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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The analgesic and anti-inflammatory effects of Litsea japonica fruit are mediated via suppression of NF-κB and JNK/p38 MAPK activation
Koo, H. J., Yoon, W., Sohn, E., Ham, Y., Jang, S., Kwon, J. E., Jeong, Y. J., Kwak, J. H., Sohn, E., Park, S., et al. (2014) · International Immunopharmacology · doi:10.1016/j.intimp.2014.06.007 · Cited by 45
“terminals in the peripheral tissue to enhance pain sensitivity [5–7].”
Background
Pain-associated signals, acidosis and lysophosphatidic acid, modulate the neuronal K2P2.1 channel
Cohen, A., Sagron, R., Somech, E., Segal-Hayoun, Y., & Zilberberg, N. (2008) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2008.12.004 · Cited by 49
A multi-scale view of skin thermal pain: from nociception to pain sensation
Zhu, Y. J., & Lu, T. J. (2010) · Philosophical Transactions of the Royal Society A Mathematical Physical and Engineering Sciences · doi:10.1098/rsta.2009.0234 · Cited by 44
“The CV is directly related to fibre diameter (Julius & Basbaum 2001), with the conduction velocities of Aδ-and C-fibres accounting for the first (fast) and second (slow) pain responses, respectively (Julius & Basbaum 2001).”
BackgroundInfluential
Characterization of Two Runx1-Dependent Nociceptor Differentiation Programs Necessary for Inflammatory versus Neuropathic Pain
Samad, O. A., Liu, Y., Yang, F.-C., Krämer, I., Arber, S., & Ma, Q. (2010) · Molecular Pain · doi:10.1186/1744-8069-6-45 · Cited by 44
“The sense of pain is initiated through the detection and transduction of noxious stimuli by specialized sensory neurons (called nociceptors), which are located in dorsal root ganglia (DRG) and trigeminal ganglia [ 1-3 ].”
Background
Neuroimmune Interaction in the Regulation of Peripheral Opioid-Mediated Analgesia in Inflammation
Hua, S. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00293 · Cited by 44
“Therefore, following the transendothelial migration of opioid-containing leukocytes into peripheral sites of inflammation, opioid peptides are released into a harsh milieu associated with an increase in temperature (21, 39, 41), low pH (21, 39, 41, 42), and high proteolytic activity (19, 20, 22, 40, 43).”
Background
Control of sensory neuron excitability by serotonin involves 5HT2C receptors and Ca2+-activated chloride channels
Salzer, I., Gantumur, E., Yousuf, A., & Boehm, S. (2016) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.08.006 · Cited by 44
“Incipiently, 5HT released from platelets and mast cells during tissue damage and inflammationwas believed to excite nociceptors via 5HT3 receptors (Julius and Basbaum, 2001), but then it turned out that this ionotropic receptor was only relevant in a minor subset of DRG neurons and only for delayed nociceptive respons…”
Influential
Understanding osteoporotic pain and its pharmacological treatment
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The brain on opioids
Ballantyne, J. C. (2018) · Pain · doi:10.1097/j.pain.0000000000001270 · Cited by 44
Evidence for the involvement of vanilloid receptor in the antinociception produced by the dialdeydes unsaturated sesquiterpenes polygodial and drimanial in rats
Andrè, E., Ferreira, J., Malheiros, Â., Yunes, R. A., & Calixto, J. Β. (2003) · Neuropharmacology · doi:10.1016/j.neuropharm.2003.10.008 · Cited by 44
Pituitary adenylate cyclase-activating polypeptide signalling as a therapeutic target in migraine
Ashina, H., Christensen, R. H., Hay, D. L., Pradhan, A. A. A., Hoffmann, J., Reglődi, D., Russo, A. F., & Ashina, M. (2024) · Nature Reviews Neurology · doi:10.1038/s41582-024-01011-4 · Cited by 44
Regulation/Modulation of Sensory Neuron Sodium Channels
Chahine, M., & O’Leary, M. E. (2014) · Handbook of experimental pharmacology · doi:10.1007/978-3-642-41588-3_6 · Cited by 44
The homeodomain transcription factor Gbx1 identifies a subpopulation of late‐born GABAergic interneurons in the developing dorsal spinal cord
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Recombinant Mouse PAP Has pH-Dependent Ectonucleotidase Activity and Acts through A1-Adenosine Receptors to Mediate Antinociception
Sowa, N. A., Vadakkan, K. I., & Zylka, M. J. (2009) · PLoS ONE · doi:10.1371/journal.pone.0004248 · Cited by 43
“‘‘inflammatory soup’’ containing protons and nucleotides [20].”
