- Open Access
Enhanced group II mGluR-mediated inhibition of pain-related synaptic plasticity in the amygdala
© Han et al; licensee BioMed Central Ltd. 2006
- Received: 27 March 2006
- Accepted: 08 May 2006
- Published: 08 May 2006
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.
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 (IC50 = 0.59 nM) than in control animals (IC50 = 15.0 nM). The inhibitory effect of LY354740 was reversed by a group II mGluR antagonist (EGLU) but not a GABAA 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.
Our data suggest that group II mGluRs act presynaptically to modulate synaptic plasticity in the amygdala in a model of arthritic pain.
- mGluR Antagonist
- mGluR Agonist
- EPSC Amplitude
- mEPSC Frequency
- mEPSC Amplitude
The amygdala plays a key role in the emotional processing of sensory stimuli [1–3]. Pain has a strong emotional component and is significantly associated with affective disorders such as depression and anxiety . Accumulating evidence suggests that the amygdala is a neural substrate of the reciprocal relationship between pain and affect . It has become clear now that lesions and pharmacological deactivation of the amygdala produce inhibitory effects on pain behavior in animals [6–8]. Several neuro-imaging studies have repeatedly identified pain-related signal changes in the amygdala in animals and humans [8–12].
The amygdala contains several anatomically and physiologically distinct nuclei. The central nucleus of the amygdala (CeA) is of particular interest because of its morphological and functional characteristics. Neurons in the latero-capsular part of the CeA (CeLC) receive relatively unprocessed nociceptive information directly (not involving thalamus and/or cortex) through the spino-parabrachio-amygdaloid pain pathway arising from lamina I neurons in the spinal cord [5, 13, 14] Direct spino-amygdaloid connections from spinal neurons in deeper laminae may also provide nociceptive information to the CeA . The CeLC receives highly processed polymodal information with affective valence from the lateral and basolateral nuclei of the amygdala, the center of the fear-anxiety circuitry . The CeA is the major output nucleus of the amygdala and projects to a variety of "upstream" and "downstream" targets that are involved in emotional behavior and emotional experience, autonomic and somatomotor functions and endogenous pain control [1, 5, 13, 16, 17].
The CeLC is now defined as the "nociceptive amygdala" because of its high content of nociceptive neurons . Previous in vivo studies showed that the majority of CeLC neurons, including multireceptive and normally non-responsive neurons, are sensitized to sensory inputs after the induction of arthritic pain in one knee [8, 18–20]. The sensitization consists of increased background activity, stronger activation by constant electrical stimulation of afferent inputs, and enhanced responses to brief noxious and innocuous stimulation (compression) of the arthritic knee and of non-injured tissue. Parallel in vitro whole-cell patch-clamp recordings in brain slices indicated that synaptic transmission to the CeLC is facilitated in the arthritis pain model [8, 21–23]. Excitability of CeLC neurons is also enhanced in brain slices from arthritic rats.
The mechanisms of pain-related plasticity in the amygdala are only beginning to emerge, but glutamate receptors appear to be of critical importance. Metabotropic glutamate receptors (mGluRs) form a family of G-protein coupled receptors and have been implicated in neuroplasticity associated with normal brain functions as well as in a variety of nervous system disorders [24, 25]. It is clear now that mGluRs also play an important role in nociception and pain [26–30]. Eight mGluR subtypes have been cloned to date and are classified into groups I (mGluR1,5), II (mGluR2,3) and III (mGluR4,6,7,8). Group I mGluRs couple to the activation of phospholipase C, resulting in calcium release from intracellular stores and protein kinase C (PKC) activation. In contrast, groups II and III mGluRs are negatively coupled to adenylyl cyclase, thereby inhibiting cyclic AMP (cAMP) formation and cAMP-dependent protein kinase (PKA) activation.
Our previous studies showed that arthritis pain-related sensitization and synaptic plasticity in the CeLC depend on presynaptic group I mGluR upregulation [19, 21] and on postsynaptic N-methyl-D-aspartate (NMDA) receptor phosphorylation through the cAMP-dependent protein kinase PKA [20, 22]. PKA activation is accomplished through postsynaptic calcitonin gene-related (CGRP1) receptors . Conversely, activation of presynaptic group III mGluRs inhibited pain-related synaptic plasticity in the CeLC .
