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.