Induction of long-term potentiation of C fibre-evoked spinal field potentials requires recruitment of group I, but not group II/III metabotropic glutamate receptors

In superficial layers of the lumbar spinal dorsal horn, N-methyl-d-aspartate-dependent long-term potentiation (LTP) of C fibre-evoked field potentials, a synaptic model of central sensitisation and hyperalgesia, ensues the application of electrical high-frequency, high-intensity conditioning stimulation to the sciatic nerve. In order to investigate the putative involvement of the G protein-coupled metabotropic glutamate receptors (mGluRs) in the induction of this form of LTP, we applied a series of mGluR antagonists exhibiting distinct group-specific activity profiles to the spinal lumbar enlargement, prior to conditioning stimulation. The group I (mGluR1/5) and group II (mGluR2/3) mGluR antagonist (S)-α-methyl-4-carboxyphenylglycine or the selective mGluR1/5 antagonist (S)-4-carboxyphenylglycine consistently impaired the development of spinal LTP. However, potentiation occurred in the presence of the inactive enantiomer (R)-α-methyl-4-carboxyphenylglycine. LTP proved insensitive to the selective mGluR2/3 antagonists (2S)-α-ethylglutamic acid and LY341495, either spinally or intravenously delivered. LTP could also be induced in the presence of the selective group III (mGluR4/mGluR6–mGluR8) mGluR antagonist (RS)-α-methylserine-O-phosphate. However, none of the mGluR-active compounds alone noticeably altered the amplitudes of C fibre-evoked field potentials in the absence of conditioning stimulation. These findings suggest that the induction of LTP of C fibre-evoked field potentials in the spinal dorsal horn by high-frequency, high-intensity stimulation of afferent C fibres requires a group-specific mGluR recruitment, activation of mGluR1/5 but not that of mGluR4/6–8 and mGluR2/3 being a requisite step.

Abbreviations: mGluR, metabotropic glutamate receptor; l-AP4, l-2-amino-4-phosphonobutanoate; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; NMDA, N-methyl-d-aspartate; LTD, long-term depression; LTP, long-term potentiation; PKC, protein kinase C; PLC, phospholipase C; aCSF, artificial cerebrospinal fluid; cAMP, cyclic adenosine monophosphate; (S)-MCPG, (S)-α-methyl-4-carboxyphenylglycine; (R)-MCPG, (R)-α-methyl-4-carboxyphenylglycine; (S)-4CPG, (S)-4-carboxyphenylglycine; MSOP, (RS)-α-methylserine-O-phosphate; EGLU, (2S)-α-ethylglutamic acid; (1S,3R)-ACPD, (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid;