Enhanced group II mGluR-mediated inhibition of pain-related synaptic plasticity in the amygdala

Fu Yu, Han, Bird, Neugebauer, Neugebauer Volker

Description

The latero-capsular part of the central nucleus of the amygdala (CeLC) is the target of the spino-parabrachio-amygdaloid pain pathway. Our previous studies showed that CeLC neurons develop synaptic plasticity and increased neuronal excitability in the kaolin/carrageenan model of arthritic pain. These pain-related changes involve presynaptic group I metabotropic glutamate receptors (mGluRs) and postsynaptic NMDA and calcitonin gene-related peptide (CGRP1) receptors. Here we address the role of group II mGluRs. Results Whole-cell current- and voltage-clamp recordings were made from CeLC neurons in brain slices from control rats and arthritic rats (>6 h postinjection of kaolin/carrageenan into the knee). Monosynaptic excitatory postsynaptic currents (EPSCs) were evoked by electrical stimulation of afferents from the pontine parabrachial (PB) area. A selective group II mGluR agonist (LY354740) decreased the amplitude of EPSCs more potently in CeLC neurons from arthritic rats (IC 50 = 0.59 nM) than in control animals (IC 50 = 15.0 nM). The inhibitory effect of LY354740 was reversed by a group II mGluR antagonist (EGLU) but not a GABA A receptor antagonist (bicuculline). LY354740 decreased frequency, but not amplitude, of miniature EPSCs in the presence of TTX. No significant changes of neuronal excitability measures (membrane slope conductance and action potential firing rate) were detected. Conclusion Our data suggest that group II mGluRs act presynaptically to modulate synaptic plasticity in the amygdala in a model of arthritic pain.

Informations

• Publié par: biomed
• Publié le: 01 janvier 2006
• Nombre de lectures: 17
• Langue: English

