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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Spinal administration of a δ opioid receptor agonist attenuates hyperalgesia and allodynia in a rat model of neuropathic pain
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Efficacy and safety of a single intrathecal methylprednisolone bolus in chronic complex regional pain syndrome
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Increase in Reactive Oxygen Species and Activation of Akt Signaling Pathway in Neuropathic Pain
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“It has been reported that several mediators and neurotransmitters participate in central sensitization ( Woolf and Salter 2000 ).”
Background
P2X4 purinoceptor signaling in chronic pain
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“synaptic connectivity and the reorganization of peripheral and central nociceptive circuitry [62, 83, 84, 89].”
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Combined Preoperative Use of Celecoxib and Gabapentin in the Management of Postoperative Pain
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Neurophysiological Correlates of Nociceptive Heterosynaptic Long-Term Potentiation in Humans
van den Broeke, E. N., van Rijn, C. M., Manresa, J. A. B., Andersen, O. K., Arendt‐Nielsen, L., & Wilder‐Smith, O. H. G. (2010) · Journal of Neurophysiology · doi:10.1152/jn.00979.2009 · Cited by 65
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“The threshold of primary afferent neurons to various stimuli is not fixed, but rather can be become sensitized during inflammation (4).”
Background
Sexual dimorphism for protein kinase cε signaling in a rat model of vincristine-induced painful peripheral neuropathy
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Acute pancreatitis results in referred mechanical hypersensitivity and neuropeptide up-regulation that can be suppressed by the protein kinase inhibitor k252a
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Activation of protein kinase C sensitizes human VR1 to capsaicin and to moderate decreases in pH at physiological temperatures in Xenopus oocytes
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“It is well known that tissue damage resulting from mechanical, thermal, or chemical insults produces an array of inflammatory mediators that trigger biochemical cascades, leading to development of hyperalgesia (Bevan, 1999; Woolf and Salter, 2000).”
Altered pain-related behaviors and spinal neuronal responses produced by s.c. injection of melittin in rats
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A comparison of oral midazolam and nitrous oxide sedation for dental extractions in children
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The Neurobiology of Nociceptive and Anti-nociceptive Systems
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“…of unmyelinated primary afferents (Apfel et al., 1996; Michael et al., 1997, 1999) and was repeatedly proposed to participate in central sensitization and inflammatory pain states (Kerr et al., 1999; Mannion et al., 1999; Woolf & Salter, 2000), as originally suggested by Snider & McMahon (1998).”
Analgesia Induced by Dietary Restriction Is Mediated by the κ-Opioid System
Santos-Arteaga, M. D. L., Sierra-Domínguez, S. A., Fontanella, G. H., Delgado-García, J. M., & Carrión, Á. M. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-35-11120.2003 · Cited by 64
“Prodynorphin blocks the nociceptive information flow through the spinal cord Nociceptive information is transmitted through a “pain pathway,” which begins at the periphery, with the stimulusdependent activation of nociceptive terminals, runs through the spinal cord, and eventually reaches the brainstem and forebrain,…”
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Light touch induces ERK activation in superficial dorsal horn neurons after inflammation: involvement of spinal astrocytes and JNK signaling in touch‐evoked central sensitization and mechanical allodynia
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Spontaneous Behavioral Responses in the Orofacial Region: A Model of Trigeminal Pain in Mouse
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High force reaching task induces widespread inflammation, increased spinal cord neurochemicals and neuropathic pain
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IL-1β signaling is required for mechanical allodynia induced by nerve injury and for the ensuing reduction in spinal cord neuronal GRK2
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“include changes in expression and responsiveness of receptors, activation of several kinases, release of neuropeptides and neurotrophins, and local production of inflammatory mediators (Kim et al., 2002; Milligan et al., 2005; Obata et al., 2004; Woolf and Salter, 2000; Yashpal et al., 2001).”
Cysteine-Rich Protein 2, a Novel Downstream Effector of cGMP/cGMP-Dependent Protein Kinase I-Mediated Persistent Inflammatory Pain
Schmidtko, A., Gao, W., Sausbier, M., Rauhmeier, I., Sausbier, U., Niederberger, E., Scholich, K., Huber, A., Neuhuber, W., Allescher, H., et al. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.5037-07.2008 · Cited by 64
“This sensitization of the nociceptive system contributes to chronic pain, a major medical problem (Woolf, 1983; Woolf and Salter, 2000; Julius and Basbaum, 2001; Scholz and Woolf, 2002).”
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Peripheral inflammation increased the synaptic expression of NMDA receptors in spinal dorsal horn
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Translational Investigation and Treatment of Neuropathic Pain
Xu, B., Descalzi, G., Ye, H.-R., Zhuo, M., & Wang, Y. (2012) · Molecular Pain · doi:10.1186/1744-8069-8-15 · Cited by 63
“Many recent studies employ chronic constriction injuries [4,5], spared nerve ligation [6,7] or common peroneal nerve ligation (CPN) [8,9], which include injury of, but not severing of peripheral nerves.”
Background
Corneal Nerve and Epithelial Cell Alterations in Corneal Allodynia: An In Vivo Confocal Microscopy Case Series
Hamrah, P., Qazi, Y., Shahatit, B. M., Dastjerdi, M. H., Pavan‐Langston, D., Jacobs, D. S., & Rosenthal, P. (2016) · The Ocular Surface · doi:10.1016/j.jtos.2016.10.002 · Cited by 64
Mouse strains that lack spinal dynorphin upregulation after peripheral nerve injury do not develop neuropathic pain
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Key Components of Pain Management for Children and Adults with Sickle Cell Disease
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The Role of Neuroglial Crosstalk and Synaptic Plasticity-Mediated Central Sensitization in Acupuncture Analgesia
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“During the process, the activated glia can release prostaglandin, BDNF, nitric oxide, and other neuroactive substances; reduce the inhibitory effects of GABA; and upregulate the expression of NMDARs, thereby increasing nerve excitability and maintaining neuropathic pain [22, 113].”
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Allergen-induced substance P synthesis in large-diameter sensory neurons innervating the lungs
Chuaychoo, B., Hunter, D. D., Myers, A. C., Kollárik, M., & Undem, B. J. (2005) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2005.04.005 · Cited by 63
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“role in synaptic plasticity and chronic pain formation [47].”
Background

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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