The Nociceptive System: Molecular, Cellular, and Systemic Mechanisms of Pain Perception



Cite item

Full Text

Abstract

Modern approaches to pain therapy largely rely on the use of non-steroidal anti-inflammatory drugs and opioids, yet remain ineffective for many patients. Furthermore, they lead to tolerance, polypharmacy, and dependence, underscoring the necessity for pathogenetically justified, multi-target treatment approaches. Nociception refers to the physiological process aimed at identifying noxious stimuli via Aδ- and C-fibers and transmitting the pain signal to higher centers. Structural and functional changes in the nociceptive system, associated with processes of peripheral and central sensitization, play a key role in the chronification of pain. TRPV1–4 and TRPA1 ion channels are molecular sensors expressed on nociceptors, which transduce thermal, chemical, and mechanical stimuli into pain signals, playing a central role in the pathogenesis of acute and chronic pain. Tissue damage and the development of a neuroinflammatory cascade lead to the sensitization of TRPV1 and TRPA1 receptors on peripheral nociceptors, lowering their activation threshold and amplifying afferent input. This review examines modern approaches to defining pain and nociception, the neurobiological basis of nociceptive signal transduction and transmission involving TRPV and TRPA receptors, as well as the role of neuroimmune factors in the function of the nociceptive system.

About the authors

D. V. Surov

State Research Institute of Military Medicine; Institute of Experimental Medicine

Email: gniiivm_5@mil.ru

Junior Researcher, State Research and Testing,  Postgraduate Student

Russian Federation, Saint Petersburg

Yuri O. Konshakov

State Research Institute of Military Medicine

Email: gniiivm_5@mil.ru
ORCID iD: 0000-0001-8596-6469
SPIN-code: 2226-5371

Candidate of Medical Sciences, Scientific Research Testing Department

Russian Federation, Санкт-Петербург

Nikolay G. Vengerovih

State Research Institute of Military Medicine, Russian Federation of Ministry of Defense

Author for correspondence.
Email: nikolai.vengerovich@pharminnotech.com
ORCID iD: 0000-0003-3219-341X
http://eco.pharminnotech.com/sotrudniki-kafedry/vengerovic-nikolaj-georgievic

Doctor of Medical Science, Head of the Research Department; Professor at the Industrial Ecology Department

