Ağrıda Merkezi ve Periferik Sinir Sistemi Biyokimyası
Özet
Bu bölüm, ağrının periferik nosiseptörlerden serebral kortekse kadar uzanan çok katmanlı nörobiyokimyasal mekanizmalarını güncel bilimsel veriler ışığında kapsamlı olarak ele almaktadır. Ağrının nörobiyolojik temelleri, nosisepsiyon basamakları, periferik ve merkezi sinir sisteminde görev alan nöronal ve glial hücreler ile bunların moleküler etkileşimleri ayrıntılı biçimde açıklanmaktadır. Ayrıca iyon kanalları, nörotransmitterler, nöropeptidler, sitokinler, kemokinler ve nörotrofik faktörlerin ağrı iletimindeki rolleri; periferik ve santral sensitizasyon süreçleri, sinaptik plastisite, nöroinflamasyon ve nöroimmün düzenleme mekanizmaları çerçevesinde değerlendirilmektedir. Endojen analjezik sistemler, inen inhibitör yolaklar, ağrının emosyonel ve bilişsel bileşenleri ile placebo ve nocebo etkileri de güncel literatür doğrultusunda tartışılmaktadır. Temel moleküler biyoloji, nörofizyoloji ve klinik ağrı bilimini bütünleştiren bu bölüm; ağrı biyokimyasını mekanistik düzeyde açıklarken, kronik ağrının patofizyolojisi ve hedefe yönelik yeni tedavi yaklaşımlarının anlaşılmasına yönelik kapsamlı bir bilimsel kaynak sunmaktadır.
This chapter provides a comprehensive overview of the biochemical mechanisms underlying pain from peripheral nociceptors to higher cortical processing centers. It integrates current knowledge on the neurobiological basis of pain, nociceptive signaling pathways, and the molecular interactions occurring within both the peripheral and central nervous systems. Particular emphasis is placed on the roles of ion channels, neurotransmitters, neuropeptides, cytokines, chemokines, neurotrophic factors, and glial cells in the initiation, amplification, modulation, and persistence of pain. The chapter further discusses peripheral and central sensitization, synaptic plasticity, neuroinflammation, and neuroimmune communication as key mechanisms contributing to chronic pain development. In addition, endogenous analgesic pathways, descending inhibitory systems, and the emotional and cognitive dimensions of pain, including placebo and nocebo responses, are reviewed in the context of recent advances in neuroscience. By integrating molecular biology, neurophysiology, and clinical pain research, this chapter offers an updated and comprehensive perspective on pain biochemistry and highlights emerging molecular targets for future therapeutic strategies in chronic pain management.
Referanslar
Raja SN, Carr DB, Cohen M, et al. The revised International Association for the Study of Pain definition of pain: concepts, challenges, and compromises. Pain. 2020;161(9):1976–1982.
Basbaum AI, Bautista DM, Scherrer G, Julius D. Cellular and molecular mechanisms of pain. Cell. 2009;139(2):267–284.
Woolf CJ, Ma Q. Nociceptors—Noxious stimulus detectors. Neuron. 2007;55(3):353–364.
Tracey I, Mantyh PW. The cerebral signature for pain perception and its modulation. Neuron. 2007;55(3):377–391.
Julius D, Basbaum AI. Molecular mechanisms of nociception. Nature. 2001;413:203–210.
Ossipov MH, Dussor GO, Porreca F. Central modulation of pain. J Clin Invest. 2010;120(11):3779–3787.
Patapoutian A, Tate S, Woolf CJ. Transient receptor potential channels: targeting pain at the source. Nat Rev Drug Discov. 2009;8(1):55–68.
Colloca L, Ludman T, Bouhassira D, et al. Neuropathic pain. Nat Rev Dis Primers. 2017;3:17002.
Dubin AE, Patapoutian A. Nociceptors: the sensors of the pain pathway. J Clin Invest. 2010;120(11):3760–3772.
Usoskin D, Furlan A, Islam S, et al. Unbiased classification of sensory neuron types by large-scale single-cell RNA sequencing. Nat Neurosci. 2015;18(1):145–153.
