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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Self-citation
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Hypernociception elicited by tibio-tarsal joint flexion in mice: A novel experimental arthritis model for pharmacological screening
Guerrero, A. T. G., Verri, W. A., Jr., Cunha, T. M., Silva, T. A., Rocha, F. A. C., Ferreira, S. H., Cunha, F. Q., & Parada, C. A. (2006) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2006.05.008 · Cited by 79
Metabolic Connection of Inflammatory Pain: Pivotal Role of a Pyruvate Dehydrogenase Kinase-Pyruvate Dehydrogenase-Lactic Acid Axis
Jha, M. K., Song, G. J., Lee, M., Jeoung, N. H., Go, Y., Harris, R. A., Park, D. H., Kook, H. Y., Lee, I., & Suk, K. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.1910-15.2015 · Cited by 79
“Several studies have demonstrated that an acidic microenvironment, at least in part, contributes to the induction of pain hypersensitivity (Birklein et al., 2000; Julius and Basbaum, 2001; Nagae et al., 2006; Kim et al., 2007; Nagae et al., 2007).”
Background
Synaesthetic metaphors are neither synaesthetic nor metaphorical
Winter, B. (2019) · Converging evidence in language and communication research · doi:10.1075/celcr.19.06win · Cited by 79
The role of TRP ion channels in migraine and headache
Iannone, L. F., Logu, F. D., Geppetti, P., & Cesaris, F. D. (2021) · Neuroscience Letters · doi:10.1016/j.neulet.2021.136380 · Cited by 78
Characterization of the Mas‐related gene family: structural and functional conservation of human and rhesus MrgX receptors
Burstein, E. S., Ott, T. R., Feddock, M., Ma, J., Fuhs, S., Wong, S., Schiffer, H. H., Brann, M. R., & Nash, N. R. (2005) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0706448 · Cited by 78
“…0007–1188/06 $30.00 www.nature.com/bjp are similar between mouse and rat, with DRG-specific receptors expressed in neurons which are IB4 positive, and express the glial cell line-derived neurotrophic factor (GDNF) receptor c-Ret (Snider & McMahon, 1998; Julius & Basbaum, 2001; Zylka et al., 2003).”
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Cytokine inhibition and time-related influence of inflammatory stimuli on the hyperalgesia induced by the nucleus pulposus
Grava, A. L. D. S., Ferrari, L. F., & Defino, H. L. A. (2011) · European Spine Journal · doi:10.1007/s00586-011-2027-8 · Cited by 78
“[35], whose in vitro study revealed that blocking cytokine activation blunts the production of factors associated with inflammation and disc matrix catabolism [36].”
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Pain mechanisms: A commentary on concepts and issues
Perl, E. R. (2011) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2011.03.001 · Cited by 78
“The concept of sensory information from nociceptors currently has moved from the existence question to that of molecular specificities and activity-based changes (Julius and Basbaum, 2001).”
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Involvement and Role of the Hypothalamo-pituitary-adrenal (HPA) Stress Axis in Animal Models of Chronic Pain and Inflammation
Bomholt, S. F., Harbuz, M. S., Blackburn-Munro, G., & Blackburn-Munro, R. E. (2004) · Stress · doi:10.1080/10253890310001650268 · Cited by 78
Mechanisms of Transient Receptor Potential Vanilloid 1 Activation and Sensitization by Allyl Isothiocyanate
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“The latter question is particularly important because it relates to the mechanisms by which AITC induces neurogenic inflammation (Jancsó et al., 1968; Inoue et al., 1997; Grant et al., 2005), where extracellular acidosis is a key feature (Julius and Basbaum, 2001; Holzer, 2009).”