Here we analyze the role of group II mGluRs in pain-related plasticity in the CeLC. The rationale is as follows. 1) Group II mGluRs couple to the inhibition of stimulated cAMP formation, and cAMP-dependent PKA plays an important role in pain-related plasticity in the CeLC [5, 20, 22]. 2) There is evidence to suggest that group II mGluRs on primary afferents, in the spinal cord and brainstem modulate nociceptive processing but the role group II mGluRs in higher brain centers in prolonged or chronic pain states remains to be determined [26, 27, 29, 30]. 3) Finally, potential clinical indications for group II mGluR agonists include anxiety disorders [24, 31], which critically involve the amygdala; the reciprocal relationship between pain and anxiety is well documented .
A selective group II mGluR agonist (LY354740) inhibits pain-related synaptic plasticity more potently than normal synaptic transmission
Our previous studies showed that CeLC neurons undergo several neuroplastic changes in the kaolin/carrageenan mono-arthritis pain model [8, 21–23]. These changes include enhanced input-output functions of synaptic transmission at the PB-CeLC synapse (part of the spino-parabrachio-amygdaloid pain pathway [see ]), enhanced excitability and altered intrinsic membrane properties such as resting membrane potential, input resistance, membrane slope conductance and action potential threshold. These observations indicate synaptic and neural plasticity because arthritis pain-related changes are preserved in the reduced slice preparation and maintained, at least in part, independently of peripheral and spinal pain mechanisms [see ].
A selective group II mGluR antagonist (EGLU) reverses the effects of LY354740
LY354740 acts pre- rather than postsynaptically in the CeLC
The analysis of spontaneous mEPSCs in the presence of TTX is a well established electrophysiological approach to determine pre- versus post-synaptic mechanisms. Presynaptic changes at the transmitter release site affect mEPSC frequency, whereas changes at the postsynaptic membrane would alter mEPSC amplitude (quantal size) [8, 33]. LY354740 decreased the frequency, but not amplitude, of mEPSCs recorded in TTX (1 μM)-containing ACSF in slices from arthritic rats (Fig. 3). This presynaptic effect is illustrated in the current traces recorded in voltage-clamp mode in an individual CeLC neuron (Fig. 3A). In the sample of neurons, LY354740 decreased the mean mEPSC frequency significantly (53.4 ± 12.8% of predrug, P < 0.05, paired t-test, n = 4; Fig. 3B). LY354740 had no effect on the amplitude of mEPSCs (103 ± 5.83% of predrug, P > 0.05, paired t-test, n = 4; Fig. 3C). In the absence of evidence for postsynaptic mechanisms at the concentration of maximal effect (1 μM), it is unlikely that any postsynaptic effects are caused by lower concentrations, at which the lower potency o fLY354740 under normal conditions compared to arthritis is revealed.
Concentrations of LY354740 that clearly decreased synaptic transmission did not change the membrane slope conductance measured from the current-voltage (I-V) relationships. Fig. 4A shows steady-state current traces elicited by a series of voltage steps in an individual CeLC neuron before (control) and during application of LY354740 (1 μM). The I-V relationship calculated from the steady state current traces shown in Fig. 4A did not change in the presence of LY354740 (1 μM; Fig. 4B). The data for the sample of neurons (n = 13) are summarized in Fig. 4C. LY354740 (1 nM – 1 μM) had no significant effect on the membrane slope conductances measured from the I-V relationships of individual neurons.
LY354740 had no significant effect on neuronal excitability (Fig. 5). Action potentials were evoked in current-clamp mode by direct intracellular depolarizing current injections (500 ms) of increasing magnitude through the patch electrode (Fig. 5A). Input-output functions of neuronal excitability were obtained by averaging the frequency of action potentials evoked at each current intensity (Fig. 5B). LY354740 (1 μM) had no significant effect on action potential ("spike") firing rate in neurons from arthritic rats.
Taken together, the significant reduction of mEPSC frequency, but not amplitude, and the lack of intrinsic membrane property changes in the presence of LY354740 suggest that group II mGluR-mediated inhibition of synaptic transmission occurs through a pre- rather than postsynaptic mechanism.
The present study is the first to show that group II mGluRs act as modulators to inhibit pain-related synaptic plasticity in the amygdala. The major findings of this study are as follows: (1) A selective group II mGluR agonist (LY354740) inhibits normal synaptic transmission in slices from normal rats and synaptic plasticity in neurons from arthritic rats. (2) LY354740 is more potent (25-fold) in CeLC neurons from animals with arthritis compared to control neurons from normal animals. (3) Antagonist (EGLU) studies show that the effects of LY354740 are receptor-mediated, but there is no evidence for intrinsic/endogenous receptor activation in slices. (4) The inhibitory effects of LY354740 on mEPSC frequency, but not amplitude, and the lack of effect on membrane properties suggest a pre- rather than postsynaptic mechanism of group II mGluR action in the CeLC.
