomiririra vamiririri. Uye mhedzisiro inobudirira ndeimwe inokonzeresa kuzvimba kushoma uye zvechokwadi marwadzo mashoma.

Biochemistry Of Pain

Zvinangwa:

• Ndivanaani vheyi vatambi
• Ndezvipi zvirongwa zvehupenyu hwehupenyu?
• Ndezvipi zvinoguma?

Kufuridzira Ongororo:

Key Players

Nei Bhegi Rangu Richirwadza? Ongororo YeNeuroanatomical & Biochemical Basis YePafudzi Pain

KUTANGA

Kana murwere akabvunza kuti "sei pfudzi rangu richirwadza?" Hurukuro yacho inokurumidza kutendeukira kune dzidziso yesainzi uye dzimwe nguva isingabvumirwe fungidziro. Kazhinji, chiremba anoziva nezve iyo miganho yesainzi hwaro hwetsananguro yavo, zvichiratidza kusakwana kwekunzwisisa kwedu chimiro chemarwadzo epafudzi. Kuongorora uku kunotora nzira yakarongeka yekubatsira kupindura mibvunzo yakakosha ine chekuita nekurwadziwa kwepafudzi, nechinangwa chekupa ruzivo rwekutsvagurudza mune ramangwana uye nzira nyowani dzekurapa kurwadziwa kwepafudzi. Tichaongorora zvinoitwa ne (1) zvinokamurwa zvinogamuchirwa, (2) periipheral pain processing kana nociception , (3) musana wesipinha, (4) uropi, (5) nzvimbo yemagamuchira mumapfudzi uye (6) ) iyo neural anatomy yepafudzi. Isu tinotarisawo kuti izvi zvinhu zvinogona sei kubatsira mukusiyana kweiyo kiriniki mharidzo, kuongororwa uye kurapwa kwemarwadzo epafudzi. Nenzira iyi isu tinovavarira kupa muongororwo wezvikamu zvehurongwa hwekuona kurwadziwa kwekurwadziwa uye epakati pekugadzirisa maratidziro ekurwadziwa kwepafudzi ayo anofambidzana kuburitsa kiriniki kurwadziwa.

NHANGAMIRIRO: CHINHU CHINOKOSHA CHINHU CHENYAYA YESAYENYU INOKOSHA KUTI VANHU VAKADHA

Hunhu hwekurwadziwa, kazhinji, hwave chinhu chekupokana kukuru pamusoro pezana ramakore rapfuura. Muzana ramakore rechi 17 Descartes theory1 yakaratidza kuti kukura kwemarwadzo kwaive kwakanangana zvakaringana nehuwandu hwehukama hwakabatana hwemanyama uye kuti marwadzo akagadziriswa mune imwe nzira yakasarudzika. Dzidziso zhinji dzekare dzaivimba neiyi inonzi ualdualist Descartian uzivi, ichiona kurwadziwa semhedzisiro yekusimudzirwa kweaspecific peripheral pain receptor muuropi. Muzana ramakore rechimakumi maviri kurwa kwesainzi pakati pedzidziso mbiri dzinopokana kwakazotevera, kureva hushe hwedzidziso uye dzidziso yemhando. Iyo Descartian specificity theory yakaona kurwadziwa senge yakasarudzika nzira yekunzwa yekuisa neyemidziyo yayo, nepo "dzidziso yepashure" yakanzwa kuti kurwadziwa kwakakonzerwa nekusimudzirwa kwakanyanya kweasina-chaiwo ma receptors.20 Muna 2, Wall neMelzack s 1965 gedhi dzidziso yekurwadziwa yakapa humbowo hwemuenzaniso umo marwadzo ekuona akarongedzwa neese mhinduro yekunzwa uye yepakati tsinga system. Kumwe kufambira mberi kukuru mukutenda kwekutambudzika panguva imwechete yakaona kuwanikwa kweiyo chaiyo nzira yezviito zveopioid.3 Shure kwaizvozvo, kufambira mberi kwazvino mukuita neuroimaging uye mishonga yemamorekuru zvakawedzera zvakanyanya kunzwisisa kwedu kwese kwekutambudzika.

