Cited by 2,685Pain Mechanisms and TreatmentsIon Channels and ReceptorsIon channel regulation and function

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Molecular mechanisms of nociception

Julius, David, Basbaum, Allan I.·2001·Nature

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Abstract

The sensation of pain alerts us to real or impending injury and triggers appropriate protective responses. Unfortunately, pain often outlives its usefulness as a warning system and instead becomes chronic and debilitating. This transition to a chronic phase involves changes within the spinal cord and brain, but there is also remarkable modulation where pain messages are initiated - at the level of the primary sensory neuron. Efforts to determine how these neurons detect pain-producing stimuli of a thermal, mechanical or chemical nature have revealed new signalling mechanisms and brought us closer to understanding the molecular events that facilitate transitions from acute to persistent pain.

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Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia
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BackgroundInfluential
Small Extracellular Vesicles From iPSC-Derived Mesenchymal Stem Cells Ameliorate Tendinopathy Pain by Inhibiting Mast Cell Activation
Gao, R., Ye, T., Zhu, Z., Li, Q., Zhang, J., Ji, Y., Zhao, B., Xie, Z., & Wang, Y. (2022) · Nanomedicine · doi:10.2217/nnm-2022-0036 · Cited by 32
Suppression by intrathecal BmK IT2 on rat spontaneous pain behaviors and spinal c-Fos expression induced by formalin
Bai, Z., Liu, T., Pang, X.-Y., Chai, Z., & Ji, Y. (2007) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2007.03.007 · Cited by 31
Up-regulated phosphorylation of signal transducer and activator of transcription 3 and cyclic AMP-responsive element binding protein by peripheral inflammation in primary afferent neurons possibly through oncostatin M receptor
Tamura, S., Morikawa, Y., & Senba, E. (2005) · Neuroscience · doi:10.1016/j.neuroscience.2005.02.046 · Cited by 31
Nociception and locomotor activity are increased in ketogenic diet fed rats
Ziegler, D. R., Gamaro, G. D., de Araújo, E. M., Bassani, M. G., Perry, M. L. S., Dalmaz, C., & Gonçalves, C. (2005) · Physiology & Behavior · doi:10.1016/j.physbeh.2005.01.003 · Cited by 31
ω-Lsp-IA, a novel modulator of P-type Ca2+ channels
Pluzhnikov, K. A., Vassilevski, A. A., Korolkova, Y. V., Fisyunov, A., Iegorova, O., Krishtal, O., & Grishin, E. V. (2007) · Toxicon · doi:10.1016/j.toxicon.2007.07.004 · Cited by 31
Activation of CaMKII and ERK1/2 contributes to the time-dependent potentiation of Ca 2+ response elicited by repeated application of capsaicin in rat DRG neurons
Zhang, X., Daugherty, S. L., & de Groat, W. C. (2010) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00672.2010 · Cited by 31
“nonneuronal cells (24, 45, 49); 3) dorsal root reflex (29);”
Background
Lentiviral Vector-Mediated RNA Silencing in the Central Nervous System
Hutson, T. H., Foster, E., Moon, L. D. F., & Yáñez‐Muñoz, R. J. (2013) · Human Gene Therapy Methods · doi:10.1089/hgtb.2013.016 · Cited by 32
“TRPV1 is a polymodal ion channel that plays an important role in nociception, particularly as an integrator of inﬂammatory stimuli (Julius and Basbaum, 2001).”
Stretchable and neuromorphic transistors for pain perception and sensitization emulation
Xu, Y., Liu, D., Dai, S., Zhang, J., Guo, Z., Liu, X., Xiong, L., & Huang, J. D. (2023) · Materials Horizons · doi:10.1039/d3mh01766d · Cited by 30
Neurocutaneous disease
Chuquilin, M., Alghalith, Y., & Fernandez, K. (2016) · Journal of the American Academy of Dermatology · doi:10.1016/j.jaad.2015.04.060 · Cited by 30
A Randomized Controlled Trial of an Individualized Preoperative Education Intervention for Symptom Management After Total Knee Arthroplasty
Wilson, R. A., Watt-Watson, J. H., HODNETT, E. D., & Tranmer, J. E. (2016) · Orthopaedic Nursing · doi:10.1097/nor.0000000000000210 · Cited by 30
Heteroreceptors Modulating CGRP Release at Neurovascular Junction: Potential Therapeutic Implications on Some Vascular-Related Diseases
González‐Hernández, A., Marichal‐Cancino, B. A., Lozano‐Cuenca, J., López‐Canales, J. S., Muñoz‐Islas, E., Ramirez-Rosas, M. B., & Villalón, C. M. (2016) · BioMed Research International · doi:10.1155/2016/2056786 · Cited by 31