The increased potency of LY354740 in neurons from arthritic rats could be explained by increased amount of receptor expression or increased receptor affinity for the agonist. Since the efficacy (maximum effect) of the agonist was not changed in the arthritis pain model, it is less likely that enhanced coupling efficiency to G-protein mediated second-messenger systems is involved. Group II mGluRs inhibit adenylyl cyclase via Gi/Go proteins, resulting in decreased cyclic AMP (cAMP) formation and cAMP-dependent protein kinase (PKA) activation [25, 26, 30].
The underlying mechanism of increased group II mGluR function remains to be determined. Differential changes of synaptic inhibition by group II mGluRs in the amygdala (including the CeLC) have been shown in other models of neuroplasticity. Chronic cocaine treatment abolished the effects of group II mGluR agonists on synaptic transmission while increased potencies of group II mGluR agonists were observed in the kindling model of epilepsy [34, 35]. Increased inhibition of synaptic transmission in the amygdala by group III mGluRs, which couple to similar signal transduction pathways as group II mGluRs, were observed in the arthritis pain model , following chronic cocaine  and in the kindling model of epilepsy [34, 35]. These data suggest that group II mGluR function depends on the type or origin of neuroplasticity and is modulated differently than that of group III mGluRs.
The inhibitory effect of LY354740 was reversed by a selective and competitive group II mGluR antagonist (EGLU), confirming that the effects of LY354740 were receptor-mediated. Although higher agonist potency was observed in the arthritic pain model, the fact that EGLU itself had no significant effect on synaptic transmission would argue against any intrinsic/endogenous activation of these receptors in vitro. The absence of effects of EGLU on its own does not seem to be due to insufficient drug concentrations at the receptor because EGLU was able to reverse the inhibitory effect of the exogenously applied agonist (LY354740). Group II mGluRs show predominantly extra-synaptic localizations [24, 25, 36] such that they are not readily accessible by endogenous glutamate release from synaptic vesicles. Thus, antagonists would fail to produce any effects by themselves. Indeed, antagonist studies have reported a lack of endogenous activation of group II mGluRs for several brain areas [34, 37, 38]. Since the exogenous activation of group II mGluRs by LY354740 inhibited presynaptic neurotransmitter release more potently in the arthritic pain model than under normal conditions, group II mGluR agonists could be useful therapeutics for the management of arthritic pain and its emotional-affective component. Importantly, group II mGluRs are becoming intriguing drug targets for a variety of neuropsychiatric disorders, most notably anxiety and depression, which are intimately linked to pain [24, 31].
The present study suggests a presynaptic mechanism of group II mGluR effects at the PB-CeLC synapse. Evidence for a presynaptic site also comes from in situ hybridization data showing a relatively high expression of group II mRNA in the parabrachial nucleus (origin of the PB-CeLC afferents) but not in the central nucleus [39, 40]. Presynaptic inhibition by group II mGluRs has been observed in several different brain regions including synapses in the basolateral and central nuclei of the amygdala [34, 35], substantia nigra pars compacta , hippocampal areas [42, 43] and corticostriatal synapses .
Group II mGluRs have been implicated in nociceptive processing at different levels of the pain neuraxis, but their roles are less well understood than those of group I mGluRs. Activation of group II mGluRs in peripheral tissues had antinociceptive effects in models of inflammatory [27, 45, 46] and neuropathic pain . Conversely, blockade of peripheral group II mGluRs (LY341495) prolonged PGE2- and carrageenan-induced mechanical allodynia, suggesting that peripheral group II mGluRs mediate endogenous anti-allodynic effects . Similarly, peripheral injection of a group II/III antagonist [MSOPPE, (RS)-alpha-methylserine-O-phosphate monophenyl ester] enhanced glutamate-induced mechanical allodynia . Activation of spinal group II mGluRs inhibited behavior [48, 49] and central sensitization [50, 51] related to inflammatory pain. Intracisternal and systemic, but not intrathecal, administration of group II agonists inhibited formalin-induced pain behavior [52, 53]. Behavioral data suggest that group II mGluRs in the periaqueductal gray (PAG) inhibit descending facilitation of pain behavior thus activating descending pain inhibition . Activation of group II in the ventrobasal thalamus resulted in the disinhibition of nociceptive processing through the presynaptic reduction of GABAergic inhibition .