Sharma N, Flaherty K, Lezgiyeva K, et al The emergence of transcriptional identity in somatosensory neurons. Nature. 2020 Jan;577(7790):392-398. doi: 10.1038/s41586-019-1900-1.
Kandel ER, Koester JD, Mack SH, Siegelbaum SA. Principles of Neural Science. 6th ed. McGraw-Hill; 2021.
Ji RR, Chamessian A, Zhang YQ. Pain regulation by non-neuronal cells and inflammation. Nat Rev Immunol. 2016;16(12):787–802.
Renthal W, Tochitsky I, Yang L, et al. Transcriptional Reprogramming of Distinct Peripheral Sensory Neuron Subtypes after Axonal Injury. Neuron. 2020;108(1):128-144.e9.
Gold MS, Gebhart GF. Nociceptor sensitization in pain pathogenesis. Nat Med. 2010;16(11):1248–1257.
Hucho T, Levine JD. Signaling pathways in sensitization: toward a nociceptor cell biology. Neuron. 2007;55(3):365–376.
Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature. 1997;389:816–24.
Chinreddy SR, Mashozhera NT, Rashrash B, et al. Unraveling TRPV1's Role in Cancer: Expression, Modulation, and Therapeutic Opportunities with Capsaicin. Molecules. 2024;29(19):4729.
Cao E, Liao M, Cheng Y, Julius D. TRPV1 structures in distinct conformations reveal activation mechanisms. Nature. 2013;504:113–18.
Szallasi A, Sheta M. Targeting TRPV1 for pain relief: limits, losers and laurels. Expert Opin Investig Drugs. 2012;21:1351–1369.
Bautista DM, Jordt SE, Nikai T, et al. TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell. 2006;124(6):1269–82.
Macpherson LJ, Dubin AE, Evans MJ, Marr F, Schultz PG, Cravatt BF, et al. Noxious compounds activate TRPA1 ion channels through covalent modification of cysteines. Nature. 2007;445(7127):541–5.
Trevisani M, Siemens J, Materazzi S, et al. 4-hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of TRPA1. Proc Natl Acad Sci U S A. 2007;104(33):13519–24.
Andersson DA, Gentry C, Moss S, Bevan S. Transient receptor potential A1 is a sensory receptor for multiple products of oxidative stress. J Neurosci. 2008;28(10):2485–94.
Bessac BF, Jordt SE. Sensory detection and responses to toxic gases: mechanisms, health effects, and countermeasures. Proc Am Thorac Soc. 2010;7(3):269–77.
Bandell M, Macpherson LJ, Patapoutian A. From chills to chilis: mechanisms for thermosensation and chemesthesis through TRP channels. Neuron. 2007;55(3):371–83.
McKemy DD, Neuhausser WM, Julius D. Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature. 2002;416(6876):52–8.
Peier AM, Moqrich A, Hergarden AC, Reeve AJ, Andersson DA, Story GM, et al. A TRP channel that senses cold stimuli and menthol. Cell. 2002;108(5):705–15.
Ongun S, Sarkisian A, McKemy DD. Selective cold pain inhibition by targeted block of TRPM8-expressing neurons with quaternary lidocaine derivative QX-314. Commun Biol. 2018(5)31;1:53.
Rohacs T, Lopes CM, Michailidis I, Logothetis DE. PI(4,5)P2 regulates TRPM8 channels through multiple binding sites. J Neurosci. 2005;25(37):8289–97.
Knowlton WM, Bifolck-Fisher A, Bautista DM, McKemy DD. TRPM8, but not TRPA1, is required for cold sensation in mice. Nat Neurosci. 2010;13(9):1125–31.
Dhaka A, Viswanath V, Patapoutian A. TRP ion channels and temperature sensation. Annu Rev Neurosci. 2006;29:135–61.
Liu B, Fan L, Balakrishna S, Sui A, Morris JB, Jordt SE. TRPM8 is the principal mediator of menthol-induced analgesia of acute and inflammatory pain. Pain. 2013;154(10):2169-2177.
