Cited by 3,781Pain Mechanisms and TreatmentsPain Management and TreatmentNeuroscience and Neuropharmacology Research

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Neuronal Plasticity: Increasing the Gain in Pain

Woolf, Clifford J., Salter, Michael W.·2000·Science

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Abstract

We describe those sensations that are unpleasant, intense, or distressing as painful. Pain is not homogeneous, however, and comprises three categories: physiological, inflammatory, and neuropathic pain. Multiple mechanisms contribute, each of which is subject to or an expression of neural plasticity-the capacity of neurons to change their function, chemical profile, or structure. Here, we develop a conceptual framework for the contribution of plasticity in primary sensory and dorsal horn neurons to the pathogenesis of pain, identifying distinct forms of plasticity, which we term activation, modulation, and modification, that by increasing gain, elicit pain hypersensitivity.

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Crossref · 10.1126/science.288.5472.1765

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Background
The c-Jun N-terminal kinase 1 (JNK1) in spinal astrocytes is required for the maintenance of bilateral mechanical allodynia under a persistent inflammatory pain condition
Gao, Y., Xu, Z., Liu, Y., Wen, Y., Décosterd, I., & Ji, R. (2009) · Pain · doi:10.1016/j.pain.2009.11.017 · Cited by 159
“It is generally believed that activation of large A-fibers (Ab) are necessary for inducing mechanical allodynia [29,41,55,67].”
Background
N-Methyl-d-aspartate Receptor- and Calpain-mediated Proteolytic Cleavage of K+-Cl− Cotransporter-2 Impairs Spinal Chloride Homeostasis in Neuropathic Pain
Zhou, H.-Y., Chen, S.-R., Byun, H., Chen, H., Li, L., Han, H., Lopez‐Berestein, G., Sood, A. K., & Pan, H. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.395830 · Cited by 159
“Activity-dependent synaptic plasticity at the spinal cord level is fundamentally important to the development of neuropathic pain (1).”
Background
Neurophysiologic and quantitative sensory testing in the diagnosis of trigeminal neuropathy and neuropathic pain
Jääskeläinen, S. K., Teerijoki‐Oksa, T., & Forssell, H. (2005) · Pain · doi:10.1016/j.pain.2005.06.028 · Cited by 159
Differential Role of N-Type Calcium Channel Splice Isoforms in Pain
Altier, C., Dale, C. S., Kisilevsky, A. E., Chapman, K., Castiglioni, A. J., Matthews, E. A., Evans, R. M., Dickenson, A. H., Lipscombe, D., Vergnolle, N., et al. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.0307-07.2007 · Cited by 159
“Detection and transmission of nociceptive stimuli in dorsal root ganglion (DRG) neurons is mediated by several types of ion channels, such as persistent Na channels, inwardly rectifying K channels, and voltage-gated Ca 2 channels, which regulate either cellular excitability or synaptic transmission (McCleskey and Gold…”
Background
CXCL1/CXCR2 signaling in pathological pain: Role in peripheral and central sensitization
Silva, R. L., Lopes, A. H., Guimarães, R. M., & Cunha, T. M. (2017) · Neurobiology of Disease · doi:10.1016/j.nbd.2017.06.001 · Cited by 161
In vivo recruitment by painful stimuli of AMPA receptor subunits to the plasma membrane of spinal cord neurons
Galán, A., Laird, J. M. A., & Cerveró, F. (2004) · Pain · doi:10.1016/j.pain.2004.09.011 · Cited by 157
“Hyperalgesia is an increase in pain sensitivity triggered by intense noxious stimulation and maintained by a state of central hyperexcitability (central sensitization) (Cervero and Laird, 2004; Treede et al., 1992; Woolf and Salter, 2000).”
Background
Phenotypes of Gastroesophageal Reflux Disease: Where Rome, Lyon, and Montreal Meet
Katzka, D. A., Pandolfino, J. E., & Kahrilas, P. J. (2019) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2019.07.015 · Cited by 157
“Other investigations suggest alterations in central pain perception with accelerated and enhanced pain transmission at the spinal level and attenuated descending inhibition [16].”
Background
Interactions of inflammatory pain and morphine in infant rats: long-term behavioral effects
Bhutta, A. T., Rovnaghi, C. R., Simpson, P. M., Gossett, J. M., Scalzo, F. M., & Anand, K. J. S. (2001) · Physiology & Behavior · doi:10.1016/s0031-9384(01)00432-2 · Cited by 157
Evidence of Nervous System Sensitization in Commonly Presenting and Persistent Painful Tendinopathies: A Systematic Review
Plinsinga, M. L., Brink, M. S., Vicenzino, B., & van Wilgen, C. P. (2015) · Journal of Orthopaedic and Sports Physical Therapy · doi:10.2519/jospt.2015.5895 · Cited by 155
“13 Collectively the data on widespread mechanical hyperalgesia and nociceptive flexion reflex 248 might be suggestive of centrally mediated hyper excitability underlying mechanisms of 249 chronic tendon pain.(58) 250 251 There appears a characteristic feature of sensitization emerging from the literature on 252 persis…”
Background