Male Sprague Dawley rats (90 g–190 g; mean 130 g) were housed in a temperature controlled room and maintained on a 12 h day/night cycle. Water and food were available ad libitum. Electrophysiological data were obtained from untreated normal rats and rats with monoarthritis in the knee (6 h after induction). All experimental procedures were approved by the Institutional Animal Care and Use Committee (IACUC) at the University of Texas Medical Branch (UTMB) and conform to the guidelines of the International Association for the Study of Pain (IASP) and of the National Institutes of Health (NIH).
Arthritis pain model
In the group of arthritic rats, arthritis was induced in the left knee joint as previously described [8, 19–21]. A kaolin suspension (4%, 100 μl) was injected into the left knee joint cavity through the patellar ligament. After repetitive flexions and extensions of the knee for 15 minutes, a carrageenan solution (2%, 100 μl) was injected into the knee joint cavity, and the leg was flexed and extended for another 5 minutes. Brain slices for the electrophysiological studies were obtained 6 hours after arthritis induction.
Amygdala slice preparation
After decapitation, the brains were quickly dissected out and blocked in cold (4°C) artificial cerebrospinal fluid (ACSF) containing (in mM) 117 NaCl, 4.7 KCl, 1.2 NaH2PO4, 2.5 CaCl2, 1.2 MgCl2, 25 NaHCO3, and 11 glucose. ACSF was oxygenated and equilibrated to pH7.4 with a mixture of 95% O2 and 5% CO2. Coronal brain slices (500 μm) containing the CeLC were prepared using a Vibroslice (Camden instruments, London, UK). The slices were then incubated in ACSF at room temperature (21°C) for at least 1 h and a single brain slice was transferred to the recording chamber and submerged in ACSF (31 ± 1°C), which superfused the slice at ~2 ml/min.
Whole-cell patch-clamp recording
Whole-cell patch-clamp recordings using the "blind" patch technique were obtained from CeLC neurons as described before [8, 13, 21, 22]. Patch electrodes were made from 1.5 mm borosilicate glass capillaries (1.5 mm outer diameter, 1.12 mm inner diameter; Drummond, Broomall, PA) pulled on a Flaming-Brown micropipette puller (P-80/PC; Sutter Instrument Co., Novato, CA). Recording electrodes were positioned in the CeLC under visual control. The boundaries of the CeLC are easily discerned under light microscopy (see Fig. 8A in ); each slice was matched with the corresponding level in Paxinos and Watson (1998). The internal solution of the recording electrodes (4- to 6-MΩ tip resistance) contained (in mM) 122 K-gluconate, 5 NaCl, 0.3 CaCl2, 2 MgCl2, 1 EGTA, 10 HEPES, 5 Na2-ATP, and 0.4 Na3-GTP; pH was adjusted to 7.2–7.3 with KOH and the osmolarity to 280 mmol/kg with sucrose.
After tight (>1GΩ) seals were formed and the whole-cell configuration was obtained, neurons were included in the sample if the resting membrane potential was more negative than -50 mV and action potentials overshooting 0 mV were evoked by direct cathodal stimulation. Voltage and current signals were low-pass filtered at 1 kHz with a dual 4-pole Bessel filter (Warner Instrument Corp., Hamden, CT), digitized at 5 KHz (Digidata 1322 interface, Axon Instruments, Foster City, CA), and stored on a Pentium 4 computer (Dell). Data were also continuously recorded on a pen chart recorder (Gould 3400, Gould Instr., Valley View, OH). Evoked potential and evoked current data were acquired and analyzed using pCLAMP8 software (Axon Instruments, Foster City, CA). Discontinuous single-electrode voltage clamp (d-SEVC) recordings were acquired using an Axoclamp-2B amplifier (Axon Instruments) with a switching frequency of 5–6 kHz (30% duty cycle), gain of 3–8 nA/mV, and time constant of 20 ms. Phase shift and anti-alias filter were optimized. The headstage voltage was monitored continuously on a digital oscilloscope (Gould 400, Gould Instr., Modesto, CA) to ensure precise performance of the amplifier. Neurons were held at -60 mV.
We studied transmission at the parabrachial area (PB)-CeLC synapse that provides nociceptive input to the CeLC from the spinal cord and brainstem (see Introduction). Using a concentric bipolar stimulating electrode (Kopf Instruments) of 22 kΩ resistance, excitatory postsynaptic currents (EPSCs) were evoked in CeA neurons by electrical stimulation (using a Grass S88 stimulator, Grass Instr.) of the PB-CeLC synapse. The stimulation electrode was positioned under microscopic control on the fibers dorsomedial to the CeA and ventral to but outside of the caudate-putamen [8, 21, 22] (see Fig. 8A in ). Electrical stimuli (150 μs square-wave pulses) were delivered at frequencies below 0.25 Hz. Input-output relations were obtained by increasing the stimulus intensity in 100 μA steps. For evaluation of a drug effect on synaptically evoked responses, the stimulus intensity was adjusted to 80% of the intensity required for orthodromic spike generation, which was on average 350–450 μA.