MrgC agonism at central terminals of primary sensory neurons inhibits neuropathic pain
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“The reasons for these contradictory findings remain unclear, but may relate to differences in animal conditions and etiologies (physiologic condition vs nerve injury) [4,29,41], behavioral measures (spontaneous vs reflex), and drug dose.”
Background
Neutrophil infiltration is implicated in the sustained thermal hyperalgesic response evoked by allergen provocation in actively sensitized rats
Lavich, T. R., Siqueira, R. D. A., Farias‐Filho, F. A., Cordeiro, R. S. B., Silva, P., & Martins, M. A. (2006) · Pain · doi:10.1016/j.pain.2006.08.006 · Cited by 43
“Since the mechanisms implicated in the processing of nociception vary and are certainly a reflection of the type of stimulus applied (Julius and Basbaum, 2001), our motivation was to dissect the role of IgE-mediated mechanisms and putative participation of leukocytes in the processing of…”
Background
AMPA and NMDA glutamate receptors are found in both peptidergic and non-peptidergic primary afferent neurons in the rat
Willcockson, H. H., & Valtschanoff, J. G. (2008) · Cell and Tissue Research · doi:10.1007/s00441-008-0662-0 · Cited by 43
“1997), the peptidergic afferents are more likely to play a role in inflammatory pain (Hunt and Mantyh 2001), while the non-peptidergic afferents may be more characteristically involved in neuropathic pain (Julius and Basbaum 2001).”
Geraniol Induces Antinociceptive Effect in Mice Evaluated in Behavioural and Electrophysiological Models
Rocca, V. L., da Fonsêca, D. V., da Silva‐Alves, K. S., Ferreira‐da‐Silva, F. W., de Sousa, D. P., Santos, P. L., Quintans‐Júnior, L. J., Leal‐Cardoso, J. H., & de Almeida, R. N. (2016) · Basic & Clinical Pharmacology & Toxicology · doi:10.1111/bcpt.12630 · Cited by 43
“Nociception process includes several signalling pathways involving central and peripheral mechanisms, immediate mediators and neurotransmitters, or mediators produced later, those that are released during the inflammation [40,41].”
BackgroundMethodInfluential
Ion Channel Sensing: Are Fluctuations the Crux of the Matter?
Kasimova, M. A., Yazici, A. T., Yudin, Y. K., Granata, D., Klein, M. L., Rohács, T., & Carnevale, V. (2018) · The Journal of Physical Chemistry Letters · doi:10.1021/acs.jpclett.7b03396 · Cited by 42
“Upon activation, it generates the signal that, transmitted to the thalamus through the dorsal root ganglia, is perceived as a painful sensation (3).”
Background
TRP Channels: New Potential Therapeutic Approaches in CNS Neuropathies
Morelli, M. B., Amantini, C., Liberati, S., Santoni, M., & Nabissi, M. (2013) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/18715273113129990056 · Cited by 43
“TRPV1 is important in the development of neurogenic pain and inflammation in sensory neurons [134, 135].”
Background
Relationship between oral burn and temperature in chili spiced pork patties evaluated by time–intensity
Reinbach, H. C., Toft, M., & Møller, P. (2008) · Food Quality and Preference · doi:10.1016/j.foodqual.2008.07.003 · Cited by 41
The unsilent majority–TRPV1 drives “spontaneous” transmission of unmyelinated primary afferents within cardiorespiratory NTS
Andresen, M. C., Hofmann, M. E., & Fawley, J. A. (2012) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00398.2012 · Cited by 42
Warm and Neutral Tumescent Anesthetic Solutions Are Essential Factors for a Less Painful Injection
Yang, C., Hsu, H., Shen, S., Juan, W., Hong, H., & Chen, C. (2006) · Dermatologic Surgery · doi:10.1097/00042728-200609000-00002 · Cited by 42
Involvement of the Melanocortin-1 Receptor in Acute Pain and Pain of Inflammatory but Not Neuropathic Origin
Delaney, A., Keighren, M., Fleetwood-Walker, S. M., & Jackson, I. J. (2010) · PLoS ONE · doi:10.1371/journal.pone.0012498 · Cited by 42
“to real or impending injury, triggering protective responses [1].”