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Unfolding the codes of short-term feed appetence in farm and companion animals. A comparative oronasal nutrient sensing biology review
Roura, E., Humphrey, B. D., Tedó, G., & Ipharraguerre, I. R. (2008) · Canadian Journal of Animal Science · doi:10.4141/cjas08014 · Cited by 83
The Effects of Air Pollutants and Irritants on the Upper Airway
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TRPM8
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Bradykinin and peripheral sensitization
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Inhibition of Cytosolic Phospholipase A2α: Hit to Lead Optimization
McKew, J. C., Foley, M. A., Thakker, P., Behnke, M. L., Lovering, F., Sum, F., Tam, S., Wu, K. K., Shen, M. W. H., Zhang, W., et al. (2005) · Journal of Medicinal Chemistry · doi:10.1021/jm0507882 · Cited by 78
Developing analgesics by enhancing spinal inhibition after injury: GABAA receptor subtypes as novel targets
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Co-expression of the voltage-gated potassium channel Kv1.4 with transient receptor potential channels (TRPV1 and TRPV2) and the cannabinoid receptor CB1 in rat dorsal root ganglion neurons
Binzen, U., Greffrath, W., Hennessy, S., Bausen, M., Saaler‐Reinhardt, S., & Treede, R. (2006) · Neuroscience · doi:10.1016/j.neuroscience.2006.06.020 · Cited by 77
Antinociceptive properties of the ethanolic extract and of the triterpene 3β,6β,16β-trihidroxilup-20(29)-ene obtained from the flowers of Combretum leprosum in mice
Pietrovski, E. F., Rosa, K. A., Facundo, V. A., Rios, K., Marques, M. C. A., & Santos, A. R. S. (2006) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2005.12.010 · Cited by 77
Sensory neuropathy and signs of central sensitization in patients with peripheral arterial disease
Lang, P. M., Schober, G. M., Rolke, R., Wagner, S., Hilge, R., Offenbächer, M., Treede, R., Hoffmann, U., & Irnich, D. (2006) · Pain · doi:10.1016/j.pain.2006.04.011 · Cited by 77
Characterization of acid signaling in rat vagal pulmonary sensory neurons
Gu, Q., & Lee, L. (2006) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00517.2005 · Cited by 77
“We also examined the relative contribution of TRPV1, another channel gated by protons (9, 19), to the acid-evoked current in these pulmonary sensory neurons.”
Background
Substance P inhibits progesterone conversion to neuroactive metabolites in spinal sensory circuit: A potential component of nociception
Patte‐Mensah, C., Kibaly, C., & Mensah‐Nyagan, A. G. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0502968102 · Cited by 77
State‐dependent phosphorylation of ε‐isozyme of protein kinase C in adult rat dorsal root ganglia after inflammation and nerve injury
Zhou, Y., Li, G., & Zhao, Z. (2003) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2003.01675.x · Cited by 77
Forced‐exercise delays neuropathic pain in experimental diabetes: effects on voltage‐activated calcium channels
Shankarappa, S. A., Piedras-Renterı́a, E. S., & Stubbs, E. B. (2011) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2011.07302.x · Cited by 78
Clinical pharmacology of analgesics assessed with human experimental pain models: bridging basic and clinical research
Oertel, B. G., & Lötsch, J. (2012) · British Journal of Pharmacology · doi:10.1111/bph.12023 · Cited by 76
“Due to the complexity of pain with many different molecular components and pathways (Julius and Basbaum, 2001), clinical pain displays a pattern of different phenotypes for which different analgesics provide therapies of varying success.”
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TRPA1 in bradykinin-induced mechanical hypersensitivity of vagal C fibers in guinea pig esophagus
Yu, S., & Ouyang, A. (2008) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.90530.2008 · Cited by 76
“Those that sense noxious stimuli are referred to as nociceptors (17, 37).”
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Hypoxia-induced sensitization of transient receptor potential vanilloid 1 involves activation of hypoxia-inducible factor-1 alpha and PKC
Ristoiu, V., Shibasaki, K., Uchida, K., Zhou, Y., Ton, B.-H. T., Flonta, M., & Tominaga, M. (2011) · Pain · doi:10.1016/j.pain.2011.02.024 · Cited by 76
“TRPV1 is a nonselective cation channel expressed predominantly in unmyelinated C fibers [19] that acts as a detector and an integrator of painful stimuli.”
