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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Background
TMEM16C facilitates Na+-activated K+ currents in rat sensory neurons and regulates pain processing
Huang, F., Wang, X., Ostertag, E. M., Nuwal, T., Huang, B., Jan, Y. N., Basbaum, A. I., & Jan, L. Y. (2013) · Nature Neuroscience · doi:10.1038/nn.3468 · Cited by 134
Self-citation
A TRPA1-dependent mechanism for the pungent sensation of weak acids
Wang, Y. Y., Chang, R. B., Allgood, S. D., Silver, W. L., & Liman, E. R. (2011) · The Journal of General Physiology · doi:10.1085/jgp.201110615 · Cited by 134
“A recent report showed that activation of TRPA1 by reactive electrophiles is conserved in the insect isoforms of TRPA1, indicating that this mode of activation existed in the ancestral channel (Kang et al., 2010).”
Background
Altered resting state attentional networks in diabetic neuropathic pain
Cauda, F., D’Agata, F., Sacco, K., Duca, S., Cocito, D., Paolasso, I., Isoardo, G., & Geminiani, G. C. (2009) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.2009.188631 · Cited by 134
“suggests that chronic pain could disrupt the synchrony of a common pool of brain areas involved in self monitoring, pain processing and salience detection that can be explored using several different functional connectivity techniques. Chronic pain-induced cortical/subcortical reorganisation has been documented in ani…”
Is fibromyalgia associated with a unique cytokine profile? A systematic review and meta-analysis
O’Mahony, L. F., Srivastava, A., Mehta, P., & Ciurtin, C. (2021) · Lara D. Veeken · doi:10.1093/rheumatology/keab146 · Cited by 133
“Increased input from peripheral nociceptors can trigger a prolonged but reversible increase in the excitability and synaptic efficacy of nociceptive pathway neurons [6].”
Roles of calcitonin gene-related peptide in facilitation of wound healing and angiogenesis
Toda, M., Suzuki, T., Hosono, K., Kurihara, Y., Kurihara, H., Hayashi, I., Kitasato, H., Hoka, S., & Majima, M. (2008) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2008.02.003 · Cited by 130
Expression of the Transient Receptor Potential Channels TRPV1, TRPA1 and TRPM8 in Mouse Trigeminal Primary Afferent Neurons Innervating the Dura
Huang, D., Li, S., Dhaka, A. K., Story, G. M., & Cao, Y. Q. (2012) · Molecular Pain · doi:10.1186/1744-8069-8-66 · Cited by 129
Phytol, a Chlorophyll Component, Produces Antihyperalgesic, Anti-inflammatory, and Antiarthritic Effects: Possible NFκB Pathway Involvement and Reduced Levels of the Proinflammatory Cytokines TNF‑α and IL‑6
Carvalho, A. M. D. S., Heimfarth, L., Pereira, E. W. M., Oliveira, F. S., de Menezes, I. R. A., Coutinho, H. D. M., Picot, L., Antoniolli, Â. R., Quintans, J. D. S. S., & Quintans‐Júnior, L. J. (2020) · Journal of Natural Products · doi:10.1021/acs.jnatprod.9b01116 · Cited by 129
Differentiating Thermal Allodynia and Hyperalgesia Using Dynamic Hot and Cold Plate in Rodents
Yalçın, İ., Charlet, A., Freund‐Mercier, M. J., Barrot, M., & Poisbeau, P. (2009) · Journal of Pain · doi:10.1016/j.jpain.2009.01.325 · Cited by 128
Acute Postoperative Pain
Hurley, R. W., & Wu, C. L. (2010) · Elsevier eBooks · doi:10.1016/b978-0-443-06959-8.00087-x · Cited by 128
Mupirocin Prophylaxis against Nosocomial Staphylococcus aureus Infections in Nonsurgical Patients
Wertheim, H. F. L., Vos, M. D., Ott, A., Voß, A., Kluytmans, J. A. J. W., Vandenbroucke‐Grauls, C. M. J. E., Meester, M. H. M., van Keulen, P. H. J., & Verbrugh, H. A. (2004) · Annals of Internal Medicine · doi:10.7326/0003-4819-140-6-200403160-00007 · Cited by 128
Sodium channelopathies and pain
Lampert, A., O’Reilly, A. O., Reeh, P. W., & Leffler, A. (2010) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-009-0779-3 · Cited by 127
“From the large number of molecules specifically involved in nociception that have been identified during the past several years, subtypes of voltage-gated sodium channels (VGSCs) have emerged as promising targets for improved analgesic drugs [66, 119].”
