Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2679_Библиотеки_им_академика_М_И_Перельмана
.pdf
156 Chronic Pain: New Molecular Insights into Pain and Treatment
https://t.me/medicina_free
recording studies, the induction of LTD was found to require activation of
the NMDA receptors, mGluR5, and L-VGCCs. Protein phosphatase 1/2A
and endocannabinoid signaling are also critical for the insular LTD
[21,22]. Interestingly, it has been reported that nicotine facilitated LTD in
the insular cortex [23]. More studies are clearly needed for future investigation of insular LTD.
Functional implication for cortical LTD
Considering LTP is important for cortical excitation after peripheral
injury, it is conceivable that ACC and IC LTD may contribute to cortical
inhibition in behavioral animals. LTD may also help to reset enhanced
synaptic transmission. For pain regulation, such resetting effects may
be analgesic in behavioral status, and the loss of LTD may lead to further potentiation of cortical responses. Studies with different types of
animal injury models found that ACC LTD was diminished after injury
(Figure 8). Tail amputation, a potential animal model for the study of
phantom pain, led to loss of LFS-induced LTD in the ACC and IC
[16,21,24]. Similar results were found in animal models of bone cancer
pain and nerve injury [25,26]. In supporting this hypothesis, it has been
reported that restoration of ACC LTD alleviated peripheral pain hypersensitivity [25].
Conclusion
ACC and IC play important roles in pain perception and emotion. Both
LTP and LTD give excitatory synapses in cortical neurons the ability to
store and erase the information. The existence of different forms of LTD
may indicate that they may contribute to various physiological and pathological functions (see Table 1). In case of injuries, the loss of LTD plays
a crucial role in cortical excitation caused by the injury. Postsynaptic
changes are likely the key mechanisms for LTD, although presynaptic
LTD is still possible in these synapses. Restoration of LTD in the cortex
may serve as a new way to reduce chronic pain and related emotional
responses.
(a)
(d)
(f)
(e)
(b) (c)
https://t.me/medicina_free
Cortical Depression 157
(g)
Figure 8. Tail amputation impairs ACC LTD. (a) The schematic view of tail amputation
experiment process. (b) The sham groups showed similar LTD as the control group (81 ±
2%; n = 7/7). (c) The 2-week tail-amputated group showed impaired ACC LTD (96 ± 2%;
n = 9/9). (d, e) The spatial distribution of activated channels during baseline (blue) and the
channels that underwent LTD (red). The spatial distribution of activated channels during
baseline in sham and amputated models is similar. However, sham group shows a wider
distribution of LTD-occurring channels compared with the tail amputated group, which
rarely shows some LTD near the stimulation site. (f) Sham showed normal chemical LTD
by applying DHPG (100 μM) and MPEP (10 μM) for 20 min (86 ± 4%; n = 7/7). (g) Tailamputated group showed no chemical LTD by applying DHPG (100 μM) and MPEP
(10μM) for 20 min (99 ± 3%; n = 8/8) (adapted from Kang et al [16]).
158 Chronic Pain: New Molecular Insights into Pain and Treatment
https://t.me/medicina_free
Table 1. Stimulation protocols for inducing LTD in the ACC slices.
Parameters Recording method
Low-frequency
stimulation
(LFS)
Pairing training Paired presynaptic 80 pulses at 2 Hz with
Chemical-induced
LTD: DHPG
1 Hz for 15 min or 3 Hz for 5 min at the
same stimulation intensity
postsynaptic depolarization at +30 mV
Paired three presynaptic stimuli that caused
three EPSPs (10 ms ahead) with three
postsynaptic APs at 30 Hz, paired 15
times every 5 s
Field potential
recording
Whole-cell patch-
clamp recording
Whole-cell patch-
clamp recording
References
[1] Bear, M.F. (1996) A synaptic basis for memory storage in the cerebral cor-
tex. Proc Natl Acad Sci USA 93, 13453–13459. 10.1073/pnas.93.24.13453.
[2] Dudek, S.M. and Bear, M.F. (1992) Homosynaptic long-term depression in
area CA1 of hippocampus and effects of N-methyl-D-aspartate receptor
blockade. Proc Natl Acad Sci USA 89, 4363–4367. 10.1073/pnas.89.10.4363.
[3] Malenka, R.C. and Bear, M.F. (2004) LTP and LTD: An embarrassment of
riches. Neuron 44, 5–21. 10.1016/j.neuron.2004.09.012.
