The Purinergic System and Glial Cells: Emerging Costars in Nociception

Abstract

It is now well established that glial cells not only provide mechanical and trophic support to neurons but can directly contribute to neurotransmission, for example, by release and uptake of neurotransmitters and by secreting pro- and anti-inflammatory mediators. This has greatly changed our attitude towards acute and chronic disorders, paving the way for new therapeutic approaches targeting activated glial cells to indirectly modulate and/or restore neuronal functions. A deeper understanding of the molecular mechanisms and signaling pathways involved in neuron-to-glia and glia-to-glia communication that can be pharmacologically targeted is therefore a mandatory step toward the success of this new healing strategy. This holds true also in the field of pain transmission, where the key involvement of astrocytes and microglia in the central nervous system and satellite glial cells in peripheral ganglia has been clearly demonstrated, and literally hundreds of signaling molecules have been identified. Here, we shall focus on one emerging signaling system involved in the cross talk between neurons and glial cells, the purinergic system, consisting of extracellular nucleotides and nucleosides and their membrane receptors. Specifically, we shall summarize existing evidence of novel “druggable” glial purinergic targets, which could help in the development of innovative analgesic approaches to chronic pain states.

Glial pannexin1 contributes to tactile hypersensitivity in a mouse model of orofacial pain

“…The critical role played by GFAP-positive glial Panx1 is likely related to cytokine production, which is prominent in satellite glial cells after injury34353637. Not only is Panx1 directly associated with inflammasome components leading to IL-1β release but also indirectly through its association with the P2x7 receptors, which are expressed in satellite glial cells383940. In addition, given the close topological proximity between satellite glial cells and sensory neuron cell bodies, efficient activation of neuronal P2x3 receptors by ATP released through Panx1 channels may be amplified by the excitatory effects of the satellite glial cytokine resultant from its activation.…”

The Emerging Role of Spinal Dynorphin in Chronic Pain: A Therapeutic Perspective

“…Purinergic receptors are ligand-gated ion channels that have a substantial role in chronic pain development and are linked to release of IL-1β (120). In human DRG, P2X7 receptor levels are elevated and co-localizes with satellite glia cells and Schwann cells (121).…”

P2Y1 Receptor Activation of the TRPV4 Ion Channel Enhances Purinergic Signaling in Satellite Glial Cells

“…Purinergic P2Y 1 Receptors Activate TRPV4 in SGCs-Purinergic signaling has been implicated in the glial modulation of neurons during pathological pain (41)(42)(43). Purinergic receptors can also regulate TRP channels (44) (Fig.…”