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
Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia
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“9, TRPV1 [2, 80, 83]}.”
Sensory neuron-specific receptor activation elicits central and peripheral nociceptive effects in rats
Grazzini, E., Puma, C., Roy, M., Xiao, Y., O’Donnell, D., Schmidt, R., Dautrey, S., Ducharme, J., Perkins, M., Panetta, R., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0307185101 · Cited by 95
Pathophysiology of Pain and Mechanisms of Neuromodulation: A Narrative Review (A Neuron Project)
Karcz, M., Abd-Elsayed, A. A., Chakravarthy, K. V., Aman, M. M., Strand, N. H., Malinowski, M. N., Latif, U., Dickerson, D. M., Suvar, T., Lubenow, T. R., et al. (2024) · Journal of Pain Research · doi:10.2147/jpr.s475351 · Cited by 130
Protein Kinases as Potential Targets for the Treatment of Pathological Pain
Ji, R., Kawasaki, Y., Zhuang, Z., Wen, Y., & Zhang, Y. Q. (2007) · Springer eBooks · doi:10.1007/978-3-540-33823-9_13 · Cited by 94
CC chemokine ligand 2 upregulates the current density and expression of TRPV1 channels and Nav1.8 sodium channels in dorsal root ganglion neurons
Kao, D.-J., Li, A. H.-L., Chen, J., Luo, R.-S., Chen, Y.-L., Lu, J., & Wang, H. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-189 · Cited by 95
Direct Role of Streptozotocin in Inducing Thermal Hyperalgesia by Enhanced Expression of Transient Receptor Potential Vanilloid 1 in Sensory Neurons
Pabbidi, R. M., Cao, D.-S., Parihar, A., Pauza, M. E., & Premkumar, L. S. (2007) · Molecular Pharmacology · doi:10.1124/mol.107.041707 · Cited by 94
“TRPV1 is activated by heat ( 42°C), capsaicin, protons, N-arachidonyl dopamine, anandamide, and leukotrienes (Caterina et al., 1997; Julius and Basbaum, 2001).”
Background
Mucosal Immune Cell Numbers and Visceral Sensitivity in Patients With Irritable Bowel Syndrome: Is There Any Relationship?
Braak, B., Klooker, T. K., Wouters, M. M., Welting, O., van der Loos, C. M., Stanisor, O. I., van Diest, S., van den Wijngaard, R. M., & Boeckxstaens, G. E. (2012) · American Journal of Gastroenterology · doi:10.1038/ajg.2012.54 · Cited by 93
Molecular and cellular mechanisms that initiate pain and itch
Luo, J., Feng, J., Liu, S., Walters, E. T., & Hu, H. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-1904-4 · Cited by 93
“The C nociceptors can be subdivided into an NGF (nerve growth factor)/TrkA-dependent, peptidergic population and a GDNF (glial cellderived neurotrophic factor)/cRet-dependent, nonpeptidergic subset [84].”
Background
Peripheral Mechanisms of Odontogenic Pain
Henry, M. A., & Hargreaves, K. (2007) · Dental Clinics of North America · doi:10.1016/j.cden.2006.09.007 · Cited by 93
Modality-specific sensory changes in humans after the induction of long-term potentiation (LTP) in cutaneous nociceptive pathways
Lang, S., Klein, T., Magerl, W., & Treede, R. (2006) · Pain · doi:10.1016/j.pain.2006.09.026 · Cited by 93
“Capsaicin activates the peripheral transduction mechanisms of primary nociceptive afferents (Julius and Basbaum, 2001) and thus mimics an injury including the patterns of primary and secondary hyperalgesia (LaMotte et al., 1991).”
Background
Translocation of GluR1-Containing AMPA Receptors to a Spinal Nociceptive Synapse during Acute Noxious Stimulation
Larsson, M., & Broman, J. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.5749-07.2008 · Cited by 95
“Although we know that they establish synapses with different neuronal populations in the dorsal horn, the functional differences between these nociceptive pathways remain poorly understood (Hunt and Mantyh, 2001; Julius and Basbaum, 2001; Braz et al., 2005).”
