Abstract
In the central nervous system, bidirectional signaling between glial cells and neurons (‘neuroimmune communication') facilitates the development of persistent pain. Spinal glia can contribute to heightened pain states by a prolonged release of neurokine signals that sensitize adjacent centrally projecting neurons. Although many persistent pain conditions are disproportionately common in females, whether specific neuroimmune mechanisms lead to this increased susceptibility remains unclear. This review summarizes the major known contributions of glia and neuroimmune interactions in pain, which has been determined principally in male rodents and in the context of somatic pain conditions. It is then postulated that studying neuroimmune interactions involved in pain attributed to visceral diseases common to females may offer a more suitable avenue for investigating unique mechanisms involved in female pain. Further, we discuss the potential for primed spinal glia and subsequent neurogenic inflammation as a contributing factor in the development of peripheral inflammation, therefore, representing a predisposing factor for females in developing a high percentage of such persistent pain conditions.
Highlights
In the central nervous system, bidirectional signaling between glial cells and neurons (‘neuroimmune communication’) facilitates the development of persistent pain
This review provides a summary of neuroimmune contributions, those provided by astrocytes and microglia, to persistent pain signaling within the spinal
The proinflammatory products subsequently released from microglia include IL-1β, IL-6, IL-18, TNFα, prostaglandin E2 (PGE2), nitric oxide and brain-derived neurotrophic factor, and IL-1β, IL-6, TNFα, IFNγ, CCL2, CXCL1, CXCL21 and MMP9 from astrocytes
Summary
Glia are a non-neuronal, immune-like cell population that constitute the vast majority of cells within the CNS. They comprise satellite glial cells in the ganglia, and microglia, astrocytes and oligodendrocytes within the spinal cord and brain. The anatomical co-localization of astrocytes and microglia in the spinal cord, combined with pre- and postsynaptic neurons, forms a key site of interaction termed the ‘tetrapartite synapse’.12,13 Each cell within this functional unit reciprocally signals to another, contributing to a ‘neuroimmune communication’ that allows glia to respond rapidly to disruptions in neuronal signaling.[14,15] The reactivity state and control of astrocytes and microglia is critical in maintaining healthy CNS activity The anatomical co-localization of astrocytes and microglia in the spinal cord, combined with pre- and postsynaptic neurons, forms a key site of interaction termed the ‘tetrapartite synapse’.12,13 Each cell within this functional unit reciprocally signals to another, contributing to a ‘neuroimmune communication’ that allows glia to respond rapidly to disruptions in neuronal signaling.[14,15] The reactivity state and control of astrocytes and microglia is critical in maintaining healthy CNS activity
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