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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Crossref · 10.1038/35093019

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“73)—all three channels being linked to nociception and hyperalgesi”
Bone cancer pain
Mantyh, P. W. (2014) · Current Opinion in Supportive and Palliative Care · doi:10.1097/spc.0000000000000048 · Cited by 196
“Cancer cells and their associated stromal cells secrete a wide variety of factors [29,30], many of which have previously been shown to sensitize or directly excite primary afferent neurons [31].”
Background
The neurobiology of skeletal pain
Mantyh, P. W. (2014) · European Journal of Neuroscience · doi:10.1111/ejn.12462 · Cited by 195
“…the neurotransmitters substance P and CGRP, and receptors (bradykinin), channels (P2X3, TRPV1, ASIC-3 and sodium channels), transcription factors (ATF-3) and structural molecules (neurofilaments and the sodium channel-anchoring molecule p11) (Julius & Basbaum, 2001; Patapoutian & Reichardt, 2001).”
Background
HTR7 Mediates Serotonergic Acute and Chronic Itch
Morita, T., McClain, S. P., Batia, L. M., Pellegrino, M., Wilson, S. R., Kienzler, M. A., Lyman, K. A., Olsen, A. S. B., Wong, J. F., Stucky, C. L., et al. (2015) · Neuron · doi:10.1016/j.neuron.2015.05.044 · Cited by 188
“In the periphery, 5-HT can act as an algogen to trigger acute pain or pain hypersensitivity (Bardin, 2011; Julius and Basbaum, 2001; Kayser et al., 2007; Zeitz et al., 2002), a pruritogen to trigger itch-evoked scratching, rash, or wheal (Imamachi et al., 2009; Kalz and Fekete, 1960; Nojima and…”
Influential
Perioperative Pain Management
Pyati, S., & Gan, T. J. (2007) · CNS Drugs · doi:10.2165/00023210-200721030-00002 · Cited by 189
Transient receptor potential vanilloid subfamily 1 expressed in pancreatic islet β cells modulates insulin secretion in rats
Akiba, Y., Kato, S., Katsube, K.-I., Nakamura, M., Takeuchi, K., Ishii, H., & Hibi∥, T. (2004) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2004.06.149 · Cited by 190
Sensitization and Translocation of TRPV1 by Insulin and IGF-I
Buren, J. J. V., Bhat, S. G., Rotello, R., Pauza, M. E., & Premkumar, L. S. (2005) · Molecular Pain · doi:10.1186/1744-8069-1-17 · Cited by 189
“TRPV1 is a Ca 2+ permeable nonspecific cation channel, located on peripheral sensory neurons, that serves as a molecular detector for heat, capsaicin, protons, and endovanilloids [ 1-4 ].”
Background
Pain hypersensitivity mechanisms at a glance
Gangadharan, V., & Kuner, R. (2013) · Disease Models & Mechanisms · doi:10.1242/dmm.011502 · Cited by 187
“…of these molecules via transcriptional regulation (e.g. via recruitment of STAT transcription factors), thus leading to an acute as well as a longterm increase in the excitability of nociceptors (Dib-Hajj et al., 1998; Julius and Basbaum, 2001; Schweizerhof et al., 2009; Zhang et al., 2005).”
BackgroundInfluential
Selective Inflammatory Pain Insensitivity in the African Naked Mole-Rat (Heterocephalus glaber)
Park, T. J., Lu, Y. C., Jüttner, R., Smith, E. S. J., Hu, J., Brand, A., Wetzel, C., Milenkovic, N., Erdmann, B., Heppenstall, P. A., et al. (2008) · PLoS Biology · doi:10.1371/journal.pbio.0060013 · Cited by 183
“Nevertheless the concentrations of capsaicin that we used in the skin nerve preparation were high, considering the low nanomolar affinity that TRPV1 has for capsaicin [1,11].”
Modification of classical neurochemical markers in identified primary afferent neurons with Aβ‐, Aδ‐, and C‐fibers after chronic constriction injury in mice
Ruscheweyh, R., Forsthuber, L., Schoffnegger, D., & Sandkühler, J. (2007) · The Journal of Comparative Neurology · doi:10.1002/cne.21311 · Cited by 183
“This classification is functionally important because about 90% of the neurons with C-fibers and 70% of the neurons with A -fibers are nociceptors, whereas 80% of the neurons with A -fibers conduct nonnociceptive information (Julius and Basbaum, 2001; Hunt and Mantyh, 2001; Fang et al., 2005).”
