Abstract
The development of neuropathic pain involves persistent changes in signalling within pain pathways. Reduced inhibitory signalling in the spinal cord following nerve-injury has been used to explain sensory signs of neuropathic pain but specific circuits that lose inhibitory input have not been identified. This study shows a specific population of spinal cord interneurons, radial neurons, lose glycinergic inhibitory input in a rat partial sciatic nerve ligation (PNL) model of neuropathic pain. Radial neurons are excitatory neurons located in lamina II of the dorsal horn, and are readily identified by their morphology. The amplitude of electrically-evoked glycinergic inhibitory post-synaptic currents (eIPSCs) was greatly reduced in radial neurons following nerve-injury associated with increased paired-pulse ratio. There was also a reduction in frequency of spontaneous IPSCs (sIPSCs) and miniature IPSCs (mIPSC) in radial neurons without significantly affecting mIPSC amplitude. A subtype selective receptor antagonist and western blots established reversion to expression of the immature glycine receptor subunit GlyRα2 in radial neurons after PNL, consistent with slowed decay times of IPSCs. This study has important implications as it identifies a glycinergic synaptic connection in a specific population of dorsal horn neurons where loss of inhibitory signalling may contribute to signs of neuropathic pain.
Highlights
Receptor positive) lamina I neurons, but in the presence of bicuculline and strychnine these fibres are able to activate projection neurons in lamina I
Glycinergic signalling is reduced in radial neurons in the spinal cord dorsal horn in nerve-injured animals
Evoked IPSCs in parasagittal spinal cord slices were evoked by placing stimulating electrodes in deeper laminae and were measured in lamina II neurons by whole-cell voltage clamp in the presence of CNQX (10 μM) and AP5 (100 μM)
Summary
Receptor positive) lamina I neurons, but in the presence of bicuculline and strychnine these fibres are able to activate projection neurons in lamina I. Studies using rat models have shown that loss of inhibitory GABAergic and glycinergic neurotransmission, or disinhibition, accompanies peripheral nerve-injury[12,13,14,15]. This was proposed to be due to apoptotic loss of inhibitory neurons, there are many discrepancies between studies investigating inhibitory neuron death, which is not thought to be necessary for pain development In order to identify specific components of the pathway that are affected by disinhibition, the present study used patch clamp recording in vitro to examine inhibitory neurotransmission onto specific cell types in lamina II after development of tactile allodynia in a rat partial sciatic nerve ligation (PNL) model of neuropathic pain. These neurons may contribute to the pain phenotype in neuropathic pain states
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