The following drugs were used: (S)-alpha-ethylglutamic acid (EGLU; selective group II mGluR antagonist [25, 32], purchased from Tocris Cookson Inc., Ellisville, MO; (+)-2-aminobicyclo [3.1.0] hexane-2,6-dicarboxylic acid (LY354740; selective group II mGluR agonist [24, 31], a generous gift from Eli Lilly and Company. All drugs were dissolved in ACSF and applied by gravity-driven superfusion of the slice in ACSF. Solution flow into the recording chamber (1 ml volume) was controlled with a three-way stopcock. Drug applications were for at least 10 min in duration to establish equilibrium in the tissue.
Data analysis and statistics
All averaged values are given as the mean ± SE. Statistical significance was accepted at the level of P < 0.05. Concentration-response relationships were compared using a two-way analysis of variance (ANOVA). IC50 values were calculated from sigmoid curves fitted to the cumulative concentration-response data by nonlinear regression using the formula y = A + (B - A)/[1 + (10 C /10 X ) D ], where A = bottom plateau, B = top plateau, C = log(IC50), D = slope coefficient (GraphPad Prism 3.0). Using the linear curve fit function of pClamp software (Axon Instruments), membrane slope conductances (in nS) in the absence and presence of agonists were calculated from the linear portion of the current-voltage (I-V) relationships recorded in voltage-clamp mode. An ANOVA with post-hoc Dunnett's test was used to compare the drug effects on membrane slope conductance to the predrug control value. Drug effects (agonist and antagonist) were compared to predrug control values using the paired t-test. mEPSCs were analyzed for frequency and amplitude distributions using the MiniAnalysis program 5.3 (Synaptosoft Inc., Decatur, GA). The detection threshold was set to 3 times the average RMS noise level during event-free sections (typically 10 pA; see Fig. 3C). The analysis was re-checked manually. The Kolmogorov-Smirnov test was used for the cumulative distribution analysis of mEPSC amplitude and frequency while the paired t-test compared mean amplitude and frequency of mEPSCs.
Activation of presynaptic group II mGluRs in the CeLC inhibits synaptic plasticity in a model of arthritis pain more potently than normal synaptic transmission, suggesting that presynaptic group II mGluRs in the CeLC may be potential therapeutic targets for pain relief.
We would like to thank Dr. William D. Willis for critical reading of and helpful comments on the manuscript. We also thank Mrs. Vicki Wilson for secretarial assistance. This work was supported by NIH grants NS38261 and NS11255 and John Sealy Endowment Fund 2521-04.
- Phelps EA, Ledoux JE: Contributions of the Amygdala to Emotion Processing: From Animal Models to Human Behavior. Neuron 2005, 48: 175–187. 10.1016/j.neuron.2005.09.025PubMedView ArticleGoogle Scholar
- Davidson RJ: Anxiety and affective style: role of prefrontal cortex and amygdala. Biol Psychiatry 2002, 51: 68–80. 10.1016/S0006-3223(01)01328-2PubMedView ArticleGoogle Scholar
- Maren S: Synaptic Mechanisms of Associative Memory in the Amygdala. Neuron 2005, 47: 783–786. 10.1016/j.neuron.2005.08.009PubMedView ArticleGoogle Scholar
- Gallagher RM, Verma S: Mood and anxiety disorders in chronic pain. Prog in Pain Res Management 2004, 27: 139–178.Google Scholar
- Neugebauer V, Li W, Bird GC, Han JS: The amygdala and persistent pain. The Neuroscientist 2004, 10: 221–234. 10.1177/1073858403261077PubMedView ArticleGoogle Scholar
- Hebert MA, Ardid D, Henrie JA, Tamashiro K, Blanchard DC, Blanchard RJ: Amygdala lesions produce analgesia in a novel, ethologically relevant acute pain test. Physiol Behav 1999, 67: 99–105. 10.1016/S0031-9384(99)00042-6PubMedView ArticleGoogle Scholar