Reduction of Anion Reversal Potential Subverts the Inhibitory Control of Firing Rate in Spinal Lamina I Neurons: Towards a Biophysical Basis for Neuropathic pain
Prescott, S. A., B, T. J. S. A., & Koninck, Y. D. (2006) · Molecular Pain · doi:10.1186/1744-8069-2-32 · Cited by 134
Reversal of acid‐induced and inflammatory pain by the selective ASIC3 inhibitor, APETx2
Karczewski, J., Spencer, R. H., Garsky, V. M., Liang, A., Leitl, M. D., Cato, M. J., Cook, S. P., Kane, S. A., & Urban, M. O. (2010) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2010.00918.x · Cited by 126
“…British Journal ofPharmacology DOI:10.1111/j.1476-5381.2010.00918.x www.brjpharmacol.org 950 British Journal of Pharmacology (2010) 161 950–960 © 2010 Merck Sharp & Dohme Corp. British Journal of Pharmacology © 2010 The British Pharmacological Society the spinal cord (Julius and Basbaum, 2001).”
BackgroundInfluential
Activation of transient receptor potential vanilloid 1 (TRPV1) by resiniferatoxin
Raisinghani, M., Pabbidi, R. M., & Premkumar, L. S. (2005) · The Journal of Physiology · doi:10.1113/jphysiol.2005.087874 · Cited by 126
“…protons, anandamide, arachidonic acid metabolites and N-arachidonyl dopamine (NADA) (Szallasi & Blumberg, 1990a,b; Caterina et al. 1997; Zygmunt et al. 1999; Hwang et al. 2000; Julius & Basbaum, 2001; Caterina & Julius, 2001; Chuang et al. 2001; De Petrocellis et al. 2001; Huang et al. 2002).”
Background
TRPV1: A Target for Next Generation Analgesics
Premkumar, L. S., & Sikand, P. (2008) · Current Neuropharmacology · doi:10.2174/157015908784533888 · Cited by 126
“Furthermore, high concentration of capsaicin has been used to alleviate pain associated with herpes zoster, AIDS neuropathy, diabetic peripheral neuropathy, etc [80, 172].”
Background
The neurotransmitter N-acetylaspartylglutamate in models of pain, ALS, diabetic neuropathy, CNS injury and schizophrenia
NEALE, J., OLSZEWSKI, R., Gehl, L. M., Wróblewska, B., & Bzdega, T. (2005) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2005.07.004 · Cited by 126
Control of inflammatory pain by chemokine-mediated recruitment of opioid-containing polymorphonuclear cells
Brack, A., Rittner, H. L., Machelska, H., Leder, K., Mousa, S. A., Schäfer, M., & Stein, C. (2004) · Pain · doi:10.1016/j.pain.2004.08.029 · Cited by 126
“During inflammation, numerous hyperalgesic mediators are produced (reviewed in (Julius and Basbaum, 2001; Scholz and Woolf, 2002)).”
Background
Plasticity and pain: role of the dorsal horn
Woolf, C. J., & Salter, M. W. (2006) · Elsevier eBooks · doi:10.1016/b0-443-07287-6/50010-2 · Cited by 125
The TRP family of cation channels: probing and advancing the concepts on receptor-activated calcium entry
Zitt, C., Halaszovich, C. R., & Lückhoff, A. (2002) · Progress in Neurobiology · doi:10.1016/s0301-0082(02)00002-3 · Cited by 126
T-Type Calcium Channel Inhibition Underlies the Analgesic Effects of the Endogenous Lipoamino Acids
Barbara, G., Alloui, A., Nargeot, J., Lory, P., Eschalier, A., Bourinet, E., & Chemin, J. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.2919-09.2009 · Cited by 125
“We found that lipoamino acids have weak effects on HVA calcium channels and sodium channels as well as on TRPV1 and TASK1 channels [both being anandamide sensitive (Zygmunt et al., 1999; Julius and Basbaum, 2001; Maingret et al., 2001; van der Stelt and Di Marzo, 2005)].”