Distinct networks of periaqueductal gray columns in pain and threat processing
Wang, S., Veinot, J., Goyal, A., Khatibi, A., Lazar, S. W., & Hashmi, J. A. (2022) · NeuroImage · doi:10.1016/j.neuroimage.2022.118936 · Cited by 29
Machine Learning Predicts Patient Tangible Outcomes After Dental Implant Surgery
Yadalam, P. K., Trivedi, S. S., Krishnamurthi, I., Anegundi, R. V., Mathew, A., Shayeb, M. A., Jayaraj, K. N., Jaber, M. A., & Rajkumar, R. (2022) · IEEE Access · doi:10.1109/access.2022.3228793 · Cited by 30
ZBTB20 regulates nociception and pain sensation by modulating TRP channel expression in nociceptive sensory neurons
Ren, A., Wang, K., Zhang, H., Liu, A., Ma, X., Liang, Q. D., Cao, D., Wood, J. N., He, D. Z. Z., Ding, Y., et al. (2014) · Nature Communications · doi:10.1038/ncomms5984 · Cited by 30
Physiologie de la douleur
Bars, D. L., & Willer, J. C. (2004) · EMC-Anesthésie réanimation/Encyclopédie médico-chirurgicale. Anesthésie, réanimation · doi:10.1016/j.emcar.2004.08.001 · Cited by 55
“Rôle de l’inflammation [55, 57, 66, 88, 111, 115]”
Evaluation of antinociceptive effect of methanolic extract of leaves of Crataeva nurvala Buch.-Ham.
Moniruzzaman, M., & Imam, M. Z. (2014) · BMC Complementary and Alternative Medicine · doi:10.1186/1472-6882-14-354 · Cited by 30
Ultra violet-induced localized inflammatory hyperalgesia in awake rats and the role of sensory and sympathetic innervation of the skin
Saadé, N. E., Farhat, O., Rahal, O. N., Safieh‐Garabedian, B., Bars, D. L., & Jabbur, S. J. (2007) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2007.08.002 · Cited by 30
Increased sensitivity to acute and persistent pain in neuron-specific endothelin-1 knockout mice
Hasue, F., Kuwaki, T., Kisanuki, Y. Y., Yanagisawa, M., Moriya, H., Fukuda, Y., & Shimoyama, M. (2004) · Neuroscience · doi:10.1016/j.neuroscience.2004.09.036 · Cited by 30
Complex Regional Pain Syndrome (CRPS/RSD) and Neuropathic Pain: Role of Intravenous Bisphosphonates as Analgesics
Yanow, J., Pappagallo, M., & Pillai, L. (2008) · The Scientific World JOURNAL · doi:10.1100/tsw.2008.33 · Cited by 30
“Acid-sensing ion channels (ASICs) and the capsaicin receptor transient receptor potential vanilloid subtype 1 (TRVP1) are involved in proton-transduction mechanisms and in pain signal transmission[7,8,9].”
Background
A novel biological role for the phospholipid lysophosphatidylinositol in nociceptive sensitization via activation of diverse G-protein signalling pathways in sensory nerves in vivo
Gangadharan, V., Selvaraj, D., Kurejová, M., Njoo, C., Gritsch, S., Škoricová, D., Horstmann, H., Offermanns, S., Brown, A. J., Kuner, T., et al. (2013) · Pain · doi:10.1016/j.pain.2013.08.019 · Cited by 32
“Calcium-activated enzymes such as CamKIIa, as well as ERK1/2, can acutely phosphorylate key ion-channels and mediators of sensory transduction/excitation/conduction, such as diverse sodium channel, potassium channels, and channels of the transient receptor potential (TRP) family [4,10,19,20].”
Background
Evidence for peripherally antinociceptive action of propofol in rats: Behavioral and spinal neuronal responses to subcutaneous bee venom
Sun, Y., Li, K., & Chen, J. (2005) · Brain Research · doi:10.1016/j.brainres.2005.02.048 · Cited by 30
“It has been suggested that the dorsal horn functional changes are state-dependent and initially evoked and/or driven by activation of peripheral nociceptors following peripheral tissue or nerve injury [13,26].”
Background
Psychophysical properties of female genital sensation
Farmer, M. A., Maykut, C. A., Huberman, J. S., Huang, L. Q., Khalifé, S., Binik, Y. M., Apkarian, A. V., & Schweinhardt, P. (2013) · Pain · doi:10.1016/j.pain.2013.05.028 · Cited by 30
“Indeed, the provocation of heat-like pain with mechanical pressure is supported by in vitro evidence that some nociceptors respond to both heat and mechanical stimulation [19,21].”
Background
The TRPV1 ion channel: Implications for respiratory sensation and dyspnea
Fisher, J. T. (2009) · Respiratory Physiology & Neurobiology · doi:10.1016/j.resp.2009.01.009 · Cited by 30
Chronic pain disrupts the reward circuitry in multiple sclerosis
Seixas, D., Palace, J. A., & Tracey, I. (2016) · European Journal of Neuroscience · doi:10.1111/ejn.13272 · Cited by 30
Efficacy of Pregabalin as Premedication for Post-Operative Analgesia in Vaginal Hysterectomy
