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

Abstract

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.

Role of Extracellular Signal-Regulated Kinase in Synaptic Transmission and Plasticity of a Nociceptive Input on Capsular Central Amygdaloid Neurons in Normal and Acid-Induced Muscle Pain Mice

“…Accordingly, we propose that, in AIMP mice, an excessive nociceptive signal triggered by acidic saline injection into the gastrocnemius muscle activates ERK in the central amygdala, thereby enhancing PBA-CeAC synaptic transmission [see also Neugebauer et al (2003Neugebauer et al ( , 2004 and Ikeda et al (2007)]. Although the observation of increased pERK levels in the CeAC is consistent with previous studies, there is a substantial difference between the results of the present study and those of previous studies, in which mechanical hypersensitivity was shown to be functionally lateralized to the right amygdala in intraplantar formalin and arthritic models (Carrasquillo and Gereau, 2008;Ji and Neugebauer, 2009;Kolber et al, 2010). However, the results of the present study showed that functional lateralization of mechanical hypersensitivity to the right amygdala did not occur in the AIMP model.…”

“…Accordingly, these observations showed that the strength of the overall synaptic inputs other than the PBA input onto CeAC neurons was also enhanced in AIMP mice, with both presynaptic and postsynaptic modulation being involved. Since previous studies have demonstrated lateralization of behavioral hypersensitivity and CeAC neuronal excitability in rats (Carrasquillo and Gereau, 2008;Ji and Neugebauer, 2009;Kolber et al, 2010), we compared aEPSC recorded from a further four left and four right CeAC neurons in slices from animals with AIMP and tested their responses to PDA application. No significant difference in the mean amplitude and the mean number of events per trial of aEPSC was found between the left and right CeAC neurons, and the values recorded from the right and left CeAC neurons were similar to the pooled data recorded from right and left CeAC neurons shown in Figure 6 (see supplemental Fig.…”

Lateralization of observational fear learning at the cortical but not thalamic level in mice

“…However, in adult humans fearful face presentation causes event-related activation in the right amygdala and ACC (24). A number of other studies also indicated specific involvement of the right amygdala in negative emotional signaling (25)(26)(27), which suggests-along with the previously mentioned observations-the relevance of a functional asymmetry in the amygdala-ACC connection. Further studies with unilateral amygdala lesions and hemispheric difference in ACC-amygdala synchronization may provide valuable information regarding whether this brain circuit is working in social fear learning unilaterally.…”

Regulation of DREAM Expression by Group I mGluR

“…mGluR5 has been implicated in various neurological and psychiatric diseases, including anxiety, depression, pain, and Alzheimer disease [9,10]. mGluR5 has also long been related to pain, since mGluR5 antagonists such as MPEP and MTEP (3-((2-Methyl-4-thiazolyl)ethynyl)pyridine) relieve pain in several animal models, and conditional mGluR5 knockout in the central nucleus of the amygdala results in the diminution of inflammation-induced hypersensitivity [22][23][24]. Interestingly, the analgesic effect of mGluR5 is reported to be mediated by its extracellular signal-regulated kinase-linked interaction with Kv4.2, the potassium channel regulated by DREAM [25].…”