Background
Assessment of Mechanisms Involved in Antinociception Caused by Myrsinoic Acid B
Hess, S., Padoani, C., Scorteganha, L. C., Holzmann, I., Malheiros, Â., Yunes, R. A., Monachè, F. D., & de Souza, M. M. (2010) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.33.209 · Cited by 42
Diacerein decreases visceral pain through inhibition of glutamatergic neurotransmission and cytokine signaling in mice
Gadotti, V. M., Martins, D. F., Pinto, H. F., Oliveira, G., Kaster, M. P., Quintão, N. L. M., & Santos, A. R. S. (2012) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2012.06.018 · Cited by 42
Mechanisms of tracheal filling in insects
Förster, T. D., & Woods, H. A. (2012) · Biological reviews/Biological reviews of the Cambridge Philosophical Society · doi:10.1111/j.1469-185x.2012.00233.x · Cited by 42
“Jungreis (1979) and later Reynolds & Samuels (1996) noticed the similarities of moulting fluid secretion to ion transport processes in the midgut (Dow & O’Donnell, 1990).”
Background
Expression of neuronal markers in the endometrium of women with and those without endometriosis
Newman, T. A., Bailey, J. L., Stocker, L. J., Woo, Y. L., Macklon, N., & Cheong, Y. C. (2013) · Human Reproduction · doi:10.1093/humrep/det274 · Cited by 43
“We explored this by probing our samples for the sensory neuronal marker VR1 (Woolf and Salter, 2000; Cortright et al., 2001; Julius and Basbaum, 2001; Sanchez et al., 2001; Szallasi et al., 2007).”
Background
Kainate Receptor Signaling in Pain Pathways
Bhangoo, S. K., & Swanson, G. T. (2012) · Molecular Pharmacology · doi:10.1124/mol.112.081398 · Cited by 43
“…of neurons, which have been categorized based on criteria that include expression of immunohistochemical markers and sensitivity to activation by specific types of stimuli (Dodd and Jessell, 1986; Carr and Nagy, 1993; Julius and Basbaum, 2001; Hjerling-Leffler et al., 2007; Teichert et al., 2012).”
Background
Primary afferent neurons containing calcitonin gene‐related peptide but not substance P in forepaw skin, dorsal root ganglia, and spinal cord of mice
Kestell, G. R., Anderson, R. L., Clarke, J. N., Haberberger, R. V., & Gibbins, I. L. (2015) · The Journal of Comparative Neurology · doi:10.1002/cne.23804 · Cited by 43
“Fine CGRP1SP- and CGRP1SP1 fibers encircled hair follicles in a distinct pattern, corresponding to previous descriptions of fine hair follicle afferents (Kruger et al., 1981; Munger, 1982; Millard and Woolf, 1988).”
Background
Smell of pain: intersection of nociception and olfaction
Lötsch, J., Haehner, A., Goßrau, G., Hummel, C., Walter, C., Ultsch, A., & Hummel, T. R. (2016) · Pain · doi:10.1097/j.pain.0000000000000599 · Cited by 42
Intratumoral acidosis fosters cancer-induced bone pain through the activation of the mesenchymal tumor-associated stroma in bone metastasis from breast carcinoma
Pompo, G. D., Lemma, S., Canti, L., Rucci, N., Ponzetti, M., Errani, C., Donati, D. M., Russell, S., Gillies, R. J., Chano, T., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.17091 · Cited by 42
“Therefore, protons are important mediators of nociceptor stimulation to evoke an allogenic signal [10, 11].”