Rajappa, G. C., Vig, S., Bevanaguddaiah, Y., & Anandaswamy, T. (2016) · Anesthesiology and Pain Medicine · doi:10.5812/aapm.34591 · Cited by 30
“Surgery produces tissue injury with consequent release of histamine and other inflammatory mediators and neurotransmitters which activate peripheral nociceptors causing pain (10).”
Background
Afferent fiber-selective shift in opiate potency following targeted opioid receptor knockdown
Jones, T. L., Sweitzer, S. M., Wilson, S. P., & Yeomans, D. C. (2003) · Pain · doi:10.1016/j.pain.2003.08.006 · Cited by 30
Antinociceptive esters of N-methylanthranilic acid: Mechanism of action in heat-mediated pain
Pinheiro, M. M. G., Radulović, N. S., Miltojević, A. B., Boylan, F., & Fernandes, P. D. (2014) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2013.12.042 · Cited by 29
“, 2003) and promotes the activation of sensitive fibers that induce the release of several substances in the dorsal horn, which also could activate the TRPV1 receptor in the spinal cord (Julius and Basbaum, 2001; Millan, 1999).”
Background
Assessment of small fibers using evoked potentials
Madsen, C. S., Finnerup, N. B., & Baumgärtner, U. (2013) · Scandinavian Journal of Pain · doi:10.1016/j.sjpain.2013.11.007 · Cited by 29
“The perceived sensation following activation of A -fibers is of a pricking, sharp, and stinging character and termed “first pain”, while that associated with C-fibers is of a burning and diffuse character and termed “second pain” due to its delayed occurrence compared to the A -fiber response [10–13].”
Background
Proton block of proton-activated TRPV1 current
Lee, B. H., & Zheng, J. (2015) · The Journal of General Physiology · doi:10.1085/jgp.201511386 · Cited by 29
“Nonetheless, in the body core where TRPV1 is expressed in many organs and tissues, temperature is stable and capsaicin is normally absent.”
Background
Granulocyte-macrophage colony-stimulating factor receptor expression in clinical pain disorder tissues and role in neuronal sensitization
DONATIEN, P. D., Anand, U., Yiangou, Y., Sinisi, M., Fox, M., MacQuillan, A. H. F., Quick, T., Korchev, Y. E., & Anand, P. (2018) · PAIN Reports · doi:10.1097/pr9.0000000000000676 · Cited by 29
Melanocortin type 4 receptor–mediated inhibition of A-type K+ current enhances sensory neuronal excitability and mechanical pain sensitivity in rats
Zhang, Y., Jiang, D., Li, H., Sun, Y., Jiang, X., Gong, S., Qian, Z., & Tao, J. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.006894 · Cited by 29
“Alterations in the excitability of nociceptive sensory neurons can directly affect allodynia and hyperalgesia, the two common symptoms of pain (11).”
Background
Comparing Caenorhabditis elegans gentle and harsh touch response behavior using a multiplexed hydraulic microfluidic device
McClanahan, P. D., Xu, J. H., & Fang-Yen, C. M. (2017) · Integrative Biology · doi:10.1039/c7ib00120g · Cited by 29
TNFα in MS and Its Animal Models: Implications for Chronic Pain in the Disease
Maguire, A. D., Bethea, J. R., & Kerr, B. J. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2021.780876 · Cited by 33
“Primary pain sensing neurons, called nociceptors, express TNFR1 (112), and signaling through this receptor can cause nociceptors to become hyperexcitable, meaning they may be more likely to fire action potentials, and do so more intensely in response to painful stimuli (113, 114).”
Background
Monotropein: A comprehensive review of biosynthesis, physicochemical properties, pharmacokinetics, and pharmacology
Wu, M., Lai, H., Peng, W., Zhou, X., Zhu, L., Tu, H., Yuan, K., & Yang, Z. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1109940 · Cited by 29
The role of transient receptor potential ankyrin 1 (TRPA1) channel in activation of single unit mechanosensitive bladder afferent activities in the rat
Minagawa, T., Aizawa, N., Igawa, Y., & Wyndaele, J. (2013) · Neurourology and Urodynamics · doi:10.1002/nau.22449 · Cited by 29
“Moreover, TRPA1 mediates not only an afferent signal to the dorsal horn of the spinal cord, but also local neurogenic inflammation through the secretion of neuropeptides, such as substance P and CGRP from the peripheral afferent nerve terminals in pathological conditions.(27) Furthermore, the peripheral inflammation p…”
Background
Further analysis of the antinociceptive action caused by p-methoxyl-diphenyl diselenide in mice