Saka izvi zvinoenderana sei nekurwadziwa kwepafudzi?Kurwadziwa kwepamuviri kunowanzova chinetso chechipatara, uye kunzwisisa kwakasimba kwenzira iyo marwadzo anogadziriswa nemuviri kwakakosha kuti unyatso kuongorora uye kurapa kurwadziwa kwemurwere. Kufambira mberi muruzivo rwedu rwekugadzirisa kurwadziwa kuvimbisa kutsanangura kusanzwisisika pakati pehurwere uye maonero ekurwadziwa, zvinogona zvakare kutibatsira kutsanangura kuti nei vamwe varwere vachitadza kupindura kune kumwe kurapa.

KUSANGWA KUNHU KWEVANHU

Peripheral sensory receptors: iyo mechanoreceptor uye iyo nociceptor

Kune akawanda marudzi eeperiipheral sensory receptors aripo mune yemunhu musculoskeletal system. 5 Vanogona kuve vakapatsanurwa zvichibva pakufara kwavo (sema mechanoreceptors, thermoreceptors kana nociceptors) kana morphology (yemahara mhedzisiro mhedzisiro kana mhando dzakasiyana dzeakavharirwa ma receptors). kuvapo kwevamwe makemikari mamaki. Iko kune akakosha kupindirana pakati pezvakasiyana zvinoshanda makirasi eanogamuchira, semuenzaniso

Peripheral Pain Kugadziriswa: ocNociception

Kukuvara kwetishu kunosanganisira akasiyana mamiririri ekuputira ari kuburitswa nemaseru akakuvara anosanganisira bradykinin, histamine, 5-hydroxytryptamine, ATP, nitric oxide uye mamwe maion (K + uye H +). Iko kushandiswa kwe arachidonic acid nzira inotungamira mukugadzirwa kwe prostaglandins, thromboxanes uye leuko- trienes. Cytokines, kusanganisira iyo interleukins uye tumor necrosis factor?, Uye maurotrophins, senge nerve yekukura chinhu (NGF), anoburitswa uye anobatanidzwa zvakanyanya mukufambisa kwekuzvimba.15 Zvimwe zvinhu zvakaita seanosimudzira amino acids (glutamate) uye opioid ( endothelin-1) zvakave zvichisanganiswazve nemhedzisiro yekuzvimba.16 17 Vamwe veavo vamiririri vanogona kumisikidza nociceptors zvakananga, nepo vamwe vachiunza kuunganidzwa kwemamwe maseru ayo anozoburitsa mamwe maanoshanda. 18 Iyi maitiro emuno zvichikonzera kuwedzera kwekuteerera ye nociceptive neurons kune yavo yakajairwa yekuisa uye / kana kuunganidzwa kwemhinduro kune zvakajairika subthreshold zvinowedzerwa zvinonzi "peripheral senitization ". Mufananidzo 1 inopfupisa dzimwe nzira dzakakosha dzinobatanidzwa.

NGF uye yekupedzisira receptor inogona cation chiteshi subfamily V nhengo 1 (TRPV1) receptor ine hukama hwekufananidza kana zvasvika pakukuvadza uye nociceptor senitization. Iwo ma cytokines anogadzirwa mumoto unopisa unoguma nekuwedzera mukugadzirwa kweNNG.19 NGF inokurudzira kuburitswa kwe histamine uye serotonin (5-HT3) nemaseru maseru, uye zvakare inosimudzira ma nociceptors, pamwe achichinja zvivakwa zveA? tambo dzakadai sekuti chikamu chikuru chichava nociceptive. Iyo TRPV1 yekugamuchira irimo mune kuwanda kweanonyanya kufefitera tambo uye inoitwa ne capsaicin, kupisa uye proton. Iyo TRPV1 receptor inogadzirwa mukati memutumbi wesero weiyo inosanganisa fiber, uye inoendeswa kune ese ari maviri epiri uye epakati ma terminals, uko kunopa kunzwisisika kweanociceptive afferents. Kuzvimba kunoguma mukugadzira NGF pariperi iyo inozosunga kune tyrosine kinase receptor type 1 receptor pane nociceptor terminals, NGF inozotakurirwa kumuviri wesero uko inotungamira kune kumusoro mutemo weTrPV1 kudhindisa uye nekudaro kuwedzera nociceptor senzwi. 19 20 NGF uye vamwe vamiririri vanoputira vanokurudzira TRPV1 kuburikidza nemhando dzakasiyana dzechipiri nzira dzevatumwa. Mazhinji mamwe maresitoreti anosanganisira cholinergic receptors,? -Aminobutyric acid (GABA) receptors uye somatostatin receptors inofungidzirwa kuve inobatanidzwa mune yekunze nociceptor senitivity.