Background
Topographical differences in distribution and responsiveness of trigeminal sensitivity within the human nasal mucosa
Meusel, T., Negoias, S., Scheibe, M., & Hummel, T. R. (2010) · Pain · doi:10.1016/j.pain.2010.08.013 · Cited by 76
“Known examples of receptors that communicate each of these sensations are the acid-sensitive ion channel (ASIC), which is activated by low pH [56] or protons [39], and the vanilloid receptor TRPV1, which was identified as the capsaicin receptor [7] and responds to noxious heat as well as to a variety of inflammatory m…”
Background
Desensitization of canonical transient receptor potential channel 5 by protein kinase C
Zhu, M. H., Chae, M. R., Kim, H. J., Lee, Y., Kim, M. J., Jin, N., Yang, D. K., So, I., & Kim, K. W. (2005) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00440.2004 · Cited by 76
“TRPV1 also exhibits a time- and Ca(2) -dependent desensitization, a long-lasting refractory state during which the receptor does not respond to vanilloids or to other stimuli (9).”
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Orofacial Pain in Cancer: Part I—Mechanisms
Benoliel, R., Epstein, J. B., Eliav, E., Jurevic, R. J., & Elad, S. (2007) · Journal of Dental Research · doi:10.1177/154405910708600604 · Cited by 75
“Pain is common (in 58.4% of patients) and interferes with daily activities in 30.8% of patients.”
Influential
Phoenixin: A novel peptide in rodent sensory ganglia
Lyu, R., Huang, X., Zhang, Y., Dun, S. L., Luo, J. J., Chang, J. K., & Dun, N. J. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.07.057 · Cited by 75
“It is generally recognized that nociception, such as thermal, mechanical or neuropathic pain, is transmitted mainly via primary afferent neurons of small diameter to the superficial layers of the dorsal horn (Julius and Basbaum, 2001).”
Molecular and functional expression of cation-chloride cotransporters in dorsal root ganglion neurons during postnatal maturation
Mao, S., Garzón-Muvdi, T., Fulvio, M. D., Chen, Y., Delpire, E. J., Álvarez, F. J., & Alvarez-Leefmans, F. J. (2012) · Journal of Neurophysiology · doi:10.1152/jn.00970.2011 · Cited by 80
Upregulations of P2X3 and ASIC3 involve in hyperalgesia induced by cisplatin administration in rats
Hori, K., Ozaki, N., Suzuki, S., & Sugiura, Y. (2010) · Pain · doi:10.1016/j.pain.2010.03.005 · Cited by 75
“Recent physiological, morphological, and molecular biological studies have elucidated the molecular mechanisms whereby primary sensory neurons detect pain-producing stimuli, thus initiating the processes referred to as nociception [29].”
Botulinum toxin B in the sensory afferent: Transmitter release, spinal activation, and pain behavior
Marino, M. J., Terashima, T., Steinauer, J., Eddinger, K. A., Yaksh, T. L., & Xu, Q. (2013) · Pain · doi:10.1016/j.pain.2013.12.009 · Cited by 75
“TRPV1 channels are present on the central and peripheral terminals of peptidergic afferents [17,43].”
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Endogenous steroid production in the spinal cord and potential involvement in neuropathic pain modulation
Mensah‐Nyagan, A. G., Kibaly, C., Schaeffer, V., Venard, C., Meyer, L., & Patte‐Mensah, C. (2008) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2008.03.002 · Cited by 75
The Molecular and Pharmacological Mechanisms of HIV-Related Neuropathic Pain
Hao, S. (2013) · Current Neuropharmacology · doi:10.2174/1570159x11311050005 · Cited by 75
“This increases the sensitivity and excitability of the nociceptor terminal–a phenomenon known as peripheral sensitization [1, 4], which produces increases in pain sensitivity that is restricted to the site of inflammation.”