Stigmatization of Patients with Chronic Pain: The Extinction of Empathy
Cohen, M. L., Quintner, J. L., Buchanan, D., Nielsen, M., & Guy, L. (2011) · Pain Medicine · doi:10.1111/j.1526-4637.2011.01264.x · Cited by 155
Forebrain-mediated sensitization of central pain pathways: ‘non-specific’ pain and a new image for MT
Zusman, M. (2002) · Manual Therapy · doi:10.1054/math.2002.0442 · Cited by 158
“The effect is to generate a more urgent, localized and rapid pain signal by suppressing surrounding extraneous neuronal activity (Woolf & Salter 2000).”
Background
Efficacy of melatonin in the treatment of endometriosis: A phase II, randomized, double-blind, placebo-controlled trial
Schwertner, A., Conceição dos Santos, C. C., Costa, G. D., Deitos, A., de Souza, A., de Souza, I. C. C., Torres, I. L. S., da Cunha Filho, J. S. L., & Caumo, W. (2013) · Pain · doi:10.1016/j.pain.2013.02.025 · Cited by 155
“Although the full pathophysiology of CPP remains unknown, cumulative evidence suggests that peripheral and central sensitization result in an amplification of sensory impulses [63].”
Background
Spinal NMDA receptor phosphorylation correlates with the presence of neuropathic signs following peripheral nerve injury in the rat
Ultenius, C., Linderoth, B., Meyerson, B. A., & Wallin, J. (2006) · Neuroscience Letters · doi:10.1016/j.neulet.2006.01.018 · Cited by 154
Pain-like behaviours in animals ? how human are they?
Blackburn-Munro, G. (2004) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2004.04.008 · Cited by 159
“tropic glutamate receptors] in the peripheral and central sensitizing responses that occur in nociceptive pathways after tissue injury [1, 2 ]; these responses contribute to the behavioural correlates of HYPERALGESIA and ALLODYNIA in response to a diverse range of sensory stimuli [1].”
Background
A common thread for pain and memory synapses? Brain-derived neurotrophic factor and trkB receptors
Malcangio, M., & Leßmann, V. (2003) · Trends in Pharmacological Sciences · doi:10.1016/s0165-6147(03)00025-7 · Cited by 155
“In the dorsal horn, activation of trkB receptors by endogenous BDNF appears to contribute to the hyperalgesia that is associated with peripheral inflammation [ 37 ], and it has been suggested that BDNF contributes to sensitization of dorsal horn neurones (e.g.”
Background
Ibudilast (AV-411)
Ledeboer, A., Hutchinson, M. R., Watkins, L. R., & Johnson, K. W. (2007) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.16.7.935 · Cited by 153
“, in the spinal cord dorsal horn) become sensitized (hyperexcitable), signaling pain despite the absence of painful stimuli [3-5] .”
Background
Outcome Predictors for Sacroiliac Joint (Lateral Branch) Radiofrequency Denervation
Cohen, S. P., Strassels, S. A., Kurihara, C., Crooks, M. T., Erdek, M. A., Forsythe, A., & Marcuson, M. (2009) · Regional Anesthesia & Pain Medicine · doi:10.1097/aap.0b013e3181958f4b · Cited by 153
“This may reflect the extent of neuroplasticity that develops secondary to persistent pain, a greater degree of intractability, or a higher prevalence of concomitant psychosocial issues.(35,36) With respect to age, prior studies have not identified a reliable independent relationship with outcome.”
Result
Clinical use of brain volumetry
Giorgio, A., & Stefano, N. D. (2012) · Journal of Magnetic Resonance Imaging · doi:10.1002/jmri.23671 · Cited by 153
“In other words, chronic pain might be regarded as a manifestation of neuronal plasticity (99,100).”
Background
Activation of JNK pathway in persistent pain
Gao, Y., & Ji, R. (2008) · Neuroscience Letters · doi:10.1016/j.neulet.2008.03.017 · Cited by 153
“Although it is generally believed that chronic pain is caused by neural plasticity that occurs both in the peripheral nervous system (peripheral sensitization) and central nervous system (central sensitization), the mechanisms underlying the induction and maintenance of chronic pain are incompletely understood [15,46].”
Background
Pain assessment and management in children in the postoperative period: A review of the most commonly used postoperative pain assessment tools, new diagnostic methods and the latest guidelines for postoperative pain therapy in children
Zieliński, J., Morawska–Kochman, M., & Zatoński, T. (2020) · Advances in Clinical and Experimental Medicine · doi:10.17219/acem/112600 · Cited by 153
“1 Pain is one of the most common complaints experienced by hospital patients 2 and is the main reason they seek medical help.”
Background
Inflammation induced by Bothrops asper venom
Teixeira, C., Cury, Y., Moreira, V., Picolo, G., & Chaves, F. (2009) · Toxicon · doi:10.1016/j.toxicon.2009.03.019 · Cited by 152
Spreading of complex regional pain syndrome: not a random process
van Rijn, M. A., Marinus, J., Putter, H., Bosselaar, S. R. J., Moseley, G. L., & van Hilten, J. J. (2011) · Journal of Neural Transmission · doi:10.1007/s00702-011-0601-1 · Cited by 152