Background
The role of endogenous molecules in modulating pain through transient receptor potential vanilloid 1 (TRPV1)
Morales‐Lázaro, S. L., Simon, S. A., & Rosenbaum, T. (2013) · The Journal of Physiology · doi:10.1113/jphysiol.2013.251751 · Cited by 127
Sex differences in non-obstructive coronary artery disease
Waheed, N., Elias‐Smale, S. E., Malas, W., Maas, A. H. E. M., Sedlak, T., Tremmel, J. A., & Mehta, P. K. (2020) · Cardiovascular Research · doi:10.1093/cvr/cvaa001 · Cited by 126
X-ray Crystal Structure of a TRPM Assembly Domain Reveals an Antiparallel Four-stranded Coiled-coil
Fujiwara, Y., & Minor, D. L. (2008) · Journal of Molecular Biology · doi:10.1016/j.jmb.2008.08.059 · Cited by 122
Anti-Inflammatory and Anti-Ulcer Activities of Carvacrol, a Monoterpene Present in the Essential Oil of Oregano
Silva, F. V., Guimarães, A. G., Silva, E. R. S., Neto, B. P. D. S., Machado, F. D. F., Quintans‐Júnior, L. J., Arcanjo, D. D. R., Oliveira, F. D. A., & Oliveira, R. C. M. (2012) · Journal of Medicinal Food · doi:10.1089/jmf.2012.0102 · Cited by 124
“34 Our results demonstrate that carvacrol was able to decrease the formation of paw edema induced by in-traplantar injection of histamine or dextran in mice and reduced the edema induced by substance P, suggesting that carvacrol possesses an activity on vascular events of in-ﬂammation possibly by…”
Pain in the brain: are hormones to blame?
Blackburn-Munro, G., & Blackburn-Munro, R. (2003) · Trends in Endocrinology & Metabolism · doi:10.1016/s1043-2760(02)00004-8 · Cited by 124
Transient receptor potential ankyrin-1 has a major role in mediating visceral pain in mice
Cattaruzza, F., Spreadbury, I., Miranda‐Morales, M., Grady, E. F., Vanner, S. J., & Bunnett, N. W. (2009) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00221.2009 · Cited by 123
Direct evidence for spinal cord microglia in the development of a neuropathic pain‐like state in mice
Narita, M., Yoshida, T., Nakajima, M., Narita, M., Miyatake, M., Takagi, T., Yajima, Y., & Suzuki, T. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.03808.x · Cited by 122
“Several lines of evidence have demonstrated that synaptic plasticity characterized by long-term potentiation is caused by chronic pain (Narita et al. 2000; Ji and Woolf 2001; Julius and Basbaum 2001; Yajima et al. 2002).”
Background
Reward‐aversion circuitry in analgesia and pain: Implications for psychiatric disorders
Borsook, D., Becerra, L. R., Carlezon, W. A., Shaw, M. E., Renshaw, P. F., Elman, I., & Levine, J. D. (2006) · European Journal of Pain · doi:10.1016/j.ejpain.2005.12.005 · Cited by 124
“Under normal physiological conditions, pain serves as a protective mechanism critical for survival (Julius and Basbaum, 2001).”