Russian Federation, Санкт-Петербург

References

  1. Mills S.E.E., Nicolson K.P, Smith BH. Chronic pain: a review of its epidemiology and associated factors in population-based studies. British Journal of Anaesthesia. 2019;123(2):e273-e283. doi: 10.1016/j.bja.2019.03.023.
  2. Green J. Epidemiology of Opioid Abuse and Addiction. Journal of Emergency Nursing. 2017;43(2):106-113. doi: 10.1016/j.jen.2016.09.004.
  3. Antropova G.A., Stepanova E.N., Okonenko T.I., Study of analgesic narcotic medicines range at the regional level. Вестник НовГУ. 2023;(4):599-610. doi: 10.34680/2076-8052.2023.4(133).599-610. (In Russ.).
  4. Wallace M.S., et al. A multicenter, double-blind, randomized, placebo-controlled crossover evaluation of a short course of 4030W92 in patients with chronic neuropathic pain. The Journal of Pain. 2002;3(3):227-233. doi: 10.1054/jpai.2002.123650.
  5. Hill R. NK1 (substance P) receptor antagonists – why are they not analgesic in humans? Trends in Pharmacological Sciences. 2000;21(7):244-246. doi: 10.1016/S0165-6147(00)01502-9.
  6. Davis K.D., Aghaeepour N., Ahn A.H., et al. Discovery and validation of biomarkers to aid the development of safe and effective pain therapeutics: challenges and opportunities. Nat Rev Neurol. 2020;16(7):381-400. doi: 10.1038/s41582-020-0362-2.
  7. Klinck M.P., Mogil J.S., Moreau M., et al. Translational pain assessment: could natural animal models be the missing link? Pain. 2017;158(9):1633-1646. doi: 10.1097/j.pain.0000000000000978.
  8. Moseley G.L., Vlaeyen J.W.S. Beyond nociception: the imprecision hypothesis of chronic pain. Pain. 2015;156(1):35-38. doi: 10.1016/j.pain.0000000000000014.
  9. Descalzi G., et al. Epigenetic mechanisms of chronic pain. Trends in Neurosciences. 2015;38(4):237-246. doi: 10.1016/j.tins.2015.02.001.
  10. Deuis J.R., Dvorakova L.S., Vetter I. Methods Used to Evaluate Pain Behaviors in Rodents. Front Mol Neurosci. 2017;10:284. doi: 10.3389/fnmol.2017.00284.
  11. Abramova, A. Y., Pertsov, S. S. Sovremennye predstavleniya o boli. Medicinskaya sestra. 2017;8:20-25. (In Russ.).
  12. Sneddon L.U., Elwood R.W., Adamo S.A., et al. Defining and assessing animal pain. Animal Behaviour. 2014;97:201-212. doi: 10.1016/j.anbehav.2014.09.007.
  13. McKune C.M., Murrell J.C., Nolan A.M. et al. Nociception and Pain. In: Grimm KA, Lamont L.A., Tranquilli W.J., Greene S.A., Robertson S.A., eds. Veterinary Anesthesia and Analgesia. 1st ed. Wiley; 2015:584-623. doi: 10.1002/9781119421375.ch29.
  14. Talbot K., Madden V.J., Jones S.L. et al. The sensory and affective components of pain: are they differentially modifiable dimensions or inseparable aspects of a unitary experience? A systematic review. British Journal of Anaesthesia. 2019;123(2):e263-e272. doi: 10.1016/j.bja.2019.03.033.
  15. Sneddon L.U. Comparative Physiology of Nociception and Pain. Physiology. 2018;33(1):63-73. doi: 10.1152/physiol.00022.2017.
  16. Langford D.J., Crager S.E., Shehzad Z., et al. Social Modulation of Pain as Evidence for Empathy in Mice. Science. 2006;312(5782):1967-1970. doi: 10.1126/science.1128322.
  17. Langford D.J., Bailey A.L., Chanda M.L., et al. Coding of facial expressions of pain in the laboratory mouse. Nat Methods. 2010;7(6):447-449. doi: 10.1038/nmeth.1455.
  18. Zhang X.J., Zhang T.W., Hu S.J., et al. Behavioral assessments of the aversive quality of pain in animals. Neurosci Bull. 2011;27(1):61-67. doi: 10.1007/s12264-011-1035-3.
  19. Hill R.Z., Bautista D.M. Getting in Touch with Mechanical Pain Mechanisms. Trends in Neurosciences. 2020;43(5):311-325. doi: 10.1016/j.tins.2020.03.004.
  20. Carstens E., Moberg G.P. Recognizing Pain and Distress in Laboratory Animals. ILAR Journal. 2000;41(2):62-71. doi: 10.1093/ilar.41.2.62.
  21. Larson C.M., Wilcox G.L., Fairbanks C.A. The Study of Pain in Rats and Mice. comp med. 2019;69(6):555-570. doi: 10.30802/AALAS-CM-19-000062.
  22. Tracey W.D. Nociception. Current Biology. 2017;27(4):R129-R133. doi: 10.1016/j.cub.2017.01.037.
  23. Smith EStJ, Lewin GR. Nociceptors: a phylogenetic view. J Comp Physiol A. 2009;195(12):1089-1106. doi: 10.1007/s00359-009-0482-z.
  24. Domínguez-Oliva A, Mota-Rojas D, Hernández-Avalos I, et al. The neurobiology of pain and facial movements in rodents: Clinical applications and current research. Front Vet Sci. 2022;9:1016720. doi: 10.3389/fvets.2022.1016720.