- Nandigama P, Borszcz GS: Affective analgesia following the administration of morphine into the amygdala of rats. Brain Res 2003, 959: 343–354. 10.1016/S0006-8993(02)03884-2PubMedView ArticleGoogle Scholar
- Han JS, Li W, Neugebauer V: Critical role of calcitonin gene-related peptide 1 receptors in the amygdala in synaptic plasticity and pain behavior. J Neurosci 2005, 25: 10717–10728. 10.1523/JNEUROSCI.4112-05.2005PubMedView ArticleGoogle Scholar
- Bornhovd K, Quante M, Glauche V, Bromm B, Weiller C, Buchel C: Painful stimuli evoke different stimulus-response functions in the amygdala, prefrontal, insula and somatosensory cortex: a single-trial fMRI study. Brain 2002, 125: 1326–1336. 10.1093/brain/awf137PubMedView ArticleGoogle Scholar
- Bonaz B, Baciu M, Papillon E, Bost R, Gueddah N, Le Bas JF, Fournet J, Segebarth C: Central processing of rectal pain in patients with irritable bowel syndrome: an fMRI study. Am J Gastroenterol 2002, 97: 654–661. 10.1111/j.1572-0241.2002.05545.xPubMedView ArticleGoogle Scholar
- Schneider F, Habel U, Holthusen H, Kessler C, Posse S, Muller-Gartner HW, Arndt JO: Subjective ratings of pain correlate with subcortical-limbic blood flow: an fMRI study. Neuropsychobiology 2001, 43: 175–185. 10.1159/000054887PubMedView ArticleGoogle Scholar
- Bingel U, Quante M, Knab R, Bromm B, Weiller C, Buchel C: Subcortical structures involved in pain processing: evidence from single-trial fMRI. Pain 2002, 99: 313–321. 10.1016/S0304-3959(02)00157-4PubMedView ArticleGoogle Scholar
- Gauriau C, Bernard J-F: Pain pathways and parabrachial circuits in the rat. Exp Physiol 2002, 87: 251–258. 10.1113/eph8702357PubMedView ArticleGoogle Scholar
- Jasmin L, Burkey AR, Card JP, Basbaum AI: Transneuronal labeling of a nociceptive pathway, the spino-(trigemino-)parabrachio-amygdaloid, in the rat. J Neurosci 1997, 17: 3751–3765.PubMedGoogle Scholar
- Braz JM, Nassar MA, Wood JN, Basbaum AI: Parallel "pain" pathways arise from subpopulations of primary afferent nociceptor. Neuron 2005, 47: 787–793. 10.1016/j.neuron.2005.08.015PubMedView ArticleGoogle Scholar
- LeDoux JE: Emotion circuits in the brain. Ann Rev Neuroscience 2000, 23: 155–184. 10.1146/annurev.neuro.23.1.155View ArticleGoogle Scholar
- Heinricher MM, McGaraughty S: Pain-modulating neurons and behavioral state. In Handbook of Behavioral State Control. Edited by: Lydic R, Baghdoyan HA. New york: CRC Press; 1999:487–503.Google Scholar
- Neugebauer V, Li W: Differential sensitization of amygdala neurons to afferent inputs in a model of arthritic pain. J Neurophysiol 2003, 89: 716–727.PubMedView ArticleGoogle Scholar
- Li W, Neugebauer V: Differential roles of mGluR1 and mGluR5 in brief and prolonged nociceptive processing in central amygdala neurons. J Neurophysiol 2004, 91: 13–24. 10.1152/jn.00485.2003PubMedView ArticleGoogle Scholar
- Li W, Neugebauer V: Block of NMDA and non-NMDA receptor activation results in reduced background and evoked activity of central amygdala neurons in a model of arthritic pain. Pain 2004, 110: 112–122. 10.1016/j.pain.2004.03.015PubMedView ArticleGoogle Scholar
- Neugebauer V, Li W, Bird GC, Bhave G, Gereau RW: Synaptic plasticity in the amygdala in a model of arthritic pain: differential roles of metabotropic glutamate receptors 1 and 5. J Neurosci 2003, 23: 52–63.PubMedGoogle Scholar
- Bird GC, Lash LL, Han JS, Zou X, Willis WD, Neugebauer V: PKA-dependent enhanced NMDA receptor function in pain-related synaptic plasticity in amygdala neurons. J Physiol 2005, 564.3: 907–921. 10.1113/jphysiol.2005.084780View ArticleGoogle Scholar
- Han JS, Bird GC, Neugebauer V: Enhanced group III mGluR-mediated inhibition of pain-related synaptic plasticity in the amygdala. Neuropharmacology 2004, 46: 918–926. 10.1016/j.neuropharm.2004.01.006PubMedView ArticleGoogle Scholar
