title: Time-dependent cross talk between spinal serotonin 5-HT2A receptor and mGluR1 subserves spinal hyperexcitability and neuropathic pain after nerve injury.
abstract: Emerging evidence implicates serotonergic descending facilitatory pathways from the brainstem to the spinal cord in the maintenance of pathologic pain. Upregulation of the serotonin receptor 2A (5-HT(2A)R) in dorsal horn neurons promotes spinal hyperexcitation and impairs spinal μ-opioid mechanisms during neuropathic pain. We investigated the involvement of spinal glutamate receptors, including metabotropic receptors (mGluRs) and NMDA, in 5-HT(2A)R-induced hyperexcitability after spinal nerve ligation (SNL) in rat. High-affinity 5-HT(2A)R agonist (4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine hydrobromide (TCB-2) enhanced C-fiber-evoked dorsal horn potentials after SNL, which was prevented by mGluR1 antagonist AIDA [(RS)-1-aminoindan-1,5-dicarboxylic acid] but not by group II mGluR antagonist LY 341495 [(2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl)propanoic acid] or NMDA antagonist d-AP5 [D-(-)-2-amino-5-phosphonopentanoic acid]. 5-HT(2A)R and mGluR1 were found to be coexpressed in postsynaptic densities in dorsal horn neurons. In the absence of SNL, pharmacological stimulation of 5-HT(2A)R with TCB-2 both induced rapid bilateral upregulation of mGluR1 expression in cytoplasmic and synaptic fractions of spinal cord homogenates, which was attenuated by PKC inhibitor chelerythrine, and enhanced evoked potentials during costimulation of mGluR1 with 3,5-DHPG [(RS)-3,5-dihydroxyphenylglycine]. SNL was followed by bilateral upregulation of mGluR1 in 5-HT(2A)R-containing postsynaptic densities. Upregulation of mGluR1 in synaptic compartments was partially prevented by chronic administration of selective 5-HT(2A)R antagonist M100907 [(R)-(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-pipidinemethanol], confirming 5-HT(2A)R-mediated control of mGluR1 upregulation triggered by SNL. Changes in thermal and mechanical pain thresholds following SNL were increasingly reversed over the days after injury by chronic 5-HT(2A)R blockade. These results emphasize a role for 5-HT(2A)R in hyperexcitation and pain after nerve injury and support mGluR1 upregulation as a novel feedforward activation mechanism contributing to 5-HT(2A)R-mediated facilitation.
authors.affiliation: Department of Neurosciences, School of Medicine and Dentistry, University of the Basque Country, 48080 Bilbao, Bizkaia, Spain.
authors.forename: Zigor
authors.initials: Z
authors.lastname: Aira
authors.forename: Itsaso
authors.initials: I
authors.lastname: Buesa
authors.forename: Mónica
authors.initials: M
authors.lastname: Gallego
authors.forename: Gontzal
authors.initials: G
authors.lastname: García del Caño
authors.forename: Nahia
authors.initials: N
authors.lastname: Mendiable
authors.forename: Janire
authors.initials: J
authors.lastname: Mingo
authors.forename: Diego
authors.initials: D
authors.lastname: Rada
authors.forename: Juan
authors.initials: J
authors.lastname: Bilbao
authors.forename: Manfred
authors.initials: M
authors.lastname: Zimmermann
authors.forename: Jon Jatsu
authors.initials: JJ
authors.lastname: Azkue
mesh_terms: D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D002461:Cell Line, Transformed; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D008744:Methylamines / Q000494:pharmacology; D036421:Nerve Fibers, Unmyelinated / Q000502:physiology; D009437:Neuralgia / Q000209:etiology* / Q000473:pathology*; D010455:Peptides / Q000494:pharmacology; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D018490:Serotonin Agents / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D013127:Spinal Nerves / Q000293:injuries*; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014162:Transfection
chemical_list: C514172:(4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine; D001643:Bridged Bicyclo Compounds; D018683:Excitatory Amino Acid Agents; D008744:Methylamines; D010455:Peptides; D044402:Receptor, Serotonin, 5-HT2A; D018094:Receptors, Metabotropic Glutamate; D018490:Serotonin Agents; C104077:metabotropic glutamate receptor type 1