[4] Bliss, T.V. et al. (2016) Synaptic plasticity in the anterior cingulate
cortex in acute and chronic pain. Nat Rev Neurosci 17, 485–496. 10.1038/
nrn.2016.68.
[5] Zhuo, M. (2008) Cortical excitation and chronic pain. Trends Neurosci 31,
199–207. 10.1016/j.tins.2008.01.003.
[6] Zhuo, M. (2016) Neural mechanisms underlying anxiety-chronic pain inter-
actions. Trends Neurosci 39, 136–145. 10.1016/j.tins.2016.01.006.
[7] Vogt, B.A. (2005) Pain and emotion interactions in subregions of the cingu-
late gyrus. Nat Rev Neurosci 6, 533–544. 10.1038/nrn1704.
[8] Bear, M.F. and Abraham, W.C. (1996) Long-term depression in hippocam-
pus. Annu Rev Neurosci 19, 437–462. 10.1146/annurev.ne.19.030196.002253.
[9] Toyoda, H. et al. (2006) NMDA receptor-dependent long-term depression
in the anterior cingulate cortex. Rev Neurosci 17, 403–413. 10.1515/
revneuro.2006.17.4.403.
[10] Artola, A. et al. (1990) Different voltage-dependent thresholds for inducing
long-term depression and long-term potentiation in slices of rat visual cortex. Nature 347, 69–72. 10.1038/347069a0.
Cortical Depression 159
https://t.me/medicina_free
[11] Bolshakov, V.Y. and Siegelbaum, S.A. (1994) Postsynaptic induction and
presynaptic expression of hippocampal long-term depression. Science 264,
1148–1152. 10.1126/science.7909958.
[12] Chen, Q.Y. et al. (2021) NMDA receptors and synaptic plasticity in
theanterior cingulate cortex. Neuropharmacology 197, 108749. 10.1016/j.
neuropharm.2021.108749.
[13] Lee, H.K. et al. (1998) NMDA induces long-term synaptic depression and
dephosphorylation of the GluR1 subunit of AMPA receptors in hippocampus. Neuron 21, 1151–1162. 10.1016/s0896-6273(00)80632-7.
[14] Liu, L. et al. (2004) Role of NMDA receptor subtypes in governing the
direction of hippocampal synaptic plasticity. Science 304, 1021–1024.
10.1126/science.1096615.
[15] Toyoda, H. et al. (2005) Roles of NMDA receptor NR2A and NR2B
subtypes for long-term depression in the anterior cingulate cortex. Eur
J Neurosci 22, 485–494. 10.1111/j.1460-9568.2005.04236.x.
[16] Kang, S.J. et al. (2012) Plasticity of metabotropic glutamate receptor-
dependent long-term depression in the anterior cingulate cortex after amputation. J Neurosci 32, 11318–11329. 10.1523/JNEUROSCI.0146-12.2012.
[17] Zakharenko, S.S. et al. (2002) Altered presynaptic vesicle release and
cycling during mGluR-dependent LTD. Neuron 35, 1099–1110. 10.1016/
s0896-6273(02)00898-x.
[18] Luthi, A. et al. (1999) Hippocampal LTD expression involves a pool of
AMPARs regulated by the NSF-GluR2 interaction. Neuron 24, 389–399.
10.1016/s0896-6273(00)80852-1.
[19] Mulkey, R.M. and Malenka, R.C. (1992) Mechanisms underlying induction
of homosynaptic long-term depression in area CA1 of the hippocampus.
Neuron 9, 967–975. 10.1016/0896-6273(92)90248-c.
[20] Mulkey, R.M. et al. (1993) An essential role for protein phosphatases
in hippocampal long-term depression. Science 261, 1051–1055. 10.1126/
science.8394601.
[21] Liu, M.G. et al. (2013) Long-term depression of synaptic transmission in
the adult mouse insular cortex in vitro. Eur J Neurosci 38, 3128–3145.
10.1111/ejn.12330.
[22] Liu, M.G. and Zhuo, M. (2014) Loss of long-term depression in the insular
cortex after tail amputation in adult mice. Mol Pain 10, 1. 10.1186/
1744-8069-10-1.
[23] Toyoda, H. (2018) Nicotine facilitates synaptic depression in layer V
pyramidal neurons of the mouse insular cortex. Neurosci Lett 672, 78–83.