Background
Elevated peritoneal expression and estrogen regulation of nociceptive ion channels in endometriosis
Greaves, E., Grieve, K., Horne, A. W., & Saunders, P. T. K. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-2282 · Cited by 89
“An increase in the expression of neuropeptides, neurotrophins, and ion channels leading to an increased responsiveness of nociceptors has been suggested as an important contributor to development of hypersensitivity (8).”
Ecto-5′-Nucleotidase (CD73) Inhibits Nociception by Hydrolyzing AMP to Adenosine in Nociceptive Circuits
Sowa, N. A., Taylor‐Blake, B., & Zylka, M. J. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.5324-09.2010 · Cited by 92
“…coexpressed with PAP, suggesting that these two ectonucleotidases might coordinately metabolize AMP in nociceptive neurons under normal and pathological conditions, including inflammation where nucleotides and protons are released as part of the “inflammatory soup” (Julius and Basbaum, 2001).”
Background
Antinociceptive and Anxiolytic and Sedative Effects of Methanol Extract of Anisomeles indica: An Experimental Assessment in Mice and Computer Aided Models
Uddin, M. J., Reza, A. S. M. A., Abdullah-Al-Mamun, M., Kabir, M. S. H., Nasrin, S., Akhter, S., Arman, M. S. I., & Rahman, M. A. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00246 · Cited by 93
“Pain is one of the most pervasive problems in current time and it has high social and economic impacts (Julius and Basbaum, 2001).”
Background
The Positive Consequences of Pain: A Biopsychosocial Approach
Bastian, B., Jetten, J., Hornsey, M. J., & Leknes, S. (2014) · Personality and Social Psychology Review · doi:10.1177/1088868314527831 · Cited by 91
“…sensitivity to pain (nociceptive sensitivity) may arise due to increased excitability of the nociceptor terminals (i.e., peripheral sensitization, Julius & Basbaum, 2001) or increased reactivity of central pain-signaling neurons (i.e., central sensitization, R.-R. Li, Kohno, Moore, & Woolf,…”
Background
Antihyperalgesic Properties of Honokiol in Inflammatory Pain Models by Targeting of NF-κB and Nrf2 Signaling
Khalid, S., Ullah, M. Z., Khan, A. U., Afridi, R., Rasheed, H., Khan, A., Ali, H., Kim, Y. S., & Khan, S. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00140 · Cited by 91
Cardiovascular Brain Circuits
Mohanta, S. K., Yin, C., Weber, C., Godinho‐Silva, C., Veiga‐Fernandes, H., Xu, Q. J., Chang, R. B., & Habenicht, A. J. R. (2023) · Circulation Research · doi:10.1161/circresaha.123.322791 · Cited by 97
Protease-Activated Receptors: Regulation of Neuronal Function
Saito, T., & Bunnett, N. W. (2005) · NeuroMolecular Medicine · doi:10.1385/nmm:7:1-2:079 · Cited by 91
Characterization of μ Opioid Receptor Binding and G Protein Coupling in Rat Hypothalamus, Spinal Cord, and Primary Afferent Neurons during Inflammatory Pain
Shaqura, M. A., Zöllner, C., Mousa, S. A., Stein, C., & Schäfer, M. (2004) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.103.057257 · Cited by 91
Differential effects of lipopolysaccharide on mouse sensory TRP channels
Boonen, B., Alpizar, Y. A., Sánchez, A., López‐Requena, A., Voets, T., & Talavera, K. (2018) · Cell Calcium · doi:10.1016/j.ceca.2018.04.004 · Cited by 91
Capsaicin: Physicochemical properties, cutaneous reactions and potential applications in painful and inflammatory conditions (Review)
