The tetrapartite synapse: Path to CNS sensitization and chronic pain

A recent plethora of studies has characterized a central nervous system (CNS) neuroimmune response in animal models of persistent pain. This response, which may be the driving force for neuronal hypersensitivity in chronic pain states, involves "activation" of spinal and supraspinal glial cells, which when stimulated may increase production of a host of inflammatory/algesic mediators, such as cytokines and chemokines. Unclear, however, is how this neuroimmune activation can actually cause the downstream electrophysiological mechanisms of enhanced neuronal firing or decreased thresholds to firing; and therefore, produce heightened responses to noxious and non-noxious stimuli. The contribution of CNS proinflammatory cytokines to neuronal sensitization is unclear. For example, the use of specific cytokine inhibitors or the administration of an anti-inflammatory cytokine for the treatment of chronic pain has lacked definitive mechanisms and/or effective outcomes. Many of these reports use terms such as "activation" and "glia", without clarity or precision. The heterogeneity of glia and the intricacies of glial function necessitate a reexamination of the terminology in the pain field. Glia, including astrocytes and microglia, rather than neurons, are now the focus in studies of the regulation of synaptic strength and plasticity and the actual generation of central sensitization. In this paper we describe a tetrapartite synapse, which includes an astrocyte, a microglial cell, and pre- and post-synaptic neuronal terminals. We suggest that this functional unit is a critical contributor to the generation and maintenance of the end-product of excessive excitatory transmission in the synapse (Fig. 1). © 2006 International Association for the Study of Pain.