Activation of Metabotropic Glutamate Receptor 5 in the Amygdala Modulates Pain-Like Behavior

Washington University Pain Center, Department of Anesthesiology, Washington University, St. Louis, Missouri 63110, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 06/2010; 30(24):8203-13. DOI: 10.1523/JNEUROSCI.1216-10.2010
Source: PubMed


The central nucleus of the amygdala (CeA) has been identified as a site of nociceptive processing important for sensitization induced by peripheral injury. However, the cellular signaling components underlying this function remain unknown. Here, we identify metabotropic glutamate receptor 5 (mGluR5) as an integral component of nociceptive processing in the CeA. Pharmacological activation of mGluRs with (R,S)-3,5-dihydroxyphenylglycine (DHPG) in the CeA of mice is sufficient to induce peripheral hypersensitivity in the absence of injury. DHPG-induced peripheral hypersensitivity is reduced via pharmacological blockade of mGluR5 or genetic disruption of mGluR5. Furthermore, pharmacological blockade or conditional deletion of mGluR5 in the CeA abrogates inflammation-induced hypersensitivity, demonstrating the necessity of mGluR5 in CeA-mediated pain modulation. Moreover, we demonstrate that phosphorylation of extracellular-signal regulated kinase 1/2 (ERK1/2) is downstream of mGluR5 activation in the CeA and is necessary for the full expression of peripheral inflammation-induced behavioral sensitization. Finally, we present evidence of right hemispheric lateralization of mGluR5 modulation of amygdalar nociceptive processing. We demonstrate that unilateral pharmacological activation of mGluR5 in the CeA produces distinct behavioral responses depending on whether the right or left amygdala is injected. We also demonstrate significantly higher levels of mGluR5 expression in the right amygdala compared with the left under baseline conditions, suggesting a potential mechanism for right hemispheric lateralization of amygdala function in pain processing. Together, these results establish an integral role for mGluR5 and ERK1/2 in nociceptive processing in the CeA.

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    • "However, opposing results were found with selective mGluR5 antagonists, with which thermal allodynia was inhibited and mechanical allodynia was enhanced in the SNL model of neuropathic pain (Zhou et al., 2013). Activation of mGluR5 within the CeA via microinjection of selective agonists was also found to induce both somatic and visceral pain-like behaviors, effects blocked with selective antagonists (Kolber et al., 2010; Crock et al., 2012). Based on the expression of mGluRs within the amygdala and PAG, there will likely be an interaction between the stress and pain circuitries, making this receptor class a prime target for novel, subclassspecific therapeutics. "
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    ABSTRACT: While current therapeutics provide relief from acute pain, drugs used for treatments of chronic pain are typically less efficacious and limited by adverse side effects including tolerance, addiction and gastrointestinal upset. Thus, there is a significant need for novel therapies for the treatment of chronic pain. In concert with chronic pain, persistent stress facilitates pain perception and sensitizes pain pathways, leading to a feed-forward cycle promoting chronic pain disorders. Stress-exacerbation of chronic pain suggests that centrally acting drugs targeting the pain and stress responsive brain regions represent a valid target for the development of novel therapeutics. This review will provide an overview of how stress modulates spinal and central pain pathways, identify key neurotransmitters and receptors within these pathways, and highlight their potential as novel therapeutics to treat chronic pain.
    No preview · Article · Sep 2014 · Journal of Pharmacology and Experimental Therapeutics
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    • "mGluR5 is a G-protein coupled receptor localized to regions of the periphery, spinal cord and brain involved with the processing of pain [6]–[8]. Activation of mGluR5 receptors in the spinal cord and amygdala, using (R,S)-3,5-dihydroxyphenylglycine (DHPG), causes pain-like behaviors in mice, while inhibition with the prototypical antagonist, 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP), decreases these responses [9], [10]. This has led to the search for other mGluR5 agents, such as fenobam [N-(3-chlorophenyl)-N′-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl)urea], that could be used to target mGluR5. "
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    ABSTRACT: Antagonists of metabotropic glutamate receptors (mGluRs) have the potential to act as analgesic drugs that may help alleviate chronic pain. This study was done to look at the possible rewarding properties of the mGluR5 antagonist, fenobam, in a cognitive assay. Analgesic conditioned place preference (aCPP) was used to examine the effects of fenobam (30 mg/kg) and the prototypical mGluR5 antagonist, MPEP, and these effects were compared to those of a drug with known analgesic properties, morphine (10 mg/kg). In each experiment, one group of mice received spared nerve injury (SNI) surgery to model chronic pain; the other group received a control sham surgery. Both fenobam and MPEP induced preference in the SNI mice, such that SNI mice spent significantly more time in the mGluR5 antagonist-paired chamber compared to a vehicle-paired chamber. No such preference developed for sham mice. Morphine induced preference in male and female mice in both the SNI and sham groups. The results showed that fenobam and MPEP likely reduced on-going distress in the SNI mice, causing them to prefer the chamber paired with the drug compared to the vehicle-paired chamber. Since sham animals did not prefer the drug-paired chamber, these data demonstrate that mGluR5 antagonism is non-rewarding in the absence of pain-like injury.
    Full-text · Article · Jul 2014 · PLoS ONE
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    • "Interestingly, the spinal antinociceptive effect by unilateral glutamate administration into the CeA was bilateral for heat-evoked responses and predominantly contralateral for mechanically evoked responses. Moreover, the opposite effect (mechanical hypersensitivity) by an mGluR 1/5 agonist in the CeA was also contralateral [7]. Together, Fig. 3 "
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    ABSTRACT: Amygdala has an important role in the processing of primary emotions, such as fear. Additionally, amygdala is involved in processing and modulation of pain. While the amygdala, particularly its central nucleus (CeA), has been shown to contribute to pain control, the descending pain regulation by the CeA is still only partly characterized. Here heat and mechanical nociception was tested in both hind limbs of healthy rats with a chronic guide cannula for microinjection of glutamate into the CeA of the left or right hemisphere. The aim was to assess whether the descending pain regulatory effect by glutamate in the amygdala varies with the submodality or the body side of nociceptive testing, brain hemisphere or the amygdaloid glutamate receptor. Motor performance was assessed with the Rotarod test. Amygdaloid glutamate, independent of the treated hemisphere, produced a dose-related heat and mechanical antinociception that varied with the submodality of testing. Heat antinociception was short lasting (minutes), bilateral and not reversed by blocking the amygdaloid NMDA receptor with MK-801. In contrast, mechanical antinociception lasted longer (> 20min), was predominantly contralateral and reversed by blocking the amygdaloid NMDA receptor. At an antinociceptive dose, amygdaloid glutamate failed to influence motor performance. The results indicate that independent of the brain hemisphere, the spatial extent and duration of the descending antinociceptive effect induced by amygdaloid glutamate varies with the amygdaloid glutamate receptor and the submodality of pain.
    Full-text · Article · Apr 2014 · Neuroscience Letters
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