Ilie, M. A., Căruntu, C., Tampa, M. Ş., Georgescu, S. R., Matei, C., Negrei, C., Ion, R., Constantin, C., Neagu, M. T., & Boda, D. (2019) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2019.7513 · Cited by 93
Habituation Is More Than Learning to Ignore: Multiple Mechanisms Serve to Facilitate Shifts in Behavioral Strategy
McDiarmid, T. A., Yu, A. J., & Rankin, C. H. (2019) · BioEssays · doi:10.1002/bies.201900077 · Cited by 96
The Role of Nerves in Skeletal Development, Adaptation, and Aging
Tomlinson, R. E., Christiansen, B., Giannone, A. A., & Genetos, D. C. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.00646 · Cited by 93
TRPV1: Receptor structure, activation, modulation and role in neuro-immune interactions and pain
Maximiano, T. K. E., Carneiro, J. A., Fattori, V., & Verri, W. A., Jr. (2024) · Cell Calcium · doi:10.1016/j.ceca.2024.102870 · Cited by 93
Anti-hyperalgesic activity of corilagin, a tannin isolated from Phyllanthus niruri L. (Euphorbiaceae)
Moreira, J., Klein‐Júnior, L. C., Filho, V. C., & Buzzi, F. D. C. (2013) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2012.12.052 · Cited by 90
“In this test, pain is caused by acetic acid directly through the activation of non-selective cation channels present at primary afferent pathways (Julius and Basbaum, 2001) and indirectly via release of endogenous mediators, including bradykinin, substance P, prostaglandins, histamine and others, which are able to inc…”
Permeation and block of TRPV1 channels by the cationic lidocaine derivative QX-314
Puopolo, M., Binshtok, A. M., Yao, G.-L., Oh, S. B., Woolf, C. J., & Bean, B. P. (2013) · Journal of Neurophysiology · doi:10.1152/jn.00012.2013 · Cited by 90
“…root ganglion, sodium channel, capsaicin 61 62 3 Introduction 63 Noxious stimulus-sensing primary sensory neurons (nociceptors) express a variety of 64 receptors and channels that have little or no expression in other types of neurons 65 (reviewed by Julius and Basbaum 2001; Woolf and Ma 2007).”
Background
Changes in the Effect of Spinal Prostaglandin E2during Inflammation: Prostaglandin E (EP1-EP4) Receptors in Spinal Nociceptive Processing of Input from the Normal or Inflamed Knee Joint
Bär, K., Natura, G., Telleria-Diaz, A., Teschner, P., Vogel, R., Vásquez, E., Schaible, H., & Ebersberger, A. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.0882-03.2004 · Cited by 90
A transcriptional network coordinately determines transmitter and peptidergic fate in the dorsal spinal cord
Bröhl, D., Strehle, M., Wende, H., Hori, K., Bormuth, I., Nave, K., Müller, T. H., & Birchmeier, C. (2008) · Developmental Biology · doi:10.1016/j.ydbio.2008.08.002 · Cited by 90
“Neurons in the dorsal horn of the spinal cord receive somatosensory information from the periphery, integrate the information and transmit it to higher brain centers (Gillespie and Walker, 2001; Julius and Basbaum, 2001).”
Background
Effect of blockade of nerve growth factor and tumor necrosis factor on pain behaviors after plantar incision
Zahn, P. K., Subieta, A. R., Park, S. S., & Brennan, T. J. (2004) · Journal of Pain · doi:10.1016/j.jpain.2004.02.538 · Cited by 90
Corneal nerves and their role in dry eye pathophysiology
Vereertbrugghen, A., & Galletti, J. G. (2022) · Experimental Eye Research · doi:10.1016/j.exer.2022.109191 · Cited by 91
“(Belmonte, 2019; Julius and Basbaum, 2001) Capsaicin-mediated triggering of TRPV1 causes corneal pain in humans, and TRPV1 activation by inflammation increases the excitability of polymodal nociceptor fibers to other agonists (Immke and Gavva, 2006).”
