Targeting cell surface trafficking of pain-facilitating receptors to treat chronic pain conditions

Abstract

Introduction: Chronic pain conditions are serious clinical concerns. Its genesis is closely associated with sensitization of nociceptive primary sensory neurons (nociceptors) and dorsal horn neurons by various pain mediators produced during inflammation and tissue injury. Growing evidence showed that increasing cell surface trafficking of pain-facilitating receptors is an important mechanism underlying the peripheral and central sensitization.

Areas covered: We summarized the progress of this area over the past decade by showing that inflammation, tissue damage or pain mediators facilitate cell surface trafficking of pain-facilitating receptors such as transient receptor potential vanilloid-1, transient receptor potential ankyrin-1, voltage-gated sodium channel 1.8, P2X3 and EP4 in primary sensory neurons, GluR1 and GluR2 of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, NR1 and NR2 of N-methyl-d-aspartate receptors and acid-sensing ion channels 1 in dorsal horn neurons and P2X4 in spinal microglia. The anti-allodynic effects of gabapentin was mediated by blocking surface trafficking of α2δ1 and α2δ2 subunits of voltage-gated calcium channels in primary sensory and dorsal horn neurons.

Expert opinion: Pain mediators stimulate forward surface trafficking of their own and/or other pain-facilitating receptors to amplify pain intensity and duration. Enhancing surface abundance of pain-facilitating receptors in nociceptors and dorsal horn neurons is an important mechanism underpinning chronic pain states. Targeting specific trafficking events of pain-facilitating receptors may open a novel therapeutic avenue to more efficiently treat chronic pