Purinergic signalling in spinal pain processing

Abstract

Purinergic signalling plays important roles in somatosensory and nociceptive transmission in the dorsal horn of the spinal cord under physiological and pathophysiological conditions. Physiologically, ATP mediates excitatory postsynaptic responses in nociceptive transmission in the superficial dorsal horn, and in transmission of innocuous primary afferent inputs in the deep dorsal horn. Additionally, extracellular conversion of ATP to adenosine mediates inhibitory postsynaptic responses from Pacinian corpuscle afferents, and is implicated in analgesia caused by transcutaneous electrical nerve stimulation in humans. In terms of pathological pain, P2X4 receptors de novo expressed on dorsal horn microglia are implicated in pain hypersensitivity following peripheral nerve injury. There is evidence that involvement of such P2X4 receptors is sexually dimorphic, occurring in males but not in females. Thus, the roles of purinergic signalling in physiological and pathological pain processing are complex and remain an ever-expanding field of research.

Keywords: Neuropathic pain; Pain; Primary afferents; Spinal dorsal horn.

Fig. 1

A unified schema for signalling in the superficial spinal dorsal horn in pain hypersensitivity. Peripheral nerve injury drives de novo expression of P2X4Rs in microglia, but only in males, leading to release of BDNF and activation of its cognate receptor, TrkB, on neurons in lamina I. Subsequent intracellular pathways in the neurons downregulate KCC2 and upregulate the function of GluN2B-containing NMDARs by activating Fyn and suppressing STEP61. In females, although microglia proliferation occurs, P2X4R expression does not increase. Nevertheless, KCC2 is downregulated and NMDAR is enhanced in females by signalling molecules and pathways that remain to be identified. Also shown is that BDNF may be released from primary sensory neurons activated by peripheral inflammation