Neuronal plasticity: Increasing the gain in pain
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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Central sensitization is initiated by peripheral sensitization and maintained by continued input from sensitized sensory afferent fibers to the central nervous system.
“Central sensitization is initiated by peripheral sensitization (Fig. 1) and maintained by continued input to the CNS from sensitized sensory afferent fibers”
From Chronic pelvic pain and endometriosis: translational evidence of the relationship and implications (2011) · cites this paper as Woolf and Salter, 2000
Central pain sensitization results from neuronal plasticity involving structural and functional changes in the central nervous system.
“Central pain sensitization (CPS) results from neuronal plasticity that involves structural and functional changes in the central nervous system (CNS).”
From Effectiveness of acceptance and commitment therapy in central pain sensitization syndromes: A systematic review (2021) · cites this paper as [1]
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Corticostriatal functional connectivity predicts transition to chronic back pain
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Pain: Moving from Symptom Control toward Mechanism-Specific Pharmacologic Management
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“The neuropeptides act on G-protein–coupled receptors to produce slow, more sustained synaptic currents than does glutamate, and brain-derived neurotrophic factor acts on tyrosine kinase receptor B to modify membrane excitability (14).”
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“activation of nociceptive specific sensory fibers and promotes intracellular events that contribute to central sensitization, which can manifest at both behavioral and cellular levels (Woolf and Salter, 2000).”
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“Animal models of neuropathic and/or inflammatory injuries that cause a persistent pain condition suggest that peripheral and spinal cord circuitry transmitting nociceptive signals cephalad undergoes dramatic reorganization (Woolf and Salter, 2000, 2006).”
Beyond Feeling: Chronic Pain Hurts the Brain, Disrupting the Default-Mode Network Dynamics
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“Mechanistically, the early stages of this cortical reorganization may be driven by peripheral and spinal cord events, such as those that have been documented in animal models of chronic pain (Woolf and Salter, 2000; Julius and Basbaum, 2001), whereas later events may be related to coping strategies necessary for livin…”
BackgroundMicroglia in neuropathic pain: cellular and molecular mechanisms and therapeutic potential
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“Exciting progress is being made in dissecting out the molecular and cellular mechanisms that operate in sensory pathways to generate those neural signals that we ultimately interpret as pai”
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“They might contribute to the functional reorganization of the spinal circuitry, but they could also be involved in maladaptive changes such as neurogenic pain or spasticit”
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“Upregulation of NMDARs seems to be crucial for the initiation and maintenance of the enhanced responsiveness of nociceptive neurons in the dorsal horn of the spinal cord that occurs in experimental pain model”
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Nociception, pain, negative moods, and behavior selection
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“They are also central to the pathogenesis of various neurological and psychiatric diseases, including neurodegenerative disorders (Arundine and Tymianski, 2003), chronic pain (Woolf and Salter, 2000), and schizophrenia (Lin et al.”
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Beyond Neurons: Evidence That Immune and Glial Cells Contribute to Pathological Pain States
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The amygdala and persistent pain
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Role of interleukin-1β during pain and inflammation
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Spinal Glia and Proinflammatory Cytokines Mediate Mirror-Image Neuropathic Pain in Rats
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American Pain Society Recommendations for Improving the Quality of Acute and Cancer Pain Management
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GLIA: A novel drug discovery target for clinical pain
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“For example, injured peripheral nerves can exhibit a number of changes: spontaneous activity can occur that signals the presence of noxious stimuli despite the fact that no such stimulus is present; novel receptors for stress hormones can be expressed, such that sympathetic activation subsequently evokes pain in peopl…”
BackgroundThe development of nociceptive circuits
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“This raises the intriguing possibility that some of the key signalling pathways for neuropathic pai”
BackgroundTFOS DEWS II pain and sensation report
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“Typically, in nociceptors this includes increased expression of TRPV1 channels and various NaV channels [358].”
Chronic pain may change the structure of the brain
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“peripheral, spinal and cerebral nervous system [25,40,50,80].”