Huwandu hukuru hwevamiririri vekuputira hwakanyatso kuverengerwa mukurwadziwa kwepafudzi uye rotator cuff chirwere. Idzi shanduko dzinogona kuve kwekutanga- kushandurwa kana kunonoka kunyorwa kunoenderana. Mienzaniso yeiyo yekutanga shanduko muiyo TRPV21 receptor kana mumagetsi- gated ion chiteshi chinokonzerwa nephosphorylation ye membrane-yakasungwa mapuroteni. Mienzaniso yeiyo yekupedzisira inosanganisira iyo NGF-inokwidziridzwa kuwedzera muTRV25 chiteshi kugadzirwa uye calcium-inokonzeresa activation yeiyo intracellular zvinyorwa zvinyorwa.

Nzira dzeMakemikari YaNociception

Kunzwa kwekutambudzika kunotinyevera kukuvara chaiko kana kuri kuuya uye kunokonzeresa mhinduro dzakakodzera dzekudzivirira. Nehurombo, kurwadziwa kazhinji kunopfuura kushanda kwayo seyambiro system uye pachinzvimbo kunogara kusingaperi uye kuchikanganisa. Iyi shanduko kuenda kuchikamu chisingaperi inosanganisira shanduko mukati memutsipa wepelinha uye huropi, asi kune zvekare kushamisa modulation uko mameseji ekurwadziwa anotangwa - padanho repuraisheni yekunzwa neuron. Kuedza kuona kuti mauroni aya anoona sei marwadzo-anoburitsa chinhu chinopisa, chinogadzirwa kana chemakemikari chakaratidza nzira nyowani dzekuratidzira uye dzakatisvitsa padhuze nekunzwisisa zviitiko zvema molecular zvinofambisa shanduko kubva kuacute kusvika pakurwadziwa kusingaperi.

The Neurochemistry Of Nociceptors

Glutamate ndiyo inonzi neurotransmitter inokurudzira kune dzose ma nociceptors. Histochemical studies of adult DRG, zvisinei, inoratidza mbiri dzakawanda dzisingazivikanwe C fiber.

Makemikari Transducers Kuti Aite Marwadzo Akaipisisa

Sezvinorondedzerwa pamusoro apa, kukuvadza kunowedzera marwadzo edu kuburikidza nekuwedzera kunzwisiswa kweavoiceice kune zvose zvinopisa uye zvinogadziriswa. Izvi zvinowanzoitika, mune chimwe chikamu, kubva pakugadzirwa uye kusunungurwa kwemakemikari emakemikari kubva pachirwere chekutanga chinotyisa uye kubva kune zvisiri-neural cells (somuenzaniso, fibroblasts, mast cells, neutrophils uye platelets) mumamiriro ezvinhu36 (Fig. 3). Zvimwe zvikamu zvehutu hunoputika (somuenzaniso, proton, ATP, serotonin kana lipids) zvinogona kuchinja neuronal kusununguka zvakananga nekubatana neyoni mitsara pane nociceptor surface, asi vamwe (semuenzaniso, bradykinin neNNG) vanosunga kumagadzirirwo emasabotropic uye kuratidzira migumisiro yavo kuburikidza nechipiri-mumiririri kuisa cascades11. Kufambira mberi kwakanyanya kwave kuchiitwa pakunzwisisa maitiro ezvinyorwa zvekugadzirisa zvinhu.

