Mechanisms of ATP release in pain: role of pannexin and connexin channels

Abstract

Pain is a physiological response to bodily damage and serves as a warning of potential threat. Pain can also transform from an acute response to noxious stimuli to a chronic condition with notable emotional and psychological components that requires treatment. Indeed, the management of chronic pain is currently an important unmet societal need. Several reports have implicated the release of the neurotransmitter adenosine triphosphate (ATP) and subsequent activation of purinergic receptors in distinct pain etiologies. Purinergic receptors are broadly expressed in peripheral neurons and the spinal cord; thus, purinergic signaling in sensory neurons or in spinal circuits may be critical for pain processing. Nevertheless, an outstanding question remains: what are the mechanisms of ATP release that initiate nociceptive signaling? Connexin and pannexin channels are established conduits of ATP release and have been suggested to play important roles in a variety of pathologies, including several models of pain. As such, these large-pore channels represent a new and exciting putative pharmacological target for pain treatment. Herein, we will review the current evidence for a role of connexin and pannexin channels in ATP release during nociceptive signaling, such as neuropathic and inflammatory pain. Collectively, these studies provide compelling evidence for an important role of connexins and pannexins in pain processing.

Keywords: ATP release; Acute pain; Chronic pain; Connexins; Pannexins.

Fig. 1

A schematic diagram of the cell types and possible sources of ATP release during pain. ATP is released from a variety of cells, including epithelial cells (keratinocytes), immune cells (mast cells, macrophages), glial cells (microglial, astrocyte, and satellite glial cells), and neurons. Pannexin and connexin channels are shown in the cell types where they have been found to play a role in pain. Similarly, P2X or P2Y receptors are displayed in sensory nerves, DRG, and spinal cord, where they can transmit acute and/or chronic pain signals