- Swanson CJ, Bures M, Johnson MP, Linden AM, Monn JA, Schoepp DD: Metabotropic glutamate receptors as novel targets for anxiety and stress disorders. Nat Rev Drug Discov 2005, 4: 131–144. 10.1038/nrd1630PubMedView ArticleGoogle Scholar
- Schoepp DD, Jane DE, Monn JA: Pharmacological agents acting at subtypes of metabotropic glutamate receptors. Neuropharmacology 1999, 38: 1431–1476. 10.1016/S0028-3908(99)00092-1PubMedView ArticleGoogle Scholar
- Neugebauer V: Metabotropic glutamate receptors: novel targets for pain relief. Exp Rev Neurother 2001, 1: 207–224. 10.1586/14737220.127.116.11View ArticleGoogle Scholar
- Neugebauer V, Carlton SM: Peripheral metabotropic glutamate receptors as drug targets for pain relief. Expert Opin on Ther Targets 2002, 6: 349–361. 10.1517/1472818.104.22.1689View ArticleGoogle Scholar
- Lesage ASJ: Role of group I metabotropic glutamate receptors mGlu1 and mGlu5 in nociceptive signalling. Curr Neuropharm 2004, 2: 363–393. 10.2174/1570159043359549View ArticleGoogle Scholar
- Fundytus ME: Glutamate receptors and nociception. Implications for the drug treatment of pain. CNS Drugs 2001, 15: 29–58. 10.2165/00023210-200115010-00004PubMedView ArticleGoogle Scholar
- Varney MA, Gereau RW: Metabotropic glutamate receptor involvement in models of acute and persistent pain: prospects for the development of novel analgesics. Current Drug Targets 2002, 1: 215–225. 10.2174/1568010023344625View ArticleGoogle Scholar
- Marek GJ: Metabotropic glutamate 2/3 receptors as drug targets. Curr Opin Pharmacol 2004, 4: 18–22. 10.1016/j.coph.2003.10.003PubMedView ArticleGoogle Scholar
- Jane DE, Thomas NK, Tse HW, Watkins JC: Potent antagonists at the L-AP4- and (1S,3S)-ACPD-sensitive presynaptic metabotropic glutamate receptors in the neonatal rat spinal cord. Neuropharmacology 1996, 35: 1029–1035. 10.1016/S0028-3908(96)00048-2PubMedView ArticleGoogle Scholar
- McKernan MG, Shinnick-Gallagher P: Fear conditioning induces a lasting potentiation of synaptic currents in vitro. Nature 1997, 390: 607–611. 10.1038/37605PubMedView ArticleGoogle Scholar
- Neugebauer V, Keele NB, Shinnick-Gallagher P: Epileptogenesis in vivo enhances the sensitivity of inhibitory presynaptic metabotropic glutamate receptors in basolateral amygdala neurons in vitro. J Neurosci 1997, 17: 983–995.PubMedGoogle Scholar
- Neugebauer V, Zinebi F, Russell R, Gallagher JP, Shinnick-Gallagher P: Cocaine and kindling alter the sensitivity of group II and III metabotropic glutamate receptors in the central amygdala. J Neurophysiol 2000, 84: 759–770.PubMedGoogle Scholar
- Cartmell J, Schoepp DD: Regulation of neurotransmitter release by metabotropic glutamate receptors. J Neurochem 2000, 75: 889–907. 10.1046/j.1471-4159.2000.0750889.xPubMedView ArticleGoogle Scholar
- Bushell TJ, Jane DE, Tse HW, Watkins JC, Garthwaite J, Collingridge GL: Pharmacological antagonism of the actions of group II and III mGluR agonists in the lateral perforant path of rat hippocampal slices. Br J Pharmacol 1996, 117: 1457–1462.PubMed CentralPubMedView ArticleGoogle Scholar
- Salt TE, Eaton SA, Turner JP: Characterization of the metabotropic glutamate receptors (mGluRs) which modulate GABA-mediated inhibition in the ventrobasal thalamus. Neurochem Int 1996, 29: 317–322. 10.1016/0197-0186(95)00146-8PubMedView ArticleGoogle Scholar
- Ohishi H, Shigemoto R, Nakanishi S, Mizuno N: Distribution of the mRNA for a metabotropic glutamate receptor (mGluR3) in the rat brain: an in situ hybridization study. J Comp Neurol 1993, 335: 252–266. 10.1002/cne.903350209PubMedView ArticleGoogle Scholar
- Ohishi H, Shigemoto R, Nakanishi S, Mizuno N: Distribution of the messenger RNA for a metabotropic glutamate receptor, mGluR2, in the central nervous system of the rat. Neuroscience 1993, 53: 1009–1018. 10.1016/0306-4522(93)90485-XPubMedView ArticleGoogle Scholar