Background
Swedish Nerve Growth Factor Mutation (NGF R100W ) Defines a Role for TrkA and p75 NTR in Nociception
Sung, K., Ferrari, L. F., Yang, W., Chung, C., Zhao, X., Gu, Y., Lin, S., Zhang, K., Cui, B., Pearn, M. L., et al. (2018) · Journal of Neuroscience · doi:10.1523/jneurosci.1686-17.2018 · Cited by 41
“NGF R100W does not potentiate low H -evoked response in sensory neurons in vitro Among the known mechanisms of pain transduction, NGF produces acute hypersensitivity by potentiating nociceptive ion channels such as the capsaicin receptor (also known as TRPV1) and acid-sensing ion channels (ASICs) (Szallasi and Blumber…”
Background
Pharmacological characterisation of the plant sesquiterpenes polygodial and drimanial as vanilloid receptor agonists
Andrè, E., Campi, B., Trevisani, M., Ferreira, J., Malheiros, Â., Yunes, R. A., Calixto, J. Β., & Geppetti, P. (2006) · Biochemical Pharmacology · doi:10.1016/j.bcp.2005.12.030 · Cited by 42
“Capsaicin, the pungent component of hot chilli pepper, excites a subset of small-diameter sensory neurons activating the transient receptor potential vanilloid 1 (TRPV1) [1].”
Background
Does Haber's Law Apply to Human Sensory Irritation?
Shusterman, D. J., Matovinovic, E., & Salmon, A. G. (2006) · Inhalation Toxicology · doi:10.1080/08958370600602322 · Cited by 42
Opioids inhibit purinergic nociceptors in the sensory neurons and fibres of rat via a G protein-dependent mechanism
Chizhmakov, I. V., Yudin, Y. K., Mamenko, M., Prudnikov, I. M., Tamarova, Z. A., & Krishtal, O. (2005) · Neuropharmacology · doi:10.1016/j.neuropharm.2004.12.009 · Cited by 42
Migraine-relevant sex-dependent activation of mouse meningeal afferents by TRPM3 agonists
Krivoshein, G., Tolner, E. A., van den Maagdenberg, A., & Giniatullin, R. A. (2022) · The Journal of Headache and Pain · doi:10.1186/s10194-021-01383-8 · Cited by 41
“tion, and propagation of this nociceptive firing [30, 31].”
Background
Sensory and sympathetic correlates of heat pain sensitization and habituation in men and women
Breimhorst, M., Hondrich, M., Rebhorn, C., May, A., & Birklein, F. (2012) · European Journal of Pain · doi:10.1002/j.1532-2149.2012.00133.x · Cited by 41
“Within each daily session, we observed a significant increase of intensity and unpleasantness ratings indicating temporal summation (Price et al., 1977) most likely due to nociceptive sensitization (Julius and Basbaum, 2001).”
Background
Pain and pain management in dermatology
Beiteke, U., Bigge, S., Reichenberger, C., & Gralow, I. (2015) · JDDG Journal der Deutschen Dermatologischen Gesellschaft · doi:10.1111/ddg.12822 · Cited by 41
Involvement of TRPM2 in a wide range of inflammatory and neuropathic pain mouse models
So, K., Haraguchi, K., Asakura, K., Isami, K., Sakimoto, S., Shirakawa, H., Mori, Y., Nakagawa, T., & Kaneko, S. (2015) · Journal of Pharmacological Sciences · doi:10.1016/j.jphs.2014.10.003 · Cited by 40
Selective regulation of 3α-hydroxysteroid oxido-reductase expression in dorsal root ganglion neurons: A possible mechanism to cope with peripheral nerve injury-induced chronic pain
Patte‐Mensah, C., Meyer, L., Schaeffer, V., & Mensah‐Nyagan, A. G. (2010) · Pain · doi:10.1016/j.pain.2010.06.004 · Cited by 43
“changes in the excitability of primary afferents and damage neuronal sensory transmission [7,19,56].”
Background
Potentiation of Nociceptive Responses to Low pH Injections in Humans by Prostaglandin E2
Rukwied, R., Chizh, B. A., Lorenz, U., Obreja, O., Mărgărit, S., Schley, M. T., & Schmelz, M. (2007) · Journal of Pain · doi:10.1016/j.jpain.2006.12.004 · Cited by 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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