10.1016/j.neulet.2018.02.046.
160 Chronic Pain: New Molecular Insights into Pain and Treatment
https://t.me/medicina_free
[24] Wei, F. et al. (1999) Loss of synaptic depression in mammalian anterior
cingulate cortex after amputation. J Neurosci 19, 9346–9354.
[25] Wang, Y.J. et al. (2020) Restoration of cingulate long-term depression by
enhancing non-apoptotic caspase 3 alleviates peripheral pain hypersensitivity. Cell Rep 33, 108369. 10.1016/j.celrep.2020.108369.
[26] Chiou, C.S. et al. (2012) Impairment of long-term depression in the anterior
cingulate cortex of mice with bone cancer pain. Pain 153, 2097–2108.
10.1016/j.pain.2012.06.031.
[27] Toyoda, H. et al. (2007) Long-term depression requires postsynaptic
AMPAGluR2 receptor in adult mouse cingulate cortex. J Cell Physiol 211,
336–343. 10.1002/jcp.20940.
Cortical Sensitization and
https://t.me/medicina_free
News and Views
Chapter 7
Reorganization
Scientists have traced chronic pain to a defect in one enzyme in a
single region of the brain. Could this be a decisive turn in the
battleagainst chronic pain?
Min Zhuo is a neuroscientist at the University of Toronto, who has
been testing potential painkillers on mice with the aim of discovering better treatments for chronic pain. In order to test this, he crimped a nerve in
161
162 Chronic Pain: New Molecular Insights into Pain and Treatment
https://t.me/medicina_free
the legs of mice to induce a chronic pain condition. In a matter of days,
the mice developed many of the symptoms — and even some of the brain
alterations — often seen in people suffering from chronic pain.
Zhuo and his colleagues then sought out different compounds that
could affect the learning that goes on during chronic pain. They focused
on the behavior of neurons in a region of the brain called theanterior cingulate cortex, which shows intense activity in scans of people with chronic
pain. The cingulate cortex contains an abundant amount of an enzyme
called AC1. Zhuo wondered if the neural learning that leads to chronic
pain was accelerated when levels of the enzyme were high.
As a test, Zhuo’s team genetically engineered mice so that they could
not make enzyme AC1. The animals turned out almost entirely normal.
They could even sense regular types of pain, however when the mice were
subject to the leg crimp procedure, they did not develop chronic pain.
Once Zhuo recognized that AC1 is essential for chronic pain, he
started the hunt for a drug that could interfere with it. He grew cells that
produced enzyme AC1 in culture and then added hundreds of different
compounds, hoping that one would latch on to the enzyme and thus block
its action.Eventually, he and his team found one that did and named it
NB001. When scientists gave an oral dose of NB001 to rats suffering from
chronic pain, the animals were rid of their symptoms in just 45 minutes.
By latching onto AC1, it seems the drug prevented the neuronal activity
that makes chronic pain possible.
NB001 shows a lot of promise as a treatment for chronic pain as it
focuses on the specific pain engine in the cingulate cortex instead of the
entire brain and nervous system. There are also no obvious side effects in
laboratory animals; the rats suffered no harm to their memory or their ability
to learn. Zhuo hopes to launch clinical trials in humans in the near future.
Summary
Investigation of the cortical synapses in in vitro brain slices found that
these sensory synapses in the brain are highly plastic, and such plastic
changes may be long-lasting. In this chapter, we will review the evidence
that supports the long-term plastic changes within the ACC synapses after
periphery injury, from inflammation and nerve injury to amputation. It is
consistently demonstrated that excitatory synaptic transmission in the layer
Cortical Sensitization and Reorganization 163
https://t.me/medicina_free
II-II synapses is significantly enhanced after peripheral injury, and such
enhancement is long-lasting. Long-term potentiation of excitatory synaptic
transmission within the ACC likely contributes to cortical sensitization and
subsequent behavioral responses. The use of in vitro brain slice models and
transgenic mice provides useful tools for identifying leading protein targets
involved in the induction and expression of chronic pain.
Keywords: ACC; LTP; AC1; intrinsic plasticity; nerve injury; PKMζ;
cortical reorganization
Introduction
The adult human somatosensory cortex is often illustrated with a distorted
human figure in order to outline the somatotopic map. Historically, it was
thought that this figure remained relatively stable in adults. However, studies
over the past 20 years have dramatically changed this perception. Cortical
representations in the mammalian brain are dynamic and can be modified by
experience [1,2]. Not only do plastic changes occur in adults but they can
also happen on a rapid time scale (from a few minutes to several hours). It
has been proposed that use-dependent changes in synaptic strength, such as
LTP and LTD, may serve as key synaptic mechanisms of cortical plasticity.
