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. 1. Introduction Long-term potentiation (LTP), an increase in the strength of synaptic transmission between neurons, has been proposed as a cellular model of learning and memory formation. Since LTP was first described for the dentate area of the hippocampal formation [1], data pertinent to mechanisms of LTP have been abundantly accumulated in diverse synapses of hippocampus and other brain areas. In contrast, investigation of LTP in the spinal dorsal horn (DH) [2] is more recent, beginning twenty years after the first description of LTP in the hippocampus, and spinal DH LTP has focused largely upon the synapses formed by primary sensory afferent fibers, because these synapses are the first checkpoint for pain signals entering the central nervous system (CNS). At these primary afferent synapses, LTP has been thought to be a cellular correlate of pain hypersensitivity and as such has been proposed as a potential target for therapeutic treatments of chronic pain. Neurons in the spinal DH, consisting of superficial (laminae I and II) and deep (laminae III–VI) DH, receive synaptic inputs from primary afferent fibers, their cell bodies located within dorsal root ganglion (DRG) as well as those from other DH neurons, or neurons in other higher brain areas. The spinal DH neurons are considered as secondary neurons because peripheral somatosensory signals conveyed by primary sensory DRG neurons first reach these neurons. Synapses formed in these DH neurons mostly use glutamate for excitatory transmission. Generally, ionotropic glutamate receptors selectively activated by the artificial agonist α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) support the largest component of glutamatergic excitatory synaptic transmission in the CNS, while the N-methyl-D-aspartate (NMDA) receptor subtype is most
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