Neurogenic Pain and Steroid Synthesis in the Spinal Cord
Patte‐Mensah, C., Kibaly, C., Boudard, D. L., Schaeffer, V., Béglé, A., Saredi, S., Meyer, L., & Mensah‐Nyagan, A. G. (2006) · Journal of Molecular Neuroscience · doi:10.1385/jmn:28:1:17 · Cited by 95
Anatomical and functional analysis of aquaporin 1, a water channel in primary afferent neurons
Shields, S. D., Mazarío, J., Skinner, K., & Basbaum, A. I. (2007) · Pain · doi:10.1016/j.pain.2006.11.018 · Cited by 89
Self-citation
Secreted Phospholipases A2 from Animal Venoms in Pain and Analgesia
Zambelli, V. O., Picolo, G., Fernandes, C. A. H., Fontes, M. R. M., & Cury, Y. (2017) · Toxins · doi:10.3390/toxins9120406 · Cited by 88
“The central sensitization also involves the release of modulatory substances, including cytokines and chemokines from neurons and glia cells (astrocytes/microglia), as well as loss of inhibitory input (descending pain inhibitory circuits) [41].”
Background
NGF-dependent neurons and neurobiology of emotions and feelings: Lessons from congenital insensitivity to pain with anhidrosis
Indo, Y. (2018) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2018.01.013 · Cited by 90
Activation of p38 MAPK in primary afferent neurons by noxious stimulation and its involvement in the development of thermal hyperalgesia
Mizushima, T., Obata, K., Yamanaka, H., Dai, Y., Fukuoka, T., Tokunaga, A., Mashimo, T., & Noguchi, K. (2004) · Pain · doi:10.1016/j.pain.2004.09.038 · Cited by 88
“Because non- nociceptor-mediated pain reflects a change in the function- ing of central neurons, i.e. central sensitization (Ji et al., 2003; Julius and Basbaum, 2001; Scholz and Woolf, 2002), we believe that the activation of p38 in primary afferents may not be involved in central…”
Background
Contribution of sensitized P2X receptors in inflamed tissue to the mechanical hypersensitivity revealed by phosphorylated ERK in DRG neurons
Dai, Y., Fukuoka, T., Wang, H., Yamanaka, H., Obata, K., Tokunaga, A., & Noguchi, K. (2004) · Pain · doi:10.1016/j.pain.2003.12.034 · Cited by 88
“Another mechanism might involve a ‘mechanochemical’ process whereby stretch evokes the release of a diffusible chemical messenger that then excites nearby primary sensory nerve terminals (Julius and Basbaum, 2001).”
Background
Similarities and Differences in Tumor Growth, Skeletal Remodeling and Pain in an Osteolytic and Osteoblastic Model of Bone Cancer
Halvorson, K. G., Sevcik, M. A., Ghilardi, J. R., Rosol, T. J., & Mantyh, P. W. (2006) · Clinical Journal of Pain · doi:10.1097/01.ajp.0000210902.67849.e6 · Cited by 88
Diabetic Peripheral Neuropathy: Should a Chaperone Accompany Our Therapeutic Approach?
Farmer, K. L., Li, C., & Dobrowsky, R. T. (2012) · Pharmacological Reviews · doi:10.1124/pr.111.005314 · Cited by 87
TRPs Make Sense
Voets, T., & Nilius, B. (2003) · The Journal of Membrane Biology · doi:10.1007/s00232-002-1059-8 · Cited by 88
Nerve growth factor and the physiology of pain: lessons from congenital insensitivity to pain with anhidrosis
Indo, Y. (2012) · Clinical Genetics · doi:10.1111/j.1399-0004.2012.01943.x · Cited by 90
“PLC-γ signaling contributes to NGF-mediated neural hypersensitivity (27).”

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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