Background
Thermodynamics of Heat Activation of Single Capsaicin Ion Channels VR1
Liu, B., Hui, K., & Qin, F. (2003) · Biophysical Journal · doi:10.1016/s0006-3495(03)74719-5 · Cited by 181
Protein Kinase A Anchoring via AKAP150 Is Essential for TRPV1 Modulation by Forskolin and Prostaglandin E2in Mouse Sensory Neurons
Schnizler, K., Shutov, L. P., Kanegan, M. J. V., Merrill, M. A., Nichols, B., McKnight, G. S., Strack, S., Hell, J. W., & Usachev, Y. M. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.0233-08.2008 · Cited by 182
Contribution of vanilloid receptors to the overt nociception induced by B2 kinin receptor activation in mice
Ferreira, J., da Silva, G. L., & Calixto, J. Β. (2004) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0705546 · Cited by 180
Voltage-gated sodium channel modulation by scorpion α-toxins
Bosmans, F., & Tytgat, J. (2006) · Toxicon · doi:10.1016/j.toxicon.2006.09.023 · Cited by 179
“In the literature there is ample evidence that several VGSCs are also major players in pain sensation (Baker and Wood, 2001; Julius and Basbaum, 2001).”
Background
Primary Afferent Activation of Thermosensitive TRPV1 Triggers Asynchronous Glutamate Release at Central Neurons
Peters, J. H., McDougall, S. J., Fawley, J. A., Smith, S. M., & Andresen, M. C. (2010) · Neuron · doi:10.1016/j.neuron.2010.02.017 · Cited by 181
“However, since temperature and pH are relatively constant in the brain, the function of TRPV1 in the CNS remains unclear (Gibson et al., 2008; Julius and Basbaum, 2001).”
Influential
From preemptive to preventive analgesia
Pogatzki-Zahn, E. M., & Zahn, P. K. (2006) · Current Opinion in Anaesthesiology · doi:10.1097/01.aco.0000245283.45529.f9 · Cited by 178
Persistent Pain Produces Stress-like Alterations in Hippocampal Neurogenesis and Gene Expression
Đurić, V., & McCarson, K. E. (2006) · Journal of Pain · doi:10.1016/j.jpain.2006.01.458 · Cited by 183
Biology of Blood-Sucking Insects
Lehane, M. J. (1991) · Springer eBooks · doi:10.1007/978-94-011-7953-9 · Cited by 177
MicroRNAs as modulators and biomarkers of inflammatory and neuropathic pain conditions
Andersen, H. H., Duroux, M., & Gazerani, P. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.08.003 · Cited by 175
Identification of a G Protein-coupled Receptor Specifically Responsive to β-Alanine
Shinohara, T., Harada, M., Ogi, K., Maruyama, M., Fujii, R., Tanaka, H., Fukusumi, S., Komatsu, H., Hosoya, M., Noguchi, Y., et al. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m314240200 · Cited by 177
Gray Matter Volumes of Pain-Related Brain Areas Are Decreased in Fibromyalgia Syndrome
Robinson, M. E., Craggs, J. G., Price, D. D., Perlstein, W. M., & Staud, R. M. (2010) · Journal of Pain · doi:10.1016/j.jpain.2010.10.003 · Cited by 175
Macrophage‐derived insulin‐like growth factor‐1 is a key neurotrophic and nerve‐sensitizing factor in pain associated with endometriosis
Forster, R., Sarginson, A., Velichkova, A. N., Hogg, C., Dorning, A., Horne, A. W., Saunders, P. T. K., & Greaves, E. (2019) · The FASEB Journal · doi:10.1096/fj.201900797r · Cited by 176
“Repeated interactions between peripheral sensory afferents (nociceptors) and cytokines and neurotrophins have been shown in other chronic pain conditions to cause nerve sensitization: an enhanced responsiveness of afferents (10), leading to a resultant increase in excitability of the nervous system and triggering pain…”
Background
TRPA1 receptors mediate environmental irritant-induced meningeal vasodilatation
Kunkler, P. E., Ballard, C. J., Oxford, G. S., & Hurley, J. H. (2010) · Pain · doi:10.1016/j.pain.2010.08.021 · Cited by 174
“TRPA1 receptors are often colocalized with the inflammatory peptides substance P and calcitonin gene-related peptide (CGRP) in primary sensory neurons [6,45] and neuronal activation leads to release of these peptides [21] producing neurogenic inflammation and vasodilatation in the dura [31,42].”