Catterall WA. Voltage-gated sodium channels at 60: structure, function and pathophysiology. J Physiol. 2012;590(11):2577–89.
Cox JJ, Reimann F, Nicholas AK, Thornton G, Roberts E, Springell K, et al. An SCN9A channelopathy causes congenital inability to experience pain. Nature. 2006;444(7121):894–8.
Dib-Hajj SD, Yang Y, Black JA, Waxman SG. The Na(V)1.7 sodium channel: from molecule to man. Nat Rev Neurosci. 2013;14(1):49–62.
Akopian AN, Sivilotti L, Wood JN. A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature. 1996;379(6562):257–62.
Priest BT. Future potential and status of voltage-gated sodium channel blockers for the treatment of pain. Curr Opin Drug Discov Devel. 2009;12(5):682–91.
Maingret F, Coste B, Padilla F, et al. Inflammatory mediators increase Nav1.9 current and excitability in nociceptors through a coincident detection mechanism. J Gen Physiol. 2008;131(3):211-225.
Leo S, D'Hooge R, Meert T. Exploring the role of nociceptor-specific sodium channels in pain transmission using Nav1.8 and Nav1.9 knockout mice. Behav Brain Res. 2010;208(1):149-157.
Bennett DL, Woods CG. Painful and painless channelopathies. Lancet Neurol. 2014;13(6):582–94.
Wemmie JA, Price MP, Welsh MJ. Acid-sensing ion channels: advances, questions and therapeutic opportunities. Trends Neurosci. 2006;29(10):578–86.
Waldmann R, Champigny G, Lingueglia E, De Weille JR, Heurteaux C, Lazdunski M. H(+)-gated cation channels. Ann N Y Acad Sci. 1999;868:67-76.
Mamet J, Baron A, Lazdunski M, Voilley N. Proinflammatory mediators, stimulators of sensory neuron excitability via the expression of acid-sensing ion channels. J Neurosci. 2002;22(24):10662-10670.
Sluka KA, Gregory NS. The dichotomized role for acid sensing ion channels in musculoskeletal pain and inflammation. Neuropharmacology. 2015 Jul;94:58-63.
Deval E, Noël J, Gasull X, Delaunay A, Alloui A, Friend V, et al. Acid-sensing ion channels in postoperative and inflammatory pain. Pain. 2011;152(9):1998–2007.
Xiong ZG, Zhu XM, Chu XP, Minami M, Hey J, Wei WL, et al. Neuroprotection in ischemia: blocking calcium-permeable acid-sensing ion channels. Proc Natl Acad Sci U S A. 2004;101(12):429–34.
Kellenberger S, Schild L. International Union of Basic and Clinical Pharmacology. Acid-sensing ion channel family nomenclature and pharmacology. Pharmacol Rev. 2015;67(1):1–32.
Saotome K, Murthy SE, Kefauver JM, et al. Structure of the mechanically activated ion channel Piezo1. Nature. 2018;554(7693):481-486.
Lin YC, Guo YR, Miyagi A, Levring J, MacKinnon R, Scheuring S. Force-induced conformational changes in PIEZO1. Nature. 2019;573(7773):230-234.
Wu J, Lewis AH, Grandl J. Touch, tension, and transduction—the function and regulation of Piezo ion channels. Trends Biochem Sci. 2017;42:57-71.
Xiao B. Mechanisms of mechanotransduction and physiological roles of PIEZO channels. Nat Rev Mol Cell Biol. 2024;25(11):886-903.
Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science. 2000;288(5472):1765–9.
Ji RR, Samad TA, Jin SX, Schmoll R, Woolf CJ. PKA and PKC phosphorylation of TRPV1 in pain sensitization. Neuron. 2002;36(1):57–68.
Tominaga M, Caterina MJ. Thermosensation and pain. J Neurobiol. 2004;61(1):3–12.
Dib-Hajj SD, Cummins TR, Black JA, Waxman SG. Sodium channels in normal and pathological pain. Annu Rev Neurosci. 2010;33:325–47.