- Wang L, Kitai ST, Xiang Z: Modulation of excitatory synaptic transmission by endogenous glutamate acting on presynaptic group II mGluRs in rat substantia nigra compacta. J Neurosci Res 2005, 82: 778–787. 10.1002/jnr.20694PubMedView ArticleGoogle Scholar
- Price CJ, Karayannis T, Pal BZ, Capogna M: Group II and III mGluRs-mediated presynaptic inhibition of EPSCs recorded from hippocampal interneurons of CA1 stratum lacunosum moleculare. Neuropharmacology 2005,49(Suppl 1):45–56. 10.1016/j.neuropharm.2005.05.009PubMedView ArticleGoogle Scholar
- Manzoni OJ, Castillo PE, Nicoll RA: Pharmacology of metabotropic glutamate receptors at the mossy fiber synapses of the guinea pig hippocampus. Neuropharmacology 1995, 34: 965–971. 10.1016/0028-3908(95)00060-JPubMedView ArticleGoogle Scholar
- Lovinger DM, McCool BA: Metabotropic glutamate receptor-mediated presynaptic depression at corticostriatal synapses involves mGLuR2 or 3. J Neurophysiol 1995, 73: 1076–1083.PubMedGoogle Scholar
- Yang D, Gereau RW: Peripheral Group II Metabotropic Glutamate Receptors (mGluR2/3) Regulate Prostaglandin E2-Mediated Sensitization of Capsaicin Responses and Thermal Nociception. J Neurosci 2002, 22: 6388–6393.PubMedGoogle Scholar
- Yang D, Gereau RW: Peripheral group II metabotropic glutamate receptors mediate endogenous anti-allodynia in inflammation. Pain 2003, 106: 411–417. 10.1016/j.pain.2003.08.011PubMedView ArticleGoogle Scholar
- Jang JH, Kim DW, Sang Nam T, Se Paik K, Leem JW: Peripheral glutamate receptors contribute to mechanical hyperalgesia in a neuropathic pain model of the rat. Neuroscience 2004, 128: 169–176. 10.1016/j.neuroscience.2004.06.040PubMedView ArticleGoogle Scholar
- Dolan S, Nolan AM: Behavioral evidence supporting a differential role for spinal group I and II metabotropic glutamate receptors in inflammatory hyperalgesia in sheep. Neuropharmacology 2002, 43: 319–326. 10.1016/S0028-3908(02)00107-7PubMedView ArticleGoogle Scholar
- Soliman AC, Yu JSC, Coderre TJ: mGlu and NMDA receptor contributions to capsaicin-induced thermal and mechanical hypersensitivity. Neuropharmacology 2005, 48: 325–332. 10.1016/j.neuropharm.2004.10.014PubMedView ArticleGoogle Scholar
- Neugebauer V, Chen P-S, Willis WD: Groups II and III metabotropic glutamate receptors differentially modulate brief and prolonged nociception in primate STT cells. J Neurophysiol 2000, 84: 2998–3009.PubMedGoogle Scholar
- Stanfa LC, Dickenson AH: Inflammation alters the effects of mGlu receptor agonists on spinal nociceptive neurones. Eur J Pharmacol 1998, 347: 165–172. 10.1016/S0014-2999(98)00098-3PubMedView ArticleGoogle Scholar
- Jones CK, Eberle EL, Peters SC, Monn JA, Shannon HE: Analgesic effects of the selective group II (mGlu2/3) metabotropic glutamate receptor agonists LY379268 and LY389795 in persistent and inflammatory pain models after acute and repeated dosing. Neuropharmacology 2005, 49: 206–218. 10.1016/j.neuropharm.2005.05.008PubMedView ArticleGoogle Scholar
- Simmons RM, Webster AA, Kalra AB, Iyengar S: Group II mGluR receptor agonists are effective in persistent and neuropathic pain models in rats. Pharmacol Biochem and Behav 2002, 73: 419–427. 10.1016/S0091-3057(02)00849-3View ArticleGoogle Scholar
- Maione S, Oliva P, Marabese I, Palazzo E, Rossi F, Berrino L, Rossi F, Filippelli A: Periaqueductal gray matter metabotropic glutamate receptors modulate formalin-induced nociception. Pain 2000, 85: 183–189. 10.1016/S0304-3959(99)00269-9PubMedView ArticleGoogle Scholar
- Salt TE: Glutamate receptor functions in sensory relay in the thalamus. Philos Trans R Soc of Lond B, Biol Sci 2002, 357: 1759–1766. 10.1098/rstb.2002.1165View ArticleGoogle Scholar
This article is published under license to 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.