scispace - formally typeset

Journal ArticleDOI

Loss of long-term depression in the insular cortex after tail amputation in adult mice

08 Jan 2014-Molecular Pain (SAGE Publications)-Vol. 10, Iss: 1, pp 1-14

TL;DR: It is found that tail amputation in adult mice produced a selective loss of low frequency stimulation-induced LTD in the IC, without affecting (RS)-3,5-dihydroxyphenylglycine (DHPG)-evoked LTD, and it is suggested that restoration of insular LTD may represent a novel therapeutic strategy against the synaptic dysfunctions underlying the pathophysiology of phantom pain.

AbstractThe insular cortex (IC) is an important forebrain structure involved in pain perception and taste memory formation. Using a 64-channel multi-electrode array system, we recently identified and characterized two major forms of synaptic plasticity in the adult mouse IC: long-term potentiation (LTP) and long-term depression (LTD). In this study, we investigate injury-related metaplastic changes in insular synaptic plasticity after distal tail amputation. We found that tail amputation in adult mice produced a selective loss of low frequency stimulation-induced LTD in the IC, without affecting (RS)-3,5-dihydroxyphenylglycine (DHPG)-evoked LTD. The impaired insular LTD could be pharmacologically rescued by priming the IC slices with a lower dose of DHPG application, a form of metaplasticity which involves activation of protein kinase C but not protein kinase A or calcium/calmodulin-dependent protein kinase II. These findings provide important insights into the synaptic mechanisms of cortical changes after peripheral amputation and suggest that restoration of insular LTD may represent a novel therapeutic strategy against the synaptic dysfunctions underlying the pathophysiology of phantom pain.

...read more

Content maybe subject to copyright    Report

Citations
More filters

Journal ArticleDOI
TL;DR: The results suggest that the expression of AMPARs is enhanced in the insular cortex after nerve injury by a pathway involving AC1, AKAP79/150, and PKA, and such enhancement may at least in part contribute to behavioral sensitization together with other cortical regions, such as the anterior cingulate and the prefrontal cortices.
Abstract: Long-term potentiation of glutamatergic transmission has been observed after physiological learning or pathological injuries in different brain regions, including the spinal cord, hippocampus, amygdala, and cortices. The insular cortex is a key cortical region that plays important roles in aversive learning and neuropathic pain. However, little is known about whether excitatory transmission in the insular cortex undergoes plastic changes after peripheral nerve injury. Here, we found that peripheral nerve ligation triggered the enhancement of AMPA receptor (AMPAR)-mediated excitatory synaptic transmission in the insular cortex. The synaptic GluA1 subunit of AMPAR, but not the GluA2/3 subunit, was increased after nerve ligation. Genetic knock-in mice lacking phosphorylation of the Ser845 site, but not that of the Ser831 site, blocked the enhancement of the synaptic GluA1 subunit, indicating that GluA1 phosphorylation at the Ser845 site by protein kinase A (PKA) was critical for this upregulation after nerve injury. Furthermore, A-kinase anchoring protein 79/150 (AKAP79/150) and PKA were translocated to the synapses after nerve injury. Genetic deletion of adenylyl cyclase subtype 1 (AC1) prevented the translocation of AKAP79/150 and PKA, as well as the upregulation of synaptic GluA1-containing AMPARs. Pharmacological inhibition of calcium-permeable AMPAR function in the insular cortex reduced behavioral sensitization caused by nerve injury. Our results suggest that the expression of AMPARs is enhanced in the insular cortex after nerve injury by a pathway involving AC1, AKAP79/150, and PKA, and such enhancement may at least in part contribute to behavioral sensitization together with other cortical regions, such as the anterior cingulate and the prefrontal cortices.

64 citations


Cites background from "Loss of long-term depression in the..."

  • ...Peripheral nerve injury or tail amputation produces long-term upregulation or activation of the synaptic NMDARs (Zhuo, 1998; Qiu et al., 2013) or loss of long-term depression in the insular cortex (Liu and Zhuo, 2014)....

    [...]

  • ..., 2013) or loss of long-term depression in the insular cortex (Liu and Zhuo, 2014)....

    [...]