Scholz J, Woolf CJ. The neuropathic pain triad: neurons, immune cells and glia. Nat Neurosci. 2007;10(11):1361–8.
Costigan M, Scholz J, Woolf CJ. Neuropathic pain: a maladaptive response of the nervous system to damage. Annu Rev Neurosci. 2009;32:1–32.
Harrison S, Geppetti P. Substance P. Int J Biochem Cell Biol. 2001;33(6):555–76.
Chang CT, Jiang BY, Chen CC. Ion Channels Involved in Substance P-Mediated Nociception and Antinociception. Int J Mol Sci. 2019 Mar 30;20(7):1596.
Russell FA, King R, Smillie SJ, Kodji X, Brain SD. Calcitonin gene-related peptide: physiology and pathophysiology. Physiol Rev. 2014;94(4):1099–142.
Edvinsson L. CGRP and migraine: from bench to bedside. Rev Neurol (Paris). 2015;171(8–9):647–53.
Caviedes-Bucheli J, Ulate E, Munoz HR, Ríos-Osorio N. The Role of Neuropeptide Y in Dental Pulp: Balancing Neurogenic Inflammation and Pain Modulation. Int Endod J. 2026;(6)5. ahead of print.
Mantyh PW. Neurobiology of substance P and the NK1 receptor. J Clin Psychiatry. 2002;63 Suppl 11:6–10.
Goadsby PJ, Holland PR, Martins-Oliveira M, Hoffmann J, Schankin C, Akerman S. Pathophysiology of migraine: a disorder of sensory processing. Physiol Rev. 2017;97(2):553–622.
Latremoliere A, Woolf CJ. Central sensitization: a generator of pain hypersensitivity. J Pain. 2009;10(9):895–926.
Gao YJ, Ji RR. Chemokines, neuronal-glial interactions, and central processing of neuropathic pain. Pharmacol Ther. 2010;126(1):56-68.
Coull JA, Beggs S, Boudreau D, et al. BDNF from microglia causes the shift in neuronal chloride gradients underlying neuropathic pain. Nature. 2005;438(7070):1017–21.
Apkarian AV, Baliki MN, Geha PY. Towards a theory of chronic pain. Prog Neurobiol. 2009;87(2):81–97.
Descalzi G, Ikegami D, Ushijima T, Nestler EJ, Zachariou V, Narita M. Epigenetic mechanisms of chronic pain. Trends Neurosci. 2015;38(4):237–46.
Li Y, Wu P, Wen Q. Effect of mitochondrial dysfunction on neuropathic pain. Biomed Pharmacother. 2025;193:118760.
Todd AJ. Neuronal circuitry for pain processing in the dorsal horn. Nat Rev Neurosci. 2010;11(12):823–36.
Willis WD, Westlund KN. Neuroanatomy of the pain system and of the pathways that modulate pain. J Clin Neurophysiol. 1997;14(1):2–31.
Zeilhofer HU, Wildner H, Yévenes GE. Fast synaptic inhibition in spinal sensory processing and pain control. Physiol Rev. 2012;92(1):193–235.
He L, Ma S, Ding Z, et al. Inhibition of NFAT5-dependent astrocyte swelling alleviates neuropathic pain. Adv Sci (Weinh). 2024;11:e2302916.
Bushnell MC, Ceko M, Low LA. Cognitive and emotional control of pain and its disruption in chronic pain. Nat Rev Neurosci. 2013;14(7):502–11.
Peyron R, Laurent B, Garcia-Larrea L. Functional imaging of brain responses to pain. Pain. 2000;79(2–3):157–76.
Rainville P. Brain mechanisms of pain affect and pain modulation. Curr Opin Neurobiol. 2002;12(2):195–204.
Neugebauer V. Amygdala pain mechanisms. Handb Exp Pharmacol. 2015;227:261–84.
Craig AD. How do you feel? Interoception. Nat Rev Neurosci. 2002;3(8):655–66.
Fields HL. State-dependent opioid control of pain. Nat Rev Neurosci. 2004;5(7):565–75.
Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain. 2011;152(3 Suppl):S2–15.
Tsuda M, Inoue K, Salter MW. Neuropathic pain and spinal microglia: a big problem from molecules in "small" glia. Trends Neurosci. 2005;28(2):101–7.
Dib-Hajj SD, Black JA, Waxman SG. NaV channels in pain. Nat Rev Neurosci. 2015;16(6):329–41.
Millan MJ. Descending control of pain. Prog Neurobiol. 2002;66(6):355–474.
Bardin L. The complex role of serotonin and 5-HT receptors in pain. Eur J Pharmacol. 2011;668(1–2):S43–S51.
Pertovaara A. Noradrenergic pain modulation. Prog Neurobiol. 2006;80(2):53–83.
McMahon SB, Malcangio M. Current challenges in glia-pain biology. Neuron. 2009;64(1):46–54.
Kuner R. Central mechanisms of pathological pain. Nat Med. 2010;16(11):1258–1266.
Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain. Lancet Neurol. 2015;14(2):162–173.
Zhuang ZY, Kawasaki Y, Tan PH, et al. Role of the CX3CR1/p38 MAPK pathway in spinal microglia. Brain Behav Immun. 2007;21(5):642-51.
Li J, Wei Y, Zhou J, et al. Activation of locus coeruleus-spinal cord noradrenergic neurons alleviates neuropathic pain in mice via reducing neuroinflammation from astrocytes and microglia in spinal dorsal horn. J Neuroinflammation. 2022;(5) 27;19(1):123.
Halassa MM, Fellin T, Haydon PG. Tripartite synapses: roles for astrocytic purines in the control of synaptic physiology and behavior. Neuropharmacology. 2009 57(4):343-6.
Grace PM, Hutchinson MR, Maier SF, Watkins LR. Pathological pain and the neuroimmune interface. Nat Rev Immunol. 2014;14(4):217–31.
Bai G, Ren K, Dubner R. Epigenetic regulation of persistent pain. Transl Res. 2015;165(2):177–99.
Bai G, Wei D, Zou S, Ren K, Dubner R. Inhibition of histone deacetylases reduces inflammatory and neuropathic pain. Pain. 2010;149(1):90–100.
Sakai A, Suzuki H. Emerging roles of microRNAs in chronic pain. Neurochem Int. 2014;77:58-67.
Apkarian AV, Hashmi JA, Baliki MN. Pain and the brain: specificity and plasticity of the brain in clinical chronic pain. Pain. 2011;152(3 Suppl):S49–64.
Gwak YS, Kang J, Unabia GC, Hulsebosch CE. Spatial and temporal activation of spinal glial cells: role of gliopathy in central neuropathic pain following spinal cord injury in rats. Exp Neurol. 2012;34(2):362-72.
Zhang ZJ, Jiang BC, Gao YJ. Chemokines in neuron-glial cell interaction and pathogenesis of neuropathic pain. Cell Mol Life Sci. 2017 Sep;74(18):3275-3291.
Salvemini D, Doyle TM, Cuzzocrea S. Superoxide, peroxynitrite and oxidative/nitrative stress in inflammation. Biochem Soc Trans. 2006;34(Pt 5):965-970.
Deval E, Lingueglia E. Acid-sensing ion channels and nociception in the peripheral and central nervous systems. Neuropharmacology. 2015;94:49–57.
Inoue K, Tsuda M. Microglia in neuropathic pain: cellular and molecular mechanisms and therapeutic potential. Nat Rev Neurosci. 2018;19(3):138–152.
Apkarian AV, Bushnell MC, Treede RD, Zubieta JK. Human brain mechanisms of pain perception and regulation in health and disease. Eur J Pain. 2005;9(4):463–484.
Colloca L, Miller FG. The nocebo effect and its implications for clinical practice. Psychosom Med. 2011;73(7):598–603.
Zubieta JK, Bueller JA, Jackson LR, et al. Placebo effects mediated by endogenous opioid activity on μ-opioid receptors. J Neurosci. 2005;25(34):7754–7762.