Cortical reorganization
Cortical reorganization has been reported in the somatosensory cortex of
adult animals after peripheral deafferentation or amputation. Cortical
reorganization acts as an adaptive mechanism during development and
learning, and it could also play a detrimental role in traumatic events, such
as the loss of a limb. It has been demonstrated that cortical reorganization
occurs after limb or digit amputation. After digit amputation, neuronal
terminals invade adjacent cortical areas representing deafferented fingers.
Similarly, human amputees experience phantom limb sensations — otherwise known as phantom pain — and the amount of cortical reorganization
directly correlates with the severity of the phantom pain.
Molecular and cellular mechanisms for cortical reorganization are
still largely unknown. However, recent progress made in animal models of
injury may provide more insight into the molecular and cellular
164 Chronic Pain: New Molecular Insights into Pain and Treatment
(a)
https://t.me/medicina_free
mechanism for such cortical reorganization [3–5]. In an animal model of
nerve injury, it was reported that activation of the ACC induced by peripheral nerve injury increases the turnover of specific synaptic proteins in a
persistent manner [6]. Neural cell adhesion molecule 1 (NCAM1) is one
of the molecules involved and it mediates spine reorganization and contributes to behavioral sensitization. This study demonstrates a synaptic
mechanism for cortical reorganization and points to potential avenues for
neuropathic pain treatment.
LTP in the ACC after injury
Expression of activity-dependent immediate early genes, such as c-fos
and Egr1, is linked to the induction of late LTP in the hippocampus, and
their expression is commonly used as a marker for LTP in studies of learning and memory [7]. Consistent with the idea that chronic pain is linked
to persistent LTP in the ACC, rodent models of chronic inflammatory
pain, neuropathic pain, bone cancer pain, and chronic visceral pain are all
associated with the activation of different immediate early genes including
c-fos and Egr1 in ACC neurons [8–12] (see Figure 1 for an example after
Figure 1. Potentiation of IEG expression in the ACC after the amputation.
Photomicrographs showing expression of c-Fos and NGFI-A (a) and phosphorylation of
CREB (b) in the coronal ACC sections from sham animals (Ctrl) and animals at different
times after the amputation of the unilateral hind paw third digit. Scale bars: 500 μm. The
numbers of c-Fos-, NGFI-A-, and pCREB-immunoreactive cells increased bilaterally after
the amputation (see a summary). AC1 and AC8 contributed to CREB activation following
formalin injection (adapted from Wei et al. [10]).
(b)
Cortical Sensitization and Reorganization 165
(a) (b)
https://t.me/medicina_free
amputation). In addition, there is evidence of increased neuronal excitability and synaptic potentiation within the ACC. For example, peripheral
digit amputation (an animal model for phantom pain) produces a longlasting enhancement of synaptic responses within the ACC to either local
or peripheral stimulation in vivo [13] (Figure 2). Peripheral nerve block
experiments have demonstrated that peripheral nerve activity is not
required for the maintenance of amputation-induced potentiation of
evoked synaptic responses in the ACC, indicating that synaptic plasticity
in the ACC is maintained by central mechanisms.
Figure 2. LTP recorded in vivo recording from the ACC. (a) Diagram of in vivo record-
ing from the ACC in an anaesthetized rat; animals were maintained in a lightly anaesthetized state by halothane. The recording electrode was placed into the ACC contralateral to
the peripheral stimulation electrode. Amputation (the removal of the third digit of the hind
paw) was performed on the non-stimulated hind paw. During amputation, a higher concentration of halothane was used. (b) Representative traces of EPSPs 5 min before amputation
(Pre) and 115–120 min after (Post) sham treatment or amputation. The latency of sensory
responses was not changed after the amputation, while the EPSP slope was increased.
Amputation of a single digit of the contralateral hind paw (indicated by an arrow) caused
long-lasting enhancement of sensory responses. Sensory responses were not significantly
changed in sham-treated animals. The test stimulation frequency was 0.01 Hz (adapted
from Wei and Zhuo [13]).
Соседние файлы в папке Библиотека им академика М.И. Перельмана