Journal ArticleDOI
Min Zhuo1
TL;DR: LTP of glutamatergic transmission in pain related cortical areas serves as a key mechanism for chronic pain.
Abstract: Animal and human studies have consistently demonstrated that cortical regions are important for pain perception and pain-related emotional changes. Studies of the anterior cingulate cortex (ACC) have shown that adult cortical synapses can be modified after peripheral injuries, and long-term changes at synaptic level may contribute to long-lasting suffering in patients. It also explains why chronic pain is resistant to conventional analgesics that act by inhibiting synaptic transmission. Insular cortex (IC), another critical cortical area, is found to be highly plastic and can undergo long-term potentiation (LTP) after injury. Inhibiting IC LTP reduces behavioral sensitization caused by injury. LTP of glutamatergic transmission in pain related cortical areas serves as a key mechanism for chronic pain.

48 citations


Journal ArticleDOI
TL;DR: It is found that genetic deletion or pharmacological blockade of ASIC1a greatly reduced, but did not fully abolish, the probability of long-term potentiation (LTP) induction by either single or repeated high frequency stimulation or theta burst stimulation in the CA1 region.
Abstract: The exact roles of acid-sensing ion channels (ASICs) in synaptic plasticity remain elusive. Here, we address the contribution of ASIC1a to five forms of synaptic plasticity in the mouse hippocampus using an in vitro multi-electrode array recording system. We found that genetic deletion or pharmacological blockade of ASIC1a greatly reduced, but did not fully abolish, the probability of long-term potentiation (LTP) induction by either single or repeated high frequency stimulation or theta burst stimulation in the CA1 region. However, these treatments did not affect hippocampal long-term depression induced by low frequency electrical stimulation or (RS)-3,5-dihydroxyphenylglycine. We also show that ASIC1a exerts its action in hippocampal LTP through multiple mechanisms that include but are not limited to augmentation of NMDA receptor function. Taken together, these results reveal new insights into the role of ASIC1a in hippocampal synaptic plasticity and the underlying mechanisms. This unbiased study also demonstrates a novel and objective way to assay synaptic plasticity mechanisms in the brain.

34 citations


Journal ArticleDOI
TL;DR: There is strong evidence that the selective AC1 inhibitor NB001 can be used to inhibit pain-related cortical L-LTP without affecting basal synaptic transmission and basic mechanisms for possible side effects of gabapentin in the central nervous system and its ineffectiveness in some patients with neuropathic pain are provided.
Abstract: Long-term potentiation (LTP) is a key cellular mechanism for pathological pain in the central nervous system. LTP contains at least two different phases: early-phase LTP (E-LTP) and late-phase LTP (L-LTP). Among several major cortical areas, the anterior cingulate cortex (ACC) is a critical brain region for pain perception and its related emotional changes. Periphery tissue or nerve injuries cause LTP of excitatory synaptic transmission in the ACC. Our previous studies have demonstrated that genetic deletion of calcium-stimulated adenylyl cyclase 1 (AC1) or pharmacological application of a selective AC1 inhibitor NB001 blocked E-LTP in the ACC. However, the effect of AC1 on L-LTP, which requires new protein synthesis and is important for the process of chronic pain, has not been investigated. Here we tested the effects of NB001 on the ACC L-LTP and found that bath application of NB001 (0.1 μM) totally blocked the induction of L-LTP and recruitment of cortical circuitry without affecting basal excitatory transmission. In contrast, gabapentin, a widely used analgesic drug for neuropathic pain, did not block the induction of L-LTP and circuitry recruitment even at a high concentration (100 μM). Gabapentin non-selectively decreased basal synaptic transmission. Our results provide strong evidence that the selective AC1 inhibitor NB001 can be used to inhibit pain-related cortical L-LTP without affecting basal synaptic transmission. It also provides basic mechanisms for possible side effects of gabapentin in the central nervous system and its ineffectiveness in some patients with neuropathic pain.

31 citations


Cites background from "Loss of long-term depression in the..."

  • ...in sensory and emotion-related cortical areas such as the insular cortex (IC) and anterior cingulate cortex (ACC), both E-LTP and L-LTP have been recently reported in adult mice [11-14]....

