Cortical excitation and chronic pain.
TL;DR: This review paper will critically examine the current literature and propose a cortical network model for chronic pain, which is based on human and mouse studies and molecular and synaptic mechanisms underlying relevant cortical plasticity.
About: This article is published in Trends in Neurosciences.The article was published on 2008-04-01. It has received 436 citations till now. The article focuses on the topics: Chronic pain & Neuroplasticity.
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TL;DR: Chronic pain could be a result of "gliopathy," that is, dysregulation of glial functions in the central and peripheral nervous system, and an update on recent advances is provided and remaining questions are discussed.
Abstract: Activation of glial cells and neuro–glial interactions are emerging as key mechanisms underlying chronic pain. Accumulating evidence has implicated 3 types of glial cells in the development and maintenance of chronic pain: microglia and astrocytes of the central nervous system (CNS), and satellite glial cells of the dorsal root and trigeminal ganglia. Painful syndromes are associated with different glial activation states: (1) glial reaction (ie, upregulation of glial markers such as IBA1 and glial fibrillary acidic protein (GFAP) and/or morphological changes, including hypertrophy, proliferation, and modifications of glial networks); (2) phosphorylation of mitogen-activated protein kinase signaling pathways; (3) upregulation of adenosine triphosphate and chemokine receptors and hemichannels and downregulation of glutamate transporters; and (4) synthesis and release of glial mediators (eg, cytokines, chemokines, growth factors, and proteases) to the extracellular space. Although widely detected in chronic pain resulting from nerve trauma, inflammation, cancer, and chemotherapy in rodents, and more recently, human immunodeficiency virus-associated neuropathy in human beings, glial reaction (activation state 1) is not thought to mediate pain sensitivity directly. Instead, activation states 2 to 4 have been demonstrated to enhance pain sensitivity via a number of synergistic neuro–glial interactions. Glial mediators have been shown to powerfully modulate excitatory and inhibitory synaptic transmission at presynaptic, postsynaptic, and extrasynaptic sites. Glial activation also occurs in acute pain conditions, and acute opioid treatment activates peripheral glia to mask opioid analgesia. Thus, chronic pain could be a result of ‘‘gliopathy,’’ that is, dysregulation of glial functions in the central and peripheral nervous system. In this review, we provide an update on recent advances and discuss remaining questions.
889 citations
Cites background from "Cortical excitation and chronic pai..."
...…history: Received 27 July 2012 Received in revised form 23 May 2013 Accepted 12 June 2013 Keywords: Astrocytes ATP receptors Chemokines Cytokines Human Microglia Rodents Satellite glial cells Spinal cord Activation of glial cells and neuro–glial interactions are emerging as key mechanisms…...
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...Ru-Rong Ji a,⇑, Temugin Berta a, Maiken Nedergaard b a Department of Anesthesiology and Neurobiology, Duke University Medical Center, Durham, NC, USA b Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, University of Rochester, Rochester, NY, USA a r t i c l e i n f o a b s t r a c t Article history: Received 27 July 2012 Received in revised form 23 May 2013 Accepted 12 June 2013 Keywords: Astrocytes ATP receptors Chemokines Cytokines Human Microglia Rodents Satellite glial cells Spinal cord Activation of glial cells and neuro–glial interactions are emerging as key mechanisms underlying chronic pain....
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TL;DR: Increasing evidence from rodent studies that ACC activation contributes to chronic pain states is discussed and several forms of synaptic plasticity that may underlie this effect are described.
Abstract: Evidence suggests that activity in the anterior cingulate cortex (ACC) contributes to acute and chronic pain. In this article, Zhuo and colleagues review the different types of synaptic plasticity observed in the ACC and the implications of these forms of plasticity for pain processing.
428 citations
TL;DR: It is found that protein kinase M zeta (PKMζ) maintains pain-induced persistent changes in the mouse anterior cingulate cortex (ACC) and could be a new therapeutic target for treating chronic pain.
Abstract: Synaptic plasticity is a key mechanism for chronic pain It occurs at different levels of the central nervous system, including spinal cord and cortex Studies have mainly focused on signaling proteins that trigger these plastic changes, whereas few have addressed the maintenance of plastic changes related to chronic pain We found that protein kinase M zeta (PKMζ) maintains pain-induced persistent changes in the mouse anterior cingulate cortex (ACC) Peripheral nerve injury caused activation of PKMζ in the ACC, and inhibiting PKMζ by a selective inhibitor, ζ-pseudosubstrate inhibitory peptide (ZIP), erased synaptic potentiation Microinjection of ZIP into the ACC blocked behavioral sensitization These results suggest that PKMζ in the ACC acts to maintain neuropathic pain PKMζ could thus be a new therapeutic target for treating chronic pain
352 citations
TL;DR: Results of clinical studies in neuropathic pain patients suggest that neuroimaging may help determine mechanisms of altered brain functions in pain as well as monitor the effects of pharmacologic interventions to optimize treatment in individual patients.
326 citations
Cites background or result from "Cortical excitation and chronic pai..."
...It should be noted, however, that activation of the ACC (Calejesan et al., 2000; Zhuo, 2008) or disinhibition of the insula (Jasmin et al....
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...…2003), S2 likely has additional affective/cognitive functions, while the insula and ACC are important for affective-motivational and certain cognitive aspects of pain, including anticipation, attention and evaluation (Seminowicz et al., 2004; Apkarian et al., 2005; Ohara et al., 2005; Zhuo, 2008)....
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...S1 cortex is generally associated with sensorydiscriminative aspects (but see Craig, 2003), S2 likely has additional affective/cognitive functions, while the insula and ACC are important for affective-motivational and certain cognitive aspects of pain, including anticipation, attention and evaluation (Seminowicz et al., 2004; Apkarian et al., 2005; Ohara et al., 2005; Zhuo, 2008)....
