title: Nerve injury-induced changes in Homer/glutamate receptor signaling contribute to the development and maintenance of neuropathic pain.
abstract: While group 1 metabotropic glutamate receptors (mGluRs) and ionotropic N-methyl-d-aspartate (NMDA) receptors regulate nociception, the precise molecular mechanism(s) contributing to glutamate signaling in chronic pain remain unclear. Here we not only confirmed the key involvement of Homer proteins in neuropathic pain, but also distinguished between the functional roles for different Homer family members and isoforms. Chronic constriction injury (CCI) of the sciatic nerve induced long-lasting, time-dependent increases in the postsynaptic density expression of the constitutively expressed (CC) isoforms Homer1b/c and/or Homer2a/b in the spinal dorsal horn and supraspinal structures involved in nociception (prefrontal cortex, thalamus), that co-occurred with increases in their associated mGluRs, NR2 subunits of the NMDA receptor, and the activation of downstream kinases. Virus-mediated overexpression of Homer1c and Homer2b after spinal (intrathecal) virus injection exacerbated CCI-induced mechanical and cold hypersensitivity, however, Homer1 and Homer2 gene knockout (KO) mice displayed no changes in their neuropathic phenotype. In contrast, overexpression of the immediate early gene (IEG) Homer1a isoform reduced, while KO of Homer1a gene potentiated neuropathic pain hypersensitivity. Thus, nerve injury-induced increases in CC-Homers expression promote pain in pathological states, but IEG-Homer induction protects against both the development and maintenance of neuropathy. Additionally, exacerbated pain hypersensitivity in transgenic mice with reduced Homer binding to mGluR5 supports also an inhibitory role for Homer interactions with mGluR5 in mediating neuropathy. Such data indicate that nerve injury-induced changes in glutamate receptor/Homer signaling contribute in dynamic but distinct ways to neuropathic pain processing, which has relevance for the etiology of chronic pain symptoms and its treatment.
authors.affiliation: Department of Psychology and The Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, CA 93106-9660, USA School of Medicine, Pharmacy and Health, Durham University, Queens Campus, Stockton on Tees TS17 6BH, UK Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA Translational Neuroscience Facility, School of Medical Sciences, UNSW Kensington Campus, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Ilona
authors.initials: I
authors.lastname: Obara
authors.forename: Scott P
authors.initials: SP
authors.lastname: Goulding
authors.forename: Jia-Hua
authors.initials: JH
authors.lastname: Hu
authors.forename: Matthias
authors.initials: M
authors.lastname: Klugmann
authors.forename: Paul F
authors.initials: PF
authors.lastname: Worley
authors.forename: Karen K
authors.initials: KK
authors.lastname: Szumlinski
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D000072233:Homer Scaffolding Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009437:Neuralgia / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding / Q000502:physiology; D017470:Receptors, Glutamate / Q000096:biosynthesis; D018092:Kainic Acid Receptors / Q000096:biosynthesis / Q000502:physiology*; D020426:Sciatic Neuropathy / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; D000072233:Homer Scaffolding Proteins; D017470:Receptors, Glutamate; D018092:Kainic Acid Receptors; C000606623:Homer1 protein, mouse; C000606625:Homer2 protein, mouse
keywords: Group 1 metabotropic glutamate receptors; Homer proteins; NMDA receptors; Neuropathic pain; Spinal cord