Extracellular Proton & Tissue Acidosis

Nharaunda yemasisitosis acidosis inoratidzirwa mupfungwa yekugadzirisa mukukuvara, uye chirwere chekurwadziwa kwakasangana kana kusagadzikana kwakanyatsobatanidzwa nehukuru hweacidification37. Kushandiswa kwesidhi (pH 5) kune ganda kunounza kusununguka kwakachengetwa mune chechitatu kana kupfuura zvema polymodal nociceptors izvo zvisina kukodzera munda unogamuchira 20.

Cellular & Molecular Maitiro Ekurwadziwa

ngovepo

Nenzira yehutano inoona uye inotsanangura zvakasiyana-siyana zvekushisa uye kushandiswa kwemajini pamwe chete nekuchengetedzwa kwemhepo uye kusagadzikana kwemakemikari anotsamwisa. Kana zvakanyanya, izvi zvinokonzera kurwadziwa kwakanyanya, uye mumamiriro ezvinhu ekukuvadza kunoramba kuripo, zvose zviri mumativi uye nheyo dzenhepfenyuro yezvirongwa zvehutano hwekutambudza mugwagwa unoratidzira kuputika kwepurasitiki, kuwedzera zvirwere zvinorwadza nekubudisa hutachiona. Apo plastiki inobatsira mafungiro ekuchengetedza, zvinogona kubatsira, asi kana kuchinja kuchiripo, chirwere chisingaperi chinogona kuguma. Genetic, electrophysiological, uye zvidzidzo zvemaprojekiti zviri kujekesa nzira dzema molecule dzinoita kuti kuve nokuona, kukodha, uye kugadzirisa zvinotyisa zvinokonzera marwadzo.

Nhanganyaya: Zvakanaka Kupesana Nokuramba Uchirwadziwa

Mufananidzo 5. Mutsara wechipfuva (Central) Sensitization

1. Glutamate / NMDA zvakagamuchirwa pamwe chete.OllowKutevera kukurudzira kwakanyanya kana kukuvara kusingaperi, yakaitwa C uye A? nociceptors anoburitsa akasiyana maurotransmitter anosanganisira dlutamate, chinhu P, calcitonin-geni inoenderana peptide (CGRP), uye ATP, kune inoburitsa mauroni mumamina I erunyoro rwekuseri runyanga (tsvuku). Semhedzisiro, inowanzo nyarara NMDA glutamate receptors iri mune postsynaptic neuron ikozvino inogona kuratidza, kuwedzera intracellular calcium, uye kumutsa yakawanda calcium inoenderana nzira yekuratidzira nzira uye yechipiri vatumwa vanosanganisira mitogen-activated protein kinase (MAPK), protein kinase C (PKC) , protein kinase A (PKA) uye Src. Uku kupaza kwezviitiko kuchawedzera kunakidzwa kweiyo inoburitsa neuron uye kufambisa kufambiswa kwemashoko ekurwadziwa kuuropi.
2. Disinhibition.NderPasi pemamiriro ezvinhu akajairika, inhibitory interneurons (bhuruu) inoramba ichiburitsa GABA uye / kana glycine (Gly) kudzikisira kusarudzika kwemamina I kuburitsa mauroni uye kugadzirisa kurwadziwa kwekutapudza (inhibitory toni). Zvisinei, mumamiriro ekukuvara, izvi zvinodzivisa zvinogona kurasikirwa, zvichikonzera hyperalgesia. Pamusoro pezvo, disinhibition inogona kugonesa isiri-nociceptive myelinated A? primary afferents yekuita marwadzo ekuparadzira mafirita akadai ayo anowanzo kuve asina hunhu zvinoonekwa sekurwadza. Izvi zvinoitika, muchidimbu, kuburikidza neiyo disinhibition yeinofadza PKC? kuratidza ma interneuron mukati memamina lamina II.
3. Microglial activation.ErPeripheral nerve kukuvara kunosimudzira kuburitswa kweATP uye chemokine fractalkine iyo inosimudzira ma microglial maseru. Kunyanya, kumisikidzwa kwepurinergic, CX3CR1, uye maToll-kunge receptors pane microglia (yepepuru) zvinoguma nekuburitswa kweuropi-yakatorwa neurotrophic factor (BDNF), iyo kubudikidza nekumisikidza kweTrkB receptors inoratidzwa ne lamina I kuburitsa mauroni, inosimudzira kuwedzera kusununguka kuwedzerwa kurwadziwa mukupindura kune zvese zvinotyisa uye zvisina mhosva kukurudzira (ndokuti, hyperalgesia uye allodynia). Yakagadziriswa microglia zvakare inoburitsa yakawanda cytokines, senge bundu necrosis chinhu? (TNF?), Interleukin-1? uye 6 (IL-1?, IL-6), uye zvimwe zvinhu zvinopa kukurudzira kwepakati.

