Inhibition of glutamate uptake in the spinal cord induces hyperalgesia and increased responses of spinal dorsal horn neurons to peripheral afferent stimulation

Glutamate is a primary excitatory neurotransmitter in the mammalian CNS. Glutamate released from presynaptic neurons is cleared from the synaptic cleft passively by diffusion and actively by glutamate transporters. In this study, the role of glutamate transporters in sensory processing in the spinal cord has been investigated in behavioral, in vivo and in vitro experiments. Intrathecal application of a non-selective glutamate transport inhibitor, l-trans-pyrrolidine-2,4-dicarboxylic acid (10μl of 100μM solution) induced hypersensitivity to peripheral mechanical and thermal stimuli. Topical application of l-trans-pyrrolidine-2,4-dicarboxylic acid (100μM) onto the dorsal surface of the L3–L6 spinal cord increased spontaneous activities, innocuous and noxious stimulus-evoked responses and after-discharges of wide dynamic range neurons in the L4–5 spinal segments. Whole cell recordings made from superficial dorsal horn neurons in an isolated whole spinal cord from newborn rats (2–3 weeks old) revealed that bath-applied l-trans-pyrrolidine-2,4-dicarboxylic acid (100μM) produced partial membrane depolarization, increased spontaneous action potentials with decreased neuronal membrane resistance and time constant, but without significant changes of capacitance. Finally, the amplitude and duration of primary afferent evoked-excitatory postsynaptic currents recorded from neurons in the substantia gelatinosa in the spinal slices from young adult rats (6–8 weeks old) were increased in the presence of l-trans-pyrrolidine-2,4-dicarboxylic acid (100μM). This study indicates that glutamate transporters regulate baseline excitability and responses of dorsal horn neurons to peripheral stimulation, and suggests that dysfunction of glutamate transporters may contribute to certain types of pathological pain.