    [...]


Journal ArticleDOI
TL;DR: Tail amputation in pigs appears to evoke acute and sustained changes in peripheral mechanical sensitivity, which resemble features of neuropathic pain reported in humans and other species and provides new information on implications for the welfare of animals subjected to this type of injury.
Abstract: Commercial pigs are frequently exposed to tail mutilations in the form of preventive husbandry procedures (tail docking) or as a result of abnormal behaviour (tail biting). Although tissue and nerve injuries are well-described causes of pain hypersensitivity in humans and in rodent animal models, there is no information on the changes in local pain sensitivity induced by tail injuries in pigs. To determine the temporal profile of sensitisation, pigs were exposed to surgical tail resections and mechanical nociceptive thresholds (MNT) were measured in the acute (one week post-operatively) and in the long-term (either eight or sixteen weeks post-surgery) phase of recovery. The influence of the degree of amputation on MNTs was also evaluated by comparing three different tail-resection treatments (intact, 'short tail', 'long tail'). A significant reduction in MNTs one week following surgery suggests the occurrence of acute sensitisation. Long-term hypersensitivity was also observed in tail-resected pigs at either two or four months following surgery. Tail amputation in pigs appears to evoke acute and sustained changes in peripheral mechanical sensitivity, which resemble features of neuropathic pain reported in humans and other species and provides new information on implications for the welfare of animals subjected to this type of injury.

30 citations


References
More filters

Book
31 Jul 2001
TL;DR: The 3rd edition of this atlas is now in more practical 14"x11" format for convenient lab use and includes a CD of all plates and diagrams, as well as Adobe Illustrator files of the diagrams, and a variety of additional useful material.
Abstract: "The Mouse Brain in Stereotaxic Coordinates" is the most widely used and cited atlas of the mouse brain in print. It provides researchers and students with both accurate stereotaxic coordinates for laboratory use, and detailed delineations and indexing of structures for reference. The accompanying DVD provides drawings of brains structures that can be used as templates for making figures for publication. The 3rd edition is both a major revision and an expansion of previous editions. Delineations and photographs in the horizontal plane of section now complement the coronal and sagittal series, and all the tissue sections are now shown in high resolution digital color photography. The photographs of the sections and the intermediate sections are also provided on the accompanying DVD in high-resolution JP 2000 format. The delineations of structures have been revised, and naming conventions made consistent with Paxinos and Watson's "Rat Brain in Stereotaxic Coordinates, 6th Edition". The 3rd edition of this atlas is now in more practical 14"x11" format for convenient lab use. This edition is in full color throughout. It includes a CD of all plates and diagrams, as well as Adobe Illustrator files of the diagrams, and a variety of additional useful material. Coronal and sagittal diagrams are completely reworked and updated. Rhombomeric borders are included in sagittal figures, for the first time in mammals. Microscopic plates are scanned with a new method in much higher quality.

14,928 citations


Journal ArticleDOI
01 Jun 1983-Pain
TL;DR: The Committee for Research and Ethical Issues of the International Association for the Study of Pain (IASP®) is concerned with the ethical aspects of studies producing experimental pain and any suffering it may cause in animals.
Abstract: The Committee for Research and Ethical Issues of the International Association for the Study of Pain (IASP®) is concerned with the ethical aspects of studies producing experimental pain and any suffering it may cause in animals. Such studies are essential if new and clinically relevant knowledge about the mechanisms of pain is to be acquired. Investigations in conscious animals intended to stimulate chronic pain in man are being performed. Such experiments require careful planning to avoid or at least minimize pain in the animals.

7,118 citations


"Loss of long-term depression in the..." refers methods in this paper

  • ...* Correspondence: min.zhuo@utoronto.ca 1Center for Neuron and Disease, Frontier Institute of Science and Technology, Xi’an Jiaotong University, Xi’an 710049, China 2Department of Physiology, Faculty of Medicine, University of Toronto, The center for the Study of Pain, 1 King’s College Circle, Toronto, Ontario M5S 1A8, Canada © 2014 Liu and Zhuo; licensee BioMed Centra Commons Attribution License (http://creativec reproduction in any medium, provided the or waiver (http://creativecommons.org/publicdom stated....