Extrait

BioMed CentralMolecular Pain
Open AccessResearch
Enhanced group II mGluR-mediated inhibition of pain-related
synaptic plasticity in the amygdala
Jeong S Han, Yu Fu, Gary C Bird and Volker Neugebauer*
Address: Department of Neuroscience and Cell Biology, The University of Texas Medical Branch, Galveston, Texas 77555-1069, USA
Email: Jeong S Han - [e-mail]; Yu Fu - [e-mail]; Gary C Bird - [e-mail]; Volker Neugebauer* - [e-mail]
* Corresponding author
Published: 08 May 2006 Received: 27 March 2006
Accepted: 08 May 2006
Molecular Pain 2006, 2:18 doi:10.1186/1744-8069-2-18
This article is available from: http://www.molecularpain.com/content/2/1/18
© 2006 Han et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Background: The latero-capsular part of the central nucleus of the amygdala (CeLC) is the target
of the spino-parabrachio-amygdaloid pain pathway. Our previous studies showed that CeLC
neurons develop synaptic plasticity and increased neuronal excitability in the kaolin/carrageenan
model of arthritic pain. These pain-related changes involve presynaptic group I metabotropic
glutamate receptors (mGluRs) and postsynaptic NMDA and calcitonin gene-related peptide
(CGRP1) receptors. Here we address the role of group II mGluRs.
Results: Whole-cell current- and voltage-clamp recordings were made from CeLC neurons in
brain slices from control rats and arthritic rats (>6 h postinjection of kaolin/carrageenan into the
knee). Monosynaptic excitatory postsynaptic currents (EPSCs) were evoked by electrical
stimulation of afferents from the pontine parabrachial (PB) area. A selective group II mGluR agonist
(LY354740) decreased the amplitude of EPSCs more potently in CeLC neurons from arthritic rats
(IC = 0.59 nM) than in control animals (IC = 15.0 nM). The inhibitory effect of LY354740 was50 50
reversed by a group II mGluR antagonist (EGLU) but not a GABA receptor antagonistA
(bicuculline). LY354740 decreased frequency, but not amplitude, of miniature EPSCs in the
presence of TTX. No significant changes of neuronal excitability measures (membrane slope
conductance and action potential firing rate) were detected.
Conclusion: Our data suggest that group II mGluRs act presynaptically to modulate synaptic
plasticity in the amygdala in a model of arthritic pain.
studies have repeatedly identified pain-related signalBackground
The amygdala plays a key role in the emotional processing changes in the amygdala in animals and humans [8-12].
of sensory stimuli [1-3]. Pain has a strong emotional com-
ponent and is significantly associated with affective disor- The amygdala contains several anatomically and physio-
ders such as depression and anxiety [4]. Accumulating logically distinct nuclei. The central nucleus of the amy-
evidence suggests that the amygdala is a neural substrate gdala (CeA) is of particular interest because of its
of the reciprocal relationship between pain and affect [5]. morphological and functional characteristics. Neurons in
It has become clear now that lesions and pharmacological the latero-capsular part of the CeA (CeLC) receive rela-
deactivation of the amygdala produce inhibitory effects tively unprocessed nociceptive information directly (not
on pain behavior in animals [6-8]. Several neuro-imaging involving thalamus and/or cortex) through the spino-
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parabrachio-amygdaloid pain pathway arising from lam- through postsynaptic calcitonin gene-related (CGRP1)
ina I neurons in the spinal cord [5,13,14] Direct spino- receptors [8]. Conversely, activation of presynaptic group
amygdaloid connections from spinal neurons in deeper III mGluRs inhibited pain-related synaptic plasticity in the
laminae may also provide nociceptive information to the CeLC [23].
CeA [15]. The CeLC receives highly processed polymodal
information with affective valence from the lateral and Here we analyze the role of group II mGluRs in pain-
basolateral nuclei of the amygdala, the center of the fear- related plasticity in the CeLC. The rationale is as follows.
anxiety circuitry [16]. The CeA is the major output nucleus 1) Group II mGluRs couple to the inhibition of stimu-
of the amygdala and projects to a variety of "upstream" lated cAMP formation, and cAMP-dependent PKA plays
and "downstream" targets that are involved in emotional an important role in pain-related plasticity in the CeLC
behavior and emotional experience, autonomic and [5,20,22]. 2) There is evidence to suggest that group II
somatomotor functions and endogenous pain control mGluRs on primary afferents, in the spinal cord and
[1,5,13,16,17]. brainstem modulate nociceptive processing but the role
group II mGluRs in higher brain centers in prolonged or
The CeLC is now defined as the "nociceptive amygdala" chronic pain states remains to be determined
because of its high content of nociceptive neurons [5]. [26,27,29,30]. 3) Finally, potential clinical indications for
Previous in vivo studies showed that the majority of CeLC group II mGluR agonists include anxiety disorders
neurons, including multireceptive and normally non- [24,31], which critically involve the amygdala; the recip-
responsive neurons, are sensitized to sensory inputs after rocal relationship between pain and anxiety is well docu-
the induction of arthritic pain in one knee [8,18-20]. The mented [5].
sensitization consists of increased background activity,
stronger activation by constant electrical stimulation of Results
A selective group II mGluR agonist (LY354740) inhibits afferent inputs, and enhanced responses to brief noxious
and innocuous stimulation (compression) of the arthritic pain-related synaptic plasticity more potently than normal
knee and of non-injured tissue. Parallel in vitro whole-cell synaptic transmission
patch-clamp recordings in brain slices indicated that syn- Our previous studies showed that CeLC neurons undergo
several neuroplastic changes in the kaolin/carrageenanaptic transmission to the CeLC is facilitated in the arthritis
pain model [8,21-23]. Excitability of CeLC neurons is also mono-arthritis pain model [8,21-23]. These changes
enhanced in brain slices from arthritic rats. include enhanced input-output functions of synaptic
transmission at the PB-CeLC synapse (part of the spino-
The mechanisms of pain-related plasticity in the amygdala parabrachio-amygdaloid pain pathway [see [5]]),
are only beginning to emerge, but glutamate receptors enhanced excitability and altered intrinsic membrane
appear to be of critical importance. Metabotropic gluta- properties such as resting membrane potential, input
mate receptors (mGluRs) form a family of G-protein cou- resistance, membrane slope conductance and action
pled receptors and have been implicated in potential threshold. These observations indicate synaptic
neuroplasticity associated with normal brain functions as and neural plasticity because arthritis pain-related
well as in a variety of nervous system disorders [24,25]. It changes are preserved in the reduced slice preparation and
is clear now that mGluRs also play an important role in maintained, at least in part, independently of peripheral
nociception and pain [26-30]. Eight mGluR subtypes have and spinal pain mechanisms [see [5]].
been cloned to date and are classified into groups I
(mGluR1,5), II (mGluR2,3) and III (mGluR4,6,7,8). In the present study, monosynaptic excitatory synaptic
Group I mGluRs couple to the activation of phospholi- currents (EPSCs; see Methods) were recorded in neurons
pase C, resulting in calcium release from intracellular of the latero-capsular division of the central nucleus of the
stores and protein kinase C (PKC) activation. In contrast, amygdala (CeLC) in brain slices from normal rats (n = 9
groups II and III mGluRs are negatively coupled to adeny- neurons) and from arthritic rats (6 h postinjection of kao-
lyl cyclase, thereby inhibiting cyclic AMP (cAMP) forma- lin/carrageenan into the knee; n = 13 neurons). Under
tion and cAMP-dependent protein kinase (PKA) normal conditions, a selective group II mGluR agonist
activation. (LY354740, 1 nM) [24,31] slightly inhibited the peak
amplitude of monosynaptic EPSCs evoked at the PB-CeLC
Our previous studies showed that arthritis pain-related synapse (see individual example in Fig. 1A). In brain slices
sensitization and synaptic plasticity in the CeLC depend from arthritic rats, the same low concentration of
on presynaptic group I mGluR upregulation [19,21] and LY354740 (1 nM) produced stronger inhibition of synap-
on postsynaptic N-methyl-D-aspartate (NMDA) receptor tic transmission (see individual example in Fig. 1B). The
phosphorylation through the cAMP-dependent protein inhibitory effects of LY354740 did not involve GABAergic
kinase PKA [20,22]. PKA activation is accomplished mechanisms since they were not blocked by bicuculline
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ABnormal arthritis C GABA -blockA
40 pA
bicuculline (20 M)20 ms
LY354740 (1nM) LY35474