RT Journal Article SR Electronic T1 Time-Dependent Cross Talk between Spinal Serotonin 5-HT2A Receptor and mGluR1 Subserves Spinal Hyperexcitability and Neuropathic Pain after Nerve Injury JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 13568 OP 13581 DO 10.1523/JNEUROSCI.1364-12.2012 VO 32 IS 39 A1 Zigor Aira A1 Itsaso Buesa A1 Mónica Gallego A1 Gontzal García del Caño A1 Nahia Mendiable A1 Janire Mingo A1 Diego Rada A1 Juan Bilbao A1 Manfred Zimmermann A1 Jon Jatsu Azkue YR 2012 UL http://www.jneurosci.org/content/32/39/13568.abstract AB 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-HT2AR) 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-HT2AR-induced hyperexcitability after spinal nerve ligation (SNL) in rat. High-affinity 5-HT2AR 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-HT2AR and mGluR1 were found to be coexpressed in postsynaptic densities in dorsal horn neurons. In the absence of SNL, pharmacological stimulation of 5-HT2AR 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-HT2AR-containing postsynaptic densities. Upregulation of mGluR1 in synaptic compartments was partially prevented by chronic administration of selective 5-HT2AR antagonist M100907 [(R)-(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-pipidinemethanol], confirming 5-HT2AR-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-HT2AR blockade. These results emphasize a role for 5-HT2AR in hyperexcitation and pain after nerve injury and support mGluR1 upregulation as a novel feedforward activation mechanism contributing to 5-HT2AR-mediated facilitation.