title: 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.
authors.affiliation: Washington University Pain Center, Department of Anesthesiology, Washington University, St. Louis, Missouri 63110, USA.
authors.forename: Benedict J
authors.initials: BJ
authors.lastname: Kolber
authors.forename: Michael C
authors.initials: MC
authors.lastname: Montana
authors.forename: Yarimar
authors.initials: Y
authors.lastname: Carrasquillo
authors.forename: Jian
authors.initials: J
authors.lastname: Xu
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Heinemann
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Muglia
authors.forename: Robert W
authors.initials: RW
authors.lastname: Gereau
mesh_terms: D000679:Amygdala / Q000187:drug effects / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005557:Formaldehyde; D007839:Functional Laterality; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D006930:Hyperalgesia / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D010146:Pain / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology*; D010147:Pain Measurement / Q000379:methods; D011725:Pyridines / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000172:deficiency; D018092:Kainic Acid Receptors / Q000172:deficiency / Q000378:metabolism*
chemical_list: D002070:Butadienes; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D005557:Formaldehyde; D049452:Green Fluorescent Proteins; D008734:Methoxyhydroxyphenylglycol; D048052:Mitogen-Activated Protein Kinase 3; D009570:Nitriles; D011725:Pyridines; D011965:Receptors, Glucocorticoid; D018092:Kainic Acid Receptors; C113580:U 0126; C121465:6-methyl-2-(phenylethynyl)pyridine; C010117:3,4-dihydroxyphenylglycol