“This accelerated occurrence has been documented for clinical manifestations of other diseases and probably reflects changes in the central nervous system, perhaps in an attempt to adapt to the altered condition by remodelling of neuronal contacts and circuits, a process also known as neuronal plasticity (Harrison 1999…”
Current Understandings on Complex Regional Pain Syndrome
de Mos, M., Sturkenboom, M., & Huygen, F. J. P. M. (2009) · Pain Practice · doi:10.1111/j.1533-2500.2009.00262.x · Cited by 152
“Spinal neuronal sensitization can follow upon continuous nociceptive input or nerve injury, and comprises a state of hyperexcitability and disinhibition, causing a decreased stimulation threshold.(29) Eventually, this can cause a normally nonpainful stimulus to become painful.”
Background
A Comparison of Gabapentin and Ketamine in Acute and Chronic Pain After Hysterectomy
Şen, H., Sızlan, A., Yanarateş, Ö., Emirkadı, H., Ozkan, S., Dağlı, G., & Turan, A. (2009) · Anesthesia & Analgesia · doi:10.1213/ane.0b013e3181b65ea0 · Cited by 151
“rons, and establishment of aberrant excitatory synaptic connections.(25) Because of their role in peripheral and”
Background
Protein kinase C in pain: Involvement of multiple isoforms
Velázquez, K. T., Mohammad, H. K., & Sweitzer, S. M. (2007) · Pharmacological Research · doi:10.1016/j.phrs.2007.04.006 · Cited by 151
Efficacy of the NMDA-receptor antagonist memantine in patients with chronic phantom limb pain – results of a randomized double-blinded, placebo-controlled trial
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Patients with sickle cell disease have increased sensitivity to cold and heat
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“hypersensitivity and/or allodynia and present as increased sensitivity to cold, heat, or mechanical stimuli [35,36].”
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Grading of monosodium iodoacetate-induced osteoarthritis reveals a concentration-dependent sensitization of nociceptors in the knee joint of the rat
Schuelert, N., & McDougall, J. J. (2009) · Neuroscience Letters · doi:10.1016/j.neulet.2009.08.063 · Cited by 150
BDNF sensitizes the response of lamina II neurons to high threshold primary afferent inputs
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Spinal cord injury‐induced attenuation of GABAergic inhibition in spinal dorsal horn circuits is associated with down‐regulation of the chloride transporter KCC2 in rat
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P2X4 receptors and neuropathic pain
Tsuda, M., Masuda, T., Tozaki‐Saitoh, H., & Inoue, K. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00191 · Cited by 154
“Extensive lines of evidence from basic pain research using diverse animal models of neuropathic pain indicated that neuropathic pain is a reflection of the aberrant excitability of dorsal horn neurons evoked by peripheral sensory inputs (Woolf and Salter, 2000; Costigan et al., 2009).”
Background
Excitatory interneurons dominate sensory processing in the spinal substantia gelatinosa of rat
Santos, S. F. A., Rebelo, S., Derkach, V. A., & Safronov, B. V. (2007) · The Journal of Physiology · doi:10.1113/jphysiol.2006.126912 · Cited by 148
Targeting Ca channels to treat pain: T-type versus N-type
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Changes in expression of sensory organ-specific microRNAs in rat dorsal root ganglia in association with mechanical hypersensitivity induced by spinal nerve ligation
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Authors: Woolf, C. J., & Salter, M. W.
Affiliations: Harvard University (US)
University of Toronto (CA)
Corresponding author: Woolf, Clifford J.
ORCID: Woolf, Clifford J.
Salter, Michael W.
Venue: Science
Publisher: American Association for the Advancement of Science (AAAS)
Published: 2000-06-09
Volume: 288
Issue: 5472
Pages: 1765-1768
ISSN: 0036-8075 (ISSN-L)
1095-9203
DOI: 10.1126/science.288.5472.1765
OpenAlex: W2133316133
Cited by: 3,781
References: 76
Citations by year: 2026: 62 · 2025: 101 · 2024: 96 · 2023: 104 · 2022: 99 · 2021: 99 · 2020: 129 · 2019: 112 · 2018: 124 · 2017: 140 · 2016: 150 · 2015: 170 · 2014: 142 · 2013: 188 · 2012: 166
FWCI: 13.94
Type: journal article
Language: en
Open access: closed
Locations: Science (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Physiology (medical) › Pain Mechanisms and Treatments
Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Treatment
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords: neuroplasticity, pain, hyperalgesia, primary sensory neurons, dorsal horn neurons, neuropathic pain, inflammatory pain, plasticity mechanisms, pain modulation
MeSH terms: Animals, Humans, Inflammation, Models, Neurological, Synaptic Transmission, Neuronal Plasticity, Neurons, Afferent, Nociceptors, Pain, Signal Transduction, Posterior Horn Cells, Peripheral Nerve Injuries

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Neuronal Plasticity: Increasing the Gain in Pain

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