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Long noncoding RNA MRAK009713 is a novel regulator of neuropathic pain in rats
Li, G., Jiang, H., Zheng, C., Zhu, G., Xu, Y., Sheng, X., Wu, B., Guo, J., Zhu, S., Zhan, Y., et al. (2017) · Pain · doi:10.1097/j.pain.0000000000001013 · Cited by 74
A Novel Mechanism Contributing to Development of Dahl Salt–Sensitive Hypertension
Wang, Y., & Wang, D. H. (2005) · Hypertension · doi:10.1161/01.hyp.0000197390.10412.c4 · Cited by 74
Sulfated polysaccharides isolated from the green seaweed Caulerpa racemosa plays antinociceptive and anti-inflammatory activities in a way dependent on HO-1 pathway activation
Ribeiro, N. A., Abreu, T. M., Chaves, H. V., Bezerra, M. M., Monteiro, H. S. A., Jorge, R. J. B., & Benevídes, N. M. B. (2014) · Inflammation Research · doi:10.1007/s00011-014-0728-2 · Cited by 75
“This transmission occurs through nociceptors that can detect a wide variety of stimuli, including those of physical and chemical natures, and convert such stimuli into electrochemical signals [2].”
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Memristor-based adaptive neuromorphic perception in unstructured environments
Wang, S., Gao, S., Tang, C., Occhipinti, E., Li, C., Wang, S., Wang, J., Zhao, H., Hu, G., Nathan, A., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-48908-8 · Cited by 77
“For better adaptation to dynamic changes in hazardous scenarios, we mimic the time window processing mechanism in organisms, thereby distinguishing between sudden threats and persistent threats 29,36 .”
ThermoTRP Channels in Nociceptors: Taking a Lead from Capsaicin Receptor TRPV1
Roufogalis, B. D., & Mandadi, S. (2008) · Current Neuropharmacology · doi:10.2174/157015908783769680 · Cited by 73
“Prostaglandin E2 (PGE2), bradykinin, NGF, extracellular ATP, glutamate, trypsin, prolactin, prokineticin2 (Bv8) are pro-inflammatory mediators that activate their respective receptors EP prostaglandin, B1/B2 bradykinin, high-affinity TrkA NGF receptor, P2Y2, mGlu 5, PAR-2, PRLR and PKR2 G protein-coupled receptors [48…”
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Perspective on Pain Management in the 21st Century
Polomano, R. C., Dunwoody, C. J., Krenzischek, D. A., & Rathmell, J. P. (2008) · Pain Management Nursing · doi:10.1016/j.pmn.2007.11.002 · Cited by 73
Independent combinatorial effect of antisense oligonucleotides and RNAi-mediated specific inhibition of the recombinant Rat P2X3 receptor
Hemmings-Mieszczak, M. (2003) · Nucleic Acids Research · doi:10.1093/nar/gkg322 · Cited by 76
NGF – the TrkA to successful pain treatment
Kumar, V., & Mahal, B. A. V. (2012) · Journal of Pain Research · doi:10.2147/jpr.s33408 · Cited by 72
“These nociceptor fibers that innervate the different parts of the body and head conduct pain signals to the dorsal root ganglia of the spinal cord or the trigeminal ganglia, respectively.(2) The signaling of NGF in these nociceptor neurons is mediated through two different receptors, the low-affinity 75 kDa neurotroph…”
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Values and Actions in Aversion
Dayan, P., & Seymour, B. (2009) · Elsevier eBooks · doi:10.1016/b978-0-12-374176-9.00012-9 · Cited by 73
“Physical pain is subserved by a sophisticated system of specialised neural pathways signalling information about actual or imminent tissue damage to many areas of the spinal cord and brain (Craig, 2002; Fields, 2004; Julius and Basbaum, 2001).”
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An integrated perspective on diabetic, alcoholic, and drug-induced neuropathy, etiology, and treatment in the US
Zeng, L., Alongkronrusmee, D., & van Rijn, R. M. (2017) · Journal of Pain Research · doi:10.2147/jpr.s125987 · Cited by 72
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“Pain should serve as protection from tissue damage [37].”
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Ultraviolet Radiation-Induced Inflammation as a Model for Cutaneous Hyperalgesia
Harrison, G. I., Young, A. R., & McMahon, S. B. (2004) · Journal of Investigative Dermatology · doi:10.1046/j.0022-202x.2003.22119.x · Cited by 72
Nerve growth factor, pain, itch and inflammation: lessons from congenital insensitivity to pain with anhidrosis
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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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