    [...]

  • ...Pain 1983, 16(2):109–110....

    [...]

  • ...Pain 2012, 153(10):2097–2108....

    [...]

  • ...Mol Pain 2009, 5:4....

    [...]

  • ...All animals were maintained and cared for in compliance with the guidelines set forth by the International Association for the Study of Pain [86]....

    [...]


Journal ArticleDOI
TL;DR: New findings suggest a fundamental role for the AIC (and the von Economo neurons it contains) in awareness, and thus it needs to be considered as a potential neural correlate of consciousness.
Abstract: The anterior insular cortex (AIC) is implicated in a wide range of conditions and behaviours, from bowel distension and orgasm, to cigarette craving and maternal love, to decision making and sudden insight. Its function in the re-representation of interoception offers one possible basis for its involvement in all subjective feelings. New findings suggest a fundamental role for the AIC (and the von Economo neurons it contains) in awareness, and thus it needs to be considered as a potential neural correlate of consciousness.

4,654 citations


"Loss of long-term depression in the..." refers background in this paper

  • ...Insular cortex (IC) is an integrating forebrain structure involved in several sensory and cognitive functions, such as interoceptive awareness, taste memory, and pain perception [1-3]....

    [...]


Journal ArticleDOI
08 Jun 1995-Nature
TL;DR: A very strong direct relationship is reported between the amount of cortical reorganization and the magnitude of phantom limb pain (but not non-painful phantom phenomena) experienced after arm amputation, indicating that phantom-limb pain is related to, and may be a consequence of, plastic changes in primary somatosensory cortex.
Abstract: Although phantom-limb pain is a frequent consequence of the amputation of an extremity, little is known about its origin. On the basis of the demonstration of substantial plasticity of the somatosensory cortex after amputation or somatosensory deafferentation in adult monkeys, it has been suggested that cortical reorganization could account for some non-painful phantom-limb phenomena in amputees and that cortical reorganization has an adaptive (that is, pain-preventing) function. Theoretical and empirical work on chronic back pain has revealed a positive relationship between the amount of cortical alteration and the magnitude of pain, so we predicted that cortical reorganization and phantom-limb pain should be positively related. Using non-invasive neuromagnetic imaging techniques to determine cortical reorganization in humans, we report a very strong direct relationship (r = 0.93) between the amount of cortical reorganization and the magnitude of phantom limb pain (but not non-painful phantom phenomena) experienced after arm amputation. These data indicate that phantom-limb pain is related to, and may be a consequence of, plastic changes in primary somatosensory cortex.

1,600 citations


"Loss of long-term depression in the..." refers background in this paper

  • ...Maladaptive plastic changes along the neuroaxis have been proposed to be associated with the occurrence and intensity of phantom pain [25,31,32,85]....

    [...]

  • ...Mechanistically, limb amputation has been shown to cause dramatic cortical reorganization in humans and primates [28-31], the amount of which correlates well with the extent of phantom pain in some reports [32-34]....

    [...]


Journal ArticleDOI
28 Jun 1991-Science
TL;DR: The results show the need for a reevaluation of both the upper limit of cortical reorganization in adult primates and the mechanisms responsible for it.
Abstract: After limited sensory deafferentations in adult primates, somatosensory cortical maps reorganize over a distance of 1 to 2 millimeters mediolaterally, that is, in the dimension along which different body parts are represented. This amount of reorganization was considered to be an upper limit imposed by the size of the projection zones of individual thalamocortical axons, which typically also extend a mediolateral distance of 1 to 2 millimeters. However, after extensive long-term deafferentations in adult primates, changes in cortical maps were found to be an order of magnitude greater than those previously described. These results show the need for a reevaluation of both the upper limit of cortical reorganization in adult primates and the mechanisms responsible for it.

1,018 citations


"Loss of long-term depression in the..." refers background in this paper

  • ...Mechanistically, limb amputation has been shown to cause dramatic cortical reorganization in humans and primates [28-31], the amount of which correlates well with the extent of phantom pain in some reports [32-34]....

    [...]