Ionotropic glutamate receptors and voltage-gated Ca²⁺ channels in long-term potentiation of spinal dorsal horn synapses and pain hypersensitivity

Abstract

Over the last twenty years of research on cellular mechanisms of pain hypersensitivity, long-term potentiation (LTP) of synaptic transmission in the spinal cord dorsal horn (DH) has emerged as an important contributor to pain pathology. Mechanisms that underlie LTP of spinal DH neurons include changes in the numbers, activity, and properties of ionotropic glutamate receptors (AMPA and NMDA receptors) and of voltage-gated Ca²⁺ channels. Here, we review the roles and mechanisms of these channels in the induction and expression of spinal DH LTP, and we present this within the framework of the anatomical organization and synaptic circuitry of the spinal DH. Moreover, we compare synaptic plasticity in the spinal DH with classical LTP described for hippocampal synapses.

Figure 1

A diagram modified from the gate control theory. Both primary afferent A and C fibers directly target the transmission system that conveys the pain signals from the spinal dorsal horn to the higher brain areas. However, both fibers differentially innervate to the substantia gelatinosa (SG) neurons in the spinal DH. Although polysynaptic inputs are possible in all SG neurons from primary afferent fibers and other SG neurons, monosynaptic inputs from A fibers reach the excitatory SG neurons (eSG) and the transmission-inhibiting SG neurons (tiSG), while those from C fibers only go into the inhibitory SG neurons (iSG), not the itSG directly. The tiSG neurons receive the excitatory synaptic inputs from the eSG and the inhibitory synaptic inputs from the iSG. The main function of tiSG is inhibiting the transmission system, both presynaptically (in the gate control theory) and postsynaptically (in this diagram). In this way, the activation and inhibition of SG neurons (here, called tiSG) by large-diameter and small-diameter fibers, respectively, are possible, shown in the gate control theory.