A TRPV2–PKA Signaling Module for Transduction of Physical Stimuli in Mast Cells
Stokes, A. J., Shimoda, L. M. N., Koblan‐Huberson, M., Adra, C. N., & Turner, H. C. (2004) · The Journal of Experimental Medicine · doi:10.1084/jem.20032082 · Cited by 174
“TRPV1 was expression cloned by virtue of its ability to confer responses to the nociomimetic lipid capsaicin upon an epithelial cell line and is activated after exposure to pathophysiological temperatures ( 42 C) (18, 19).”
Background
Similar nociceptive afferents mediate psychophysical and electrophysiological responses to heat stimulation of glabrous and hairy skin in humans
Iannetti, G. D., Zambreanu, L., & Tracey, I. (2006) · The Journal of Physiology · doi:10.1113/jphysiol.2006.115675 · Cited by 174
Delayed Upregulation of ATP P2X3 Receptors of Trigeminal Sensory Neurons by Calcitonin Gene-Related Peptide
Fabbretti, E., D’Arco, M., Fabbro, A., Simonetti, M., Nistri, A., & Giniatullin, R. A. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.0647-06.2006 · Cited by 173
“CGRP has no effect on TRPV1 receptor function Because TG neurons also express capsaicin-sensitive TRPV1 receptors as transducers of nociception (Julius and Basbaum, 2001; Wang and Woolf, 2005), we explored whether CGRP treatment (1 M) preincubated for 1 h could modify them.”
The signaling pathways of traditional Chinese medicine in promoting diabetic wound healing
Zhou, X., Guo, Y., Yang, K., Liu, P., & Wang, J. (2021) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2021.114662 · Cited by 173
Antidepressant Agents for the Treatment of Chronic Pain and Depression
Jann, M. W., & Slade, J. H. (2007) · Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy · doi:10.1592/phco.27.11.1571 · Cited by 172
“Pain has been described as a complex emotional experience involving not only the transduction of noxious stimuli, but also cognitive and emotional processing by the brain.(4) Pain is not homogeneous and involves multiple genetic and biochemical mechanisms, nervous system pathways, and neuronal plasticity.”
BackgroundInfluential
TRPV1: A Potential Drug Target for Treating Various Diseases
Brito, R., Sheth, S., Mukherjea, D., Rybak, L. P., & Ramkumar, V. (2014) · Cells · doi:10.3390/cells3020517 · Cited by 172
“Acidic conditions normally occur during hypoxia, ischemia and inflammation [27].”
Background
Matrix metalloprotease regulation of neuropathic pain
Ji, R., Xu, Z., Wang, X., & Lo, E. H. (2009) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2009.04.002 · Cited by 171
“Early studies focused on neuronal mechanisms of neuropathic pain and established that neuropathic pain is an expression of neural plasticity both in the PNS (peripheral sensitization) and CNS (central sensitization) [10-12].”
Beyond metaphor: Contrasting mechanisms of social and physical pain
Iannetti, G. D., Salomons, T. V., Moayedi, M., Mouraux, A., & Davis, K. D. (2013) · Trends in Cognitive Sciences · doi:10.1016/j.tics.2013.06.002 · Cited by 166
“The nociceptive system has dedicated peripheral receptors with speciﬁc molecular transduction mechanisms [47–51], as well as speciﬁc spinal and supraspinal projections [52–54].”
Osteoclasts play a part in pain due to the inflammation adjacent to bone
Nagae, M., Hiraga, T., Wakabayashi, H., Wang, L., Iwata, K., & Yoneda, T. (2006) · Bone · doi:10.1016/j.bone.2006.04.033 · Cited by 168
“Because hyperalgesia is a widely accepted indicator for pain [12,18,31], these results collectively suggest that osteoclasts contribute to the pain due to the inflammation around bone.”
Disruption of ErbB receptor signaling in adult non-myelinating Schwann cells causes progressive sensory loss
Chen, S., Río, C., Ji, R., Dikkes, P., Coggeshall, R. E., Woolf, C. J., & Corfas, G. (2003) · Nature Neuroscience · doi:10.1038/nn1139 · Cited by 167
Understanding how opioids contribute to reward and analgesia
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Cytokine Signaling Mediates UV-Induced Nociceptive Sensitization in Drosophila Larvae
Babcock, D. T., Landry, C., & Galko, M. J. (2009) · Current Biology · doi:10.1016/j.cub.2009.03.062 · Cited by 171
“Some of these mediators, such as the inflammatory cytokines tumor necrosis factor-alpha (TNF-a) and interleukin-1b (IL-1b), are proteinaceous, whereas others are lipids (prostaglandins), peptides (kinins and Substance P), or small-molecule neurotransmitters such as ATP and serotonin [4–7].”

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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