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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.
Abstract: The 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.

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Citations
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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.

76 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)....

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

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Journal ArticleDOI
Min Zhuo1
TL;DR: LTP of glutamatergic transmission in pain related cortical areas serves as a key mechanism for chronic pain.

65 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.

41 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]....

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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.

39 citations

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.

35 citations

References
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Journal ArticleDOI
03 Dec 2010-Science
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


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

  • ...Procedures for preparation of the MED64 probe and multi-channel field potential recordings were similar to those described previously [23,38,43,44]....

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  • ...In the present study, we used a 64-channel multi-electrode dish (MED64) recording system [23,38,43] to examine injury-related metaplastic changes in insular LTD caused by tail amputation in the adult mice....

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Journal ArticleDOI
TL;DR: Metaplasticity may serve several functions including providing a way for synapses to integrate a response across temporally spaced episodes of synaptic activity and keeping synapses within a dynamic functional range, and thus preventing them from entering states of saturated LTP or LTD.

345 citations

Journal ArticleDOI
TL;DR: This study shows that the amygdala contributes not only to emotional-affective but also cognitive effects of pain, which has important implications for the understanding of amygdala functions and amygdalo-cortical interactions.
Abstract: Cognitive deficits such as impaired decision-making can be a consequence of persistent pain. Normal functions of the intact amygdala and prefrontal cortex are required for emotion-based decision-making that relies on the ability to assess risk, attribute value, and identify advantageous strategies. We tested the hypothesis that pain-related cognitive deficits result from amygdala-driven impairment of medial prefrontal cortical (mPFC) function. To do this, we used electrophysiological single-unit recordings in vivo, patch clamp in brain slices, and various behavioral assays to show that increased neuronal activity in the amygdala in an animal model of arthritis pain was accompanied by decreased mPFC activation and impaired decision-making. Furthermore, pharmacologic inhibition (with a corticotropin-releasing factor 1 receptor antagonist) of pain-related hyperactivity in the basolateral amygdala (BLA), but not central amygdala (CeA), reversed deactivation of mPFC pyramidal cells and improved decision-making deficits. Pain-related cortical deactivation resulted from a shift of balance between inhibitory and excitatory synaptic transmission. Direct excitatory transmission to mPFC pyramidal cells did not change in the pain model, whereas polysynaptic inhibitory transmission increased. GABAergic transmission was reduced by non-NMDA receptor antagonists, suggesting that synaptic inhibition was glutamate driven. The results are consistent with a model of BLA-driven feedforward inhibition of mPFC neurons. In contrast to the differential effects of BLA versus CeA hyperactivity on cortical-cognitive functions, both amygdala nuclei modulate emotional-affective pain behavior. Thus, this study shows that the amygdala contributes not only to emotional-affective but also cognitive effects of pain. The novel amygdalo-cortical pain mechanism has important implications for our understanding of amygdala functions and amygdalo-cortical interactions.

319 citations


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

  • ...It has been previously reported that peripheral inflammation or nerve injury could trigger a long-term enhancement of excitatory synaptic transmission in various brain regions, such as ACC [51-54], amygdala [55-57], and hippocampus [58]....

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Journal ArticleDOI
17 Jul 2003-Nature
TL;DR: It is shown that changes in GABA neurotransmission in the RAIC can raise or lower the pain threshold—producing analgesia or hyperalgesia, respectively—in freely moving rats.
Abstract: It is known that pain perception can be altered by mood, attention and cognition, or by direct stimulation of the cerebral cortex, but we know little of the neural mechanisms underlying the cortical modulation of pain. One of the few cortical areas consistently activated by painful stimuli is the rostral agranular insular cortex (RAIC) where, as in other parts of the cortex, the neurotransmitter gamma-aminobutyric acid (GABA) robustly inhibits neuronal activity. Here we show that changes in GABA neurotransmission in the RAIC can raise or lower the pain threshold--producing analgesia or hyperalgesia, respectively--in freely moving rats. Locally increasing GABA, by using an enzyme inhibitor or gene transfer mediated by a viral vector, produces lasting analgesia by enhancing the descending inhibition of spinal nociceptive neurons. Selectively activating GABA(B)-receptor-bearing RAIC neurons produces hyperalgesia through projections to the amygdala, an area involved in pain and fear. Whereas most studies focus on the role of the cerebral cortex as the end point of nociceptive processing, we suggest that cerebral cortex activity can change the set-point of pain threshold in a top-down manner.

315 citations


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

  • ...Genetic [14,15] or pharmacological [16-19] manipulation of the IC could alter the pain sensitivity....

    [...]

  • ...There is considerable evidence indicating the critical role of the IC in pain perception and memory storage [2,3,16-18]....

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Journal ArticleDOI
TL;DR: Genetic modification of forebrain NMDA receptors can influence pain perception, which suggests that forebrain-selective NMDA receptor antagonists, including NR2B- selective agents, may be useful analgesics for persistent pain.
Abstract: N-methyl-D-aspartate (NMDA) receptors contribute to many brain functions. We studied the effect of forebrain-targeted overexpression of the NMDA receptor subunit NR2B on the response of mice to tissue injury and inflammation. Transgenic mice exhibited prominent NR2B expression and enhanced NMDA receptor-mediated synaptic responses in two pain-related forebrain areas, the anterior cingulate cortex and insular cortex, but not in the spinal cord. Although transgenic and wild type mice were indistinguishable in tests of acute pain, transgenic mice exhibited enhanced responsiveness to peripheral injection of two inflammatory stimuli, formalin and complete Freund's adjuvant. Genetic modification of forebrain NMDA receptors can therefore influence pain perception, which suggests that forebrain-selective NMDA receptor antagonists, including NR2B-selective agents, may be useful analgesics for persistent pain.

312 citations


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

  • ...Genetic [14,15] or pharmacological [16-19] manipulation of the IC could alter the pain sensitivity....

    [...]