  25. Armstrong S.A., Herr M.J. Physiology, Nociception. In: StatPearls. StatPearls Publishing; 2025. Accessed September 22, 2025. http://www.ncbi.nlm.nih.gov/books/NBK551562/.
  26. Cain D.M., Khasabov SG, Simone DA. Response Properties of Mechanoreceptors and Nociceptors in Mouse Glabrous Skin: An In Vivo Study. Journal of Neurophysiology. 2001;85(4):1561-1574. doi: 10.1152/jn.2001.85.4.1561.
  27. Asiri Y.I., Moni S.S., Ramar M., et al. Advancing Pain Understanding and Drug Discovery: Insights from Preclinical Models and Recent Research Findings. Pharmaceuticals. 2024;17(11):1439. doi: 10.3390/ph17111439.
  28. Green BG. Temperature perception and nociception. J Neurobiol. 2004;61(1):13-29. doi: 10.1002/neu.20081.
  29. Szolcsányi J., Sándor Z. Multisteric TRPV1 nocisensor: a target for analgesics. Trends in Pharmacological Sciences. 2012;33(12):646-655. doi: 10.1016/j.tips.2012.09.002
  30. Ackerley R., Watkins RH. Microneurography as a tool to study the function of individual C-fiber afferents in humans: responses from nociceptors, thermoreceptors, and mechanoreceptors. Journal of Neurophysiology. 2018;120(6):2834-2846. doi: 10.1152/jn.00109.2018.
  31. St. John Smith E. Advances in understanding nociception and neuropathic pain. J Neurol. 2018;265(2):231-238. doi: 10.1007/s00415-017-8641-6.
  32. Julius D. TRP Channels and Pain. Annu Rev Cell Dev Biol. 2013;29(1):355-384. doi: 10.1146/annurev-cellbio-101011-155833.
  33. Callahan B.L., Gil A.S.C., Levesque A., et al. Modulation of Mechanical and Thermal Nociceptive Sensitivity in the Laboratory Mouse by Behavioral State. The Journal of Pain. 2008;9(2):174-184. doi: 10.1016/j.jpain.2007.10.011.
  34. Frias B., Merighi A. Capsaicin, Nociception and Pain. Molecules. 2016;21(6):797. doi: 10.3390/molecules21060797.
  35. Woller S.A., Eddinger K.A., Corr M., et al. An overview of pathways encoding nociception. Clin Exp Rheumatol. 2017;35 Suppl 107(5):40-46.
  36. Chen G., Kim Y.H., Li H., et al. PD-L1 inhibits acute and chronic pain by suppressing nociceptive neuron activity via PD-1. Nat Neurosci. 2017;20(7):917-926. doi: 10.1038/nn.4571.
  37. Vriens J., Nilius B., Voets T. Peripheral thermosensation in mammals. Nat Rev Neurosci. 2014;15(9):573-589. doi: 10.1038/nrn3784.
  38. Whittaker A.L., Muns R., Wang D., et al. Assessment of Pain and Inflammation in Domestic Animals Using Infrared Thermography: A Narrative Review. Animals. 2023;13(13):2065. doi: 10.3390/ani13132065.
  39. Tominaga M., Caterina M.J.. Thermosensation and pain. J Neurobiol. 2004;61(1):3-12. doi: 10.1002/neu.20079.
  40. Lawson J.J., McIlwrath S.L., Woodbury C.J., et al. TRPV1 Unlike TRPV2 Is Restricted to a Subset of Mechanically Insensitive Cutaneous Nociceptors Responding to Heat. The Journal of Pain. 2008;9(4):298-308. doi: 10.1016/j.jpain.2007.12.001.
  41. Moqrich A., Hwang S.W., Earley TJ, et al. Impaired Thermosensation in Mice Lacking TRPV3, a Heat and Camphor Sensor in the Skin. Science. 2005;307(5714):1468-1472. doi: 10.1126/science.1108609.
  42. Kashio M., Tominaga M. TRP channels in thermosensation. Current Opinion in Neurobiology. 2022;75:102591. doi: 10.1016/j.conb.2022.102591.
  43. Holzer P. Acid-Sensitive Ion Channels and Receptors. In: Canning BJ, Spina D, eds. Sensory Nerves. Vol 194. Handbook of Experimental Pharmacology. Springer Berlin Heidelberg; 2009:283-332. doi: 10.1007/978-3-540-79090-7_9.
  44. Hoffmann T., Kistner K., Miermeister F, et al. TRPA1 and TRPV1 are differentially involved in heat nociception of mice. European Journal of Pain. 2013;17(10):1472-1482. doi: 10.1002/j.1532-2149.2013.00331.x.
  45. Honore P., Chandran P., Hernandez G, et al. Repeated dosing of ABT-102, a potent and selective TRPV1 antagonist, enhances TRPV1-mediated analgesic activity in rodents, but attenuates antagonist-induced hyperthermia. Pain. 2009;142(1):27-35. doi: 10.1016/j.pain.2008.11.004.
  46. Laursen W.J., Schneider E.R., Merriman D.K., et al. Low-cost functional plasticity of TRPV1 supports heat tolerance in squirrels and camels. Proc Natl Acad Sci USA. 2016;113(40):11342-11347. doi: 10.1073/pnas.1604269113.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) Eco-Vector

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС 77 - 76969 от 11.10.2019.