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“AMPA and NMDA currents) or/and a reduction in inhibitory synaptic transmission (e.g. GABA currents) [ 7-9 ].”
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“It is not the aim of this article to review the mechanisms of neuropathic pain, and we encourage the reader to see the many excellent reviews on the subject (Costigan et al., 2009b; Latremoliere and Woolf, 2009; Woolf, 2004; Woolf and Salter, 2000).”
GlyR α3: An Essential Target for Spinal PGE 2 -Mediated Inflammatory Pain Sensitization
Harvey, R. J., Depner, U. B., Wässle, H., Ahmadi, S., Heindl, C., Reinold, H., Smart, T. G., Harvey, K., Schütz, B., Abo‐Salem, O. M., et al. (2004) · Science · doi:10.1126/science.1094925 · Cited by 623 · see citing works
Resolvins RvE1 and RvD1 attenuate inflammatory pain via central and peripheral actions
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“Central sensitization manifests as increased sensitivity in spinal cord dorsal horn neurons after tissue and nerve injury and plays an essential role in persistent pain sensitization (Woolf and Salter, 2000).”
BackgroundNeurophysiologic evidence for a central sensitization in patients with fibromyalgia
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“This is further facilitated by a rise in intracellular calcium (due to the release of calcium from internal stores) and the activation of calcium-dependent protein kinases which then phosphorylate the NMDA receptor channel and facilitate glutamate-evoked channel conductance (457).”
BackgroundAstrocytes in chronic pain and itch
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Chronic pain patients are impaired on an emotional decision-making task
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“The effect is to generate a more urgent, localized, and rapid pain signal by suppressing surrounding neuronal activity [45].”
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“Regarding chronic pain, a lot of thought has been devoted to considering changes in primary afferents, dorsal root ganglia, and spinal cord dorsal horn (Woolf and Salter, 2000).”
BackgroundPathogenesis, Diagnosis, and Treatment of Lumbar Zygapophysial (Facet) Joint Pain
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“tion, and if the underlying stimulus is not removed, central sensitization and neuroplasticity can develop.(85)”
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“…plasticity in the dorsal horn postulate that induction of the spinal plasticity requires activation of intracellular signaling events including protein kinases for transcriptional and posttranscriptional modifications of various proteins such as cell surface receptors (Woolf and Salter, 2000).”
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“NMDARs are prominently involved in activity-dependent synaptic plasticity and persistent pain (Ren and Dubner, 1999; Woolf and Salter, 2000).”
BackgroundMolecular mechanisms of cancer pain
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“After tissue injury, many nociceptors alter their patterns of signalling-peptide and growth-factor expressio”
BackgroundWhen does acute pain become chronic?
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“The increased neuronal excitability appears to result from post-translational regulation, such as phosphorylation, of key membrane receptors and channels (Woolf and Salter, 2000; Ji and Woolf, 2001).”
BackgroundThe Symptoms of Osteoarthritis and the Genesis of Pain
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“…central neural processing can be ‘modified’ so that initially peripherally induced central sensitization becomes independent of peripheral sensitization (Woolf and Salter, 2000) via neural mechanisms similar to those underlying memory (Melzack et al., 2001; Ji et al., 2003a; Ren and Dubner, 2007).”
BackgroundReactive oxygen species (ROS) play an important role in a rat model of neuropathic pain
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BackgroundMorphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl− homeostasis
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RetractedReversal of pathological pain through specific spinal GABAA receptor subtypes
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“These include afferent activity-evoked central sensitization (Woolf and Salter, 2000), microglia activation (Tsuda et al., 2005), and altered modulation of sensory transmission by pathways descending from the brainstem (Mantyh and Hunt, 2004; Suzuki et al., 2004).”
Background
- Authors
- Woolf, C. J., & Salter, M. W.
- Affiliations
- Harvard University (US)
- University of Toronto (CA)
- Corresponding author
- Woolf, Clifford J.
- Venue
- Science
- Published
- 2000-06-09
- Volume
- 288
- Issue
- 5472
- Pages
- 1765-1768
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- 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 › 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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