Chimiro Chimiro Chekuvhiringidza

Peripheral sensitization zvinowanzoitika kubva mukuzvimba-kwakabatana shanduko mune kemikari nharaunda yeiyo nerve fiber (McMahon et al., 2008). Nekudaro, kukuvara kwemasuru kunowanzo kuperekedzwa pamwe nekuunganidzwa kwezvinhu zvisingagumi zvinoburitswa kubva kune akaomeswa nociceptors kana asiri-neural maseru anogara mukati kana kupinda mukati menzvimbo yakakuvara (kusanganisira mast mast, basophils, maplatelet, macrophages, neutrophils, endothelial maseru, keratinocytes, uye Fibroblasts). Pamwe chete. izvi zvinhu, zvinodaidzwa kuti infigueatory soup , inomiririra huwandu hwakawanda hwekusainisa mamorekuru, anosanganisira maurotransmitter, peptides (chinhu P, CGRP, bradykinin), eicosinoids uye zvine hukama lipids (prostaglandins, thromboxanes, leukotrienes, endocannabinoids), maurotrophins, cytokines , uye chemokines, pamwe nema extracellular proteases nemaproton. Zvinoshamisa kuti, ma nociceptors anoratidza imwe kana anopfuura maseru epasiromendi anokwanisa kucherechedza nekupindura kune yega yeaya pro-anogumbura kana pro-algesic vamiririri (Mufananidzo 4). Kudyidzana kwakadaro kunowedzera kunakidzwa kweiyo fiber fiber, nokudaro ichisimudzira kunzwisisika kwayo kune tembiricha kana kubata.

Hapana mubvunzo kuti nzira inowanzoita yekuderedza kunetseka kunokonzera kunosanganisira kudzivisa kubatanidza kana kuunganidza zvikamu zvehutu hunopisa. Izvi zvakanakisisa zvinoratidzwa ne-non-steroidal anti-inflammatory drugs, zvakadai sa aspirin kana ibuprofen, izvo zvinoderedza marwadzo ekuputira uye hyperalgesia nekudzivisa cyclooxygenase (Cox-1 uye Cox-2) inobatanidzwa mu prostaglandin synthesis. Nzira yechipiri ndeyokudzivisa zviito zvezvokuvhiringidza vashandi ku-nociceptor. Pano, tinosimbisa mienzaniso inopa hutsva hutsva mumagadzirirwo emagetsi ekunze kwekushungurudzika, kana kuti iyo inoumba hwaro hwemishonga matsva ekurapa kurwadza nekuputika.

NGF ingangodaro inonyatsozivikanwa nokuda kwebasa rayo seurourotrophic chinotarisirwa kuponesa uye kukura kwezvinonzi sensory neurons panguva yembryogenesis, asi kune munhu mukuru, NGF inogadzirwawo mumamiriro ezvinhu ekukuvara kwepanyama uye inoumba chikamu chinokosha chekuvhiringidza muto (Ritner et al., 2009). Pakati pezvinangwa zvaro zvemasero, NGF inonyatsoshanda pa peptidergic C fiber nociceptors, iyo inoratidzira ukama hwakasimba hweNFF receptor tyrosine kinase, TrkA, uyewo hukama hwakaderera neurotrophin receptor, p75 (Chao, 2003; Snider naMcMahon, 1998). NGF inobereka hukuru hwehutachiona hwekupisa nekupisa uye kushandiswa kwemagetsi kuburikidza nemaitiro maviri akasiyana kwenguva. Pakutanga, kutaurirana kwe NGF-TrkA kunobatsira nzira dzekuyerera pasi, kusanganisira phospholipase C (PLC), mitogen-activated protein kinase (MAPK), uye phosphoinositide 3-kinase (PI3K). Izvi zvinokonzera kushanda kwemaitiro ezvirongwa zvepuroteni pane imwe nzvimbo ye nociceptor terminal, kunyanya TRPV1, zvichiita kuti kuve nekukurumidza kushanduka mumasero uye maitiro ekupisa kwehuni (Chuang et al., 2001).