Background
How Do Acupuncture and Moxibustion Act? – Focusing on the Progress in Japanese Acupuncture Research –
Kawakita, K., SHINBARA, H., Imai, K., FUKUDA, F., Yano, T., & Kuriyama, K. (2006) · Journal of Pharmacological Sciences · doi:10.1254/jphs.crj06004x · Cited by 122
Role of adult hippocampal neurogenesis in persistent pain
Apkarian, A. V., Mutso, A., Centeno, M. V., Kan, L., Wu, M. V., Levinstein, M. R., Banisadr, G., Gobeske, K. T., Miller, R. J., Radulović, J., et al. (2015) · Pain · doi:10.1097/j.pain.0000000000000332 · Cited by 120
“Inflammatory tissue injuries give rise to peripheral and spinal cord reorganization specific to such injuries.(27,50) Such injuries are commonly associated with increased sensitivity to tactile, heat, and cold stimuli, and importantly the related behaviors and neural”
Background
The five “Ws” for bone pain due to the administration of granulocyte-colony stimulating factors (G-CSFs)
Lambertini, M., Mastro, L. D., Bellodi, A., & Pronzato, P. (2013) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2013.08.006 · Cited by 122
Structural determinants of gating in the TRPV1 channel
Salazar, H., Jara-Oseguera, A., Hernández‐García, E., Llorente, I., Arias‐Olguín, I. I., Soriano-García, M., Islas, L. D., & Rosenbaum, T. (2009) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1633 · Cited by 117
Hippocampal neurokinin-1 receptor and brain-derived neurotrophic factor gene expression is decreased in rat models of pain and stress
Duric, V., & McCarson, K. E. (2005) · Neuroscience · doi:10.1016/j.neuroscience.2005.04.002 · Cited by 118
Protein Kinase C Stimulates the Acid-sensing Ion Channel ASIC2a via the PDZ Domain-containing Protein PICK1
Baron, A., Deval, E., Salinas, M., Lingueglia, É., Voilley, N., & Lazdunski, M. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m208848200 · Cited by 118
Hypothalamo-pituitary-adrenal axis dysfunction as a contributory factor to chronic pain and depression
Blackburn-Munro, G. (2004) · Current Pain and Headache Reports · doi:10.1007/s11916-004-0025-9 · Cited by 119
Comparison of the pain suppressive effects of clinical and experimental painful conditioning stimuli
Bouhassira, D., Danziger, N., Atta, N., & Guirimand, F. (2003) · Brain · doi:10.1093/brain/awg106 · Cited by 117
Lentinus edodes heterogalactan: Antinociceptive and anti-inflammatory effects
Carbonero, E. R., Gracher, A. H. P., Komura, D. L., Marcon, R., Freitas, C. S., Baggio, C. H., Santos, A. R. S., Torri, G., Gorin, P. A. J., & Iacomini, M. (2008) · Food Chemistry · doi:10.1016/j.foodchem.2008.04.015 · Cited by 116
Acid Activation of Trpv1 Leads to an Up-Regulation of Calcitonin Gene-related Peptide Expression in Dorsal Root Ganglion Neurons via the CaMK-CREB Cascade: A Potential Mechanism of Inflammatory Pain
Nakanishi, M., Hata, K., Nagayama, T., Sakurai, T., Nishisho, T., Wakabayashi, H., Hiraga, T., Ebisu, S., & Yoneda, T. (2010) · Molecular Biology of the Cell · doi:10.1091/mbc.e10-01-0049 · Cited by 116
“Accumulating evidence has shown that Trpv1 is a critical mediator of inflammatory pain (Caterina et al., 1997; Julius and Basbaum, 2001).”
Background
Differences in electrical stimulation thresholds between men and women
Maffiuletti, N. A., Herrero, A. J., Jubeau, M., Impellizzeri, F. M., & Bizzini, M. (2008) · Annals of Neurology · doi:10.1002/ana.21346 · Cited by 116
Periostin Activation of Integrin Receptors on Sensory Neurons Induces Allergic Itch
Mishra, S. K., Wheeler, J. J., Pitake, S., Ding, H., Jiang, C., Fukuyama, T., Paps, J. S., Ralph, P., Coyne, J., Parkington, M. K., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.03.036 · Cited by 116
“10 Cell Reports 31, 107472, April 7, 2020 The Integrin aVb3 Uses TRP Channels and the Neuropeptide NPPB to Transmit Periostin-Induced Itch Both TRPV1 and TRPA1 are generally required for the transmission of itch and pain stimuli to the CNS in rodents (Basbaum et al., 2009; Bautista et al., 2013; Julius, 2013; Julius a…”
Sensory irritation: risk assessment approaches.
Nielsen, G., Wolkoff, P., & Alarie, Y. (2007) · Regulatory toxicology and pharmacology : RTP · doi:10.1016/j.yrtph.2006.11.005 · Cited by 124
“…pathway’’ uses activation of two types of nerve fibres: fine unmyelinated C-fibres and small myelinated Ad-fibres, which are often polymodal nociceptors (Julius and Basbaum, 2001; Doty et al., 2004; Belmonte et al., 2004) and thus may be stimulated by noxious heat, mechanical and chemical stimuli.”
BackgroundInfluential
Leptin derived from adipocytes in injured peripheral nerves facilitates development of neuropathic pain via macrophage stimulation
Maeda, T., Kiguchi, N., Kobayashi, Y., Ikuta, T., Ozaki, M., & Kishioka, S. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0903524106 · Cited by 116
“Different pain modalities have distinct mechanisms (27).”
Pathophysiology of bone cancer pain.
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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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