Jessé, C. R., da Rocha, J. B. T., Nogueira, C. W., & Savegnago, L. (2008) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2008.09.012 · Cited by 29
Temporal changes in MrgC expression after spinal nerve injury
He, S.-Q., Han, L., Li, Z., Xu, Q., Tiwari, V., Yang, F., Guan, X., Wang, Y., Raja, S. N., Dong, X., et al. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.12.041 · Cited by 29
“Both peptidergic and non-peptidergic nociceptors are important to the expression of pathological pain (Julius and Basbaum, 2001; Braz et al., 2005; Cavanaugh et al., 2009).”
Pharmacological profile of the clonidine‐induced inhibition of vasodepressor sensory outflow in pithed rats: correlation with α2A/2C‐adrenoceptors
Villalón, C. M., Albarrán-Juárez, J., Lozano‐Cuenca, J., Pertz, H. H., Görnemann, T., & Centurión, D. (2008) · British Journal of Pharmacology · doi:10.1038/bjp.2008.49 · Cited by 29
“C fibres are primary sensory nerves originating from the spinal cord (Julius and Basbaum, 2001) and, upon stimulation, cause a non-adrenergic, non-cholinergic (NANC) vasodilatation via the release of vasodilator neurotransmitters, particularly calcitonin gene-related peptide (CGRP; Kawasaki et…”
Summation model of pelvic pain in interstitial cystitis
Klumpp, D. J., & Rudick, C. N. (2008) · Nature Clinical Practice Urology · doi:10.1038/ncpuro1203 · Cited by 29
“C-fibers) is increased, resulting in enhanced responses to subsequent stimulation or a reduced threshold for depolarization, which is required to generate action potentials”
Background
Reduced pain behaviors and extracellular signal‐related protein kinase activation in primary sensory neurons by peripheral tissue injury in mice lacking platelet‐activating factor receptor
Tsuda, M., Ishii, S., Masuda, T., Hasegawa, S., Nakamura, K., Nagata, K., Yamashita, T., Furue, H., Tozaki‐Saitoh, H., Yoshimura, M., et al. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.04796.x · Cited by 29
Analgesic and anti-inflammatory effects of ethyl acetate fraction ofPolygonum cuspidatumin experimental animals
Han, J.-H., Koh, W., Lee, H., Lee, H., Lee, E., Lee, S. J., Khil, J., Kim∥, J. T., Jeong, S., & Kim, S. (2011) · Immunopharmacology and Immunotoxicology · doi:10.3109/08923973.2011.590499 · Cited by 29
“Nociceptive pain is perceived from different modes of sources, mainly from chemical, mechanical, or thermal factors.((20,21)) In hot plate test and tail-flicking test, EAPC shows significant analgesic effect, whereas it did not in acid-induced writhing test, suggesting EAPC may be more effective in thermal and physica…”
Background
Fish oil concentrate delays sensitivity to thermal nociception in mice
Veigas, J. M., Williams, P. J., Halade, G. V., Rahman, M., Yoneda, T., & Fernandes, G. (2011) · Pharmacological Research · doi:10.1016/j.phrs.2011.02.004 · Cited by 29
“Activation of these ion channels is a complex mechanism and involves one or more factors such as proton sensitive ion channels, the ASICs and transient receptor potential cation channels being the most important ones involved in pain perception [41].”

Authors: Julius, D., & Basbaum, A. I.
Affiliations: University of California, San Francisco (US)
Corresponding author: Julius, David
ORCID: Julius, David
Basbaum, Allan I.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2001-09
Volume: 413
Issue: 6852
Pages: 203-210
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/35093019
OpenAlex: W1883044208
Cited by: 2,685
References: 73
Citations by year: 2026: 63 · 2025: 66 · 2024: 95 · 2023: 91 · 2022: 100 · 2021: 103 · 2020: 94 · 2019: 138 · 2018: 119 · 2017: 113 · 2016: 109 · 2015: 114 · 2014: 147 · 2013: 144 · 2012: 117
FWCI: 8.09
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Funders: Bristol-Myers Squibb
National Institutes of Health
National Institute of Mental Health
Topics: Health Sciences › Medicine › Physiology (medical) › Pain Mechanisms and Treatments
Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
Keywords: nociception, pain, chronic pain, primary sensory neurons, pain detection, thermal pain, mechanical pain, chemical pain, acute to chronic pain transition, pain signalling, molecular mechanisms
MeSH terms: Animals, Forecasting, Humans, Neurons, Afferent, Pain, Signal Transduction

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Molecular mechanisms of nociception

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