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...This socalled “pain matrix” or “homeostatic afferent processing network” consistently includes primary (S1) and secondary (S2) somatosensory cortices, insular cortex, anterior cingulate cortex (ACC), and thalamic nuclei....
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...Among cortical regions, S1 and S2 cortices, ACC, insular cortex, and PFC areas consistently respond to acute “physiological” pain stimuli in healthy subjects Importantly, depending on the stimulus applied (i.e., somatosensory or visceral stimuli), specific cortical network activation or deactivation has been found in human brain imaging studies (Dunckley et al., 2005; Iannetti et al., 2005)....
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TL;DR: This review focuses on the mechanisms by which resolvins act on their receptors in immune cells and neurons to normalize exaggerated pain via regulation of inflammatory mediators, transient receptor potential (TRP) ion channels, and spinal cord synaptic transmission.
317 citations
References
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TL;DR: These findings suggest that the BOLD contrast mechanism reflects the input and intracortical processing of a given area rather than its spiking output, and that LFPs yield a better estimate of BOLD responses than the multi-unit responses.
Abstract: Functional magnetic resonance imaging (fMRI) is widely used to study the operational organization of the human brain, but the exact relationship between the measured fMRI signal and the underlying neural activity is unclear. Here we present simultaneous intracortical recordings of neural signals and fMRI responses. We compared local field potentials (LFPs), single- and multi-unit spiking activity with highly spatio-temporally resolved blood-oxygen-level-dependent (BOLD) fMRI responses from the visual cortex of monkeys. The largest magnitude changes were observed in LFPs, which at recording sites characterized by transient responses were the only signal that significantly correlated with the haemodynamic response. Linear systems analysis on a trialby-trial basis showed that the impulse response of the neurovascular system is both animal- and site-specific, and that LFPs yield a better estimate of BOLD responses than the multi-unit responses. These findings suggest that the BOLD contrast mechanism reflects the input and intracortical processing of a given area rather than its spiking output.
6,140 citations
TL;DR: Only that part of the pain network associated with its affective qualities, but not its sensory qualities, mediates empathy, suggesting that the neural substrate for empathic experience does not involve the entire "pain matrix".
Abstract: Our ability to have an experience of another's pain is characteristic of empathy. Using functional imaging, we assessed brain activity while volunteers experienced a painful stimulus and compared it to that elicited when they observed a signal indicating that their loved one--present in the same room--was receiving a similar pain stimulus. Bilateral anterior insula (AI), rostral anterior cingulate cortex (ACC), brainstem, and cerebellum were activated when subjects received pain and also by a signal that a loved one experienced pain. AI and ACC activation correlated with individual empathy scores. Activity in the posterior insula/secondary somatosensory cortex, the sensorimotor cortex (SI/MI), and the caudal ACC was specific to receiving pain. Thus, a neural response in AI and rostral ACC, activated in common for "self" and "other" conditions, suggests that the neural substrate for empathic experience does not involve the entire "pain matrix." We conclude that only that part of the pain network associated with its affective qualities, but not its sensory qualities, mediates empathy.
3,425 citations
TL;DR: A neuroimaging study examined the neural correlates of social exclusion and tested the hypothesis that the brain bases of social pain are similar to those of physical pain, suggesting that RVPFC regulates the distress of socialclusion by disrupting ACC activity.
Abstract: A neuroimaging study examined the neural correlates of social exclusion and tested the hypothesis that the brain bases of social pain are similar to those of physical pain. Participants were scanned while playing a virtual ball-tossing game in which they were ultimately excluded. Paralleling results from physical pain studies, the anterior cingulate cortex (ACC) was more active during exclusion than during inclusion and correlated positively with self-reported distress. Right ventral prefrontal cortex (RVPFC) was active during exclusion and correlated negatively with self-reported distress. ACC changes mediated the RVPFC-distress correlation, suggesting that RVPFC regulates the distress of social exclusion by disrupting ACC activity.
3,188 citations
TL;DR: A systematic review of the literature regarding how activity in diverse brain regions creates and modulates the experience of acute and chronic pain states, emphasizing the contribution of various imaging techniques to emerging concepts is presented in this paper.
2,686 citations
TL;DR: It is shown that overexpression ofNMDA receptor 2B (NR2B) in the forebrains of transgenic mice leads to enhanced activation of NMDA receptors, facilitating synaptic potentiation in response to stimulation at 10–100 Hz, suggesting that genetic enhancement of mental and cognitive attributes such as intelligence and memory in mammals is feasible.
Abstract: Hebb's rule (1949) states that learning and memory are based on modifications of synaptic strength among neurons that are simultaneously active. This implies that enhanced synaptic coincidence detection would lead to better learning and memory. If the NMDA (N-methyl-D-aspartate) receptor, a synaptic coincidence detector, acts as a graded switch for memory formation, enhanced signal detection by NMDA receptors should enhance learning and memory. Here we show that overexpression of NMDA receptor 2B (NR2B) in the forebrains of transgenic mice leads to enhanced activation of NMDA receptors, facilitating synaptic potentiation in response to stimulation at 10-100 Hz. These mice exhibit superior ability in learning and memory in various behavioural tasks, showing that NR2B is critical in gating the age-dependent threshold for plasticity and memory formation. NMDA-receptor-dependent modifications of synaptic efficacy, therefore, represent a unifying mechanism for associative learning and memory. Our results suggest that genetic enhancement of mental and cognitive attributes such as intelligence and memory in mammals is feasible.
1,838 citations