Zvisinei nemaitiro avo epro-nociceptive, kupindira neurotrophin kana chiratidzo checytokine rave zano rakakura rekudzora chirwere chinoputika kana kurwadziwa kunokonzerwa. Maitiro makuru anosanganisira kuvhara NGF kana TNF-? chiito nechirwere chinopesana. Munyaya yeTNF-?, Izvi zvave zvichinyatso shanda mukurapa kweakawanda autoimmune hosha, kusanganisira rheumatoid arthritis, zvichikonzera kudzikira kukuru mukuparadza kwese kwenyama uye kuperekedza hyperalgesia (Atzeni et al., 2005). Nekuti zviito zvikuru zveNNGF pane mukuru nociceptor zvinoitika mukugadzika kwekuzvimba, mukana weiyi nzira ndeyekuti hyperalgesia inoderera isina kukanganisa kunzwisisika kurwadziwa kwepfungwa. Zvechokwadi, zvirwere zvinopesana neNNG zvinowanikwa mumakiriniki ekuedza kurapwa kwezvirwere zvinokonzera kurwadziwa (Hefti et al., 2006).

Glutamate / NMDA Receptor-Mediated Sensitization

Kunetseka kwakanyanya kunoratidzwa nekubudiswa kwema glutamate kubva kumativi ekupedzisira emascicptptors, zvichiita kuti pave nemasikirati emashure-synaptic currents (EPSCs) muchipiri chegorosi rehondo neuron. Izvi zvinowanzoitika kuburikidza nekushanda kwe postsynaptic AMPA uye kainate subtypes ye ionotropic glutamate receptors. Kupfupisa kwechikamu chechikamu cheEPSCs mumashure endsynaptic chizoguma chichiita chiito chinogona kupisa uye kutumirwa kwehurombo hwemashoko kusvika kune yepamusoro neurons.

Zvimwe zvidzidzo zvinoratidza kuti kuchinja kwekuratidzwa neuron, iyo pachayo, kunobatsira pakuita zvinodzivisa. Semuenzaniso, kuputika kweropa kunenge kuchidzika-kunogadzirisa K + - Cl-co-transporter KCC2, iyo inokosha kuti uchengetedze kazhinji K + uye Cl-gradients pamativi ose eplasma (Coull et al., 2003). Kunyoresa KCC2, iyo inoratidzirwa mumarina I kujekesa neurons, inoguma pakuchinja kweC Cl-gradient, zvakadai kuti kushandiswa kweGABA-A receptors kuderedza, panzvimbo yekusimudzira marina I projection neurons. Izvi zvingaitawo kuti zviwedzere kufadza uye kuwedzerwa kurwadziwa kwekutambudzika. Zvechokwadi, kudzivirirwa kwemapurisa kana siRNA-mediated downregulation yeKCC2 muhutano inotes mechanical allodynia.

Sources:

Nei mafudzi angu achikuvadza? Kuongororwa kwehutano hwehutano nehupenyu hwehutambudzi hwemapfudzi

Benjamin John Floyd Dean, Stephen Edward Gwilym, Andrew Jonathan Carr

Nzira uye Maitiro Maitiro Okurwadziwa

Allan I. Basbaum1, Diana M. Bautista2, Gre? Gory Scherrer1, naDavid Julius3

1Department of Anatomy, University of California, San Francisco 94158

2Department of Molecular and Cell Biology, University of California, Berkeley CA 94720 3Department of Physiology, University of California, San Francisco 94158

Nzira dzemu Molecule dzomusanaciception

David Julius * & Allan I. Basbaum

*Dhipatimendi reCellular uye Molecular Pharmacology, uye �Dhipatimendi reAnatomy nePhysiology uye WM Keck Foundation Center yeIntegrative Neuroscience, University of California San Francisco, San Francisco, California 94143, USA (e-mail: julius@socrates.ucsf.edu)