Role of spinal cord glia in the central processing of peripheral pain perception

Abstract

Background: The discovery that glial activation plays a critical role in the modulation of neuronal functions and affects the spinal processing of nociceptive signalling has brought new understanding on the mechanisms underlying central sensitization involved in chronic pain facilitation. Spinal glial activation is now considered an important component in the development and maintenance of allodynia and hyperalgesia in various models of chronic pain, including neuropathic pain and pain associated with peripheral inflammation. In addition, spinal glial activation is also involved in some forms of visceral hyperalgesia.

Purpose: We discuss the signalling pathways engaged in central glial activation, including stress pathways, and the neuron-glia bidirectional relationships involved in the modulation of synaptic activity and pain facilitation. In this expanding field of research, the characterization of the mechanisms by which glia affect spinal neuro-transmission will increase our understanding of central pain facilitation, and has the potential for the development of new therapeutic agents for common chronic pain conditions.

Figure 1

Schematic illustration of potential mechanisms by which glia modulate pain signaling in the dorsal horn of the spinal cord. In conditions of spinal cord injury, peripheral nerve injury, or inflammation, spinal microglia and astrocytes are activated by neurotransmitters and mediators (such as glutamate (Glut), substance P (SP), ATP or fractalkine) released from sensitized primary afferent terminals. Glia can also be activated by stress, via direct or indirect GCs-mediated pathways or neural-mediated signals. Activated glia in turn, release a variety of mediators, which act on neurons or glial cells generating a neuro-glial amplification loop. Pro-inflammatory cytokines can act directly on post-synaptic neurons affecting their excitability and are also involved in the modulation of various genes expression including genes for NMDA receptors (NMDAR) or GLT1. The confluence of excessive release of neurotransmitters and pro-inflammatory mediators, the downregulation of glutamate transporters, the compromised glutamate reuptake by astrocytes ultimately lead to post synaptic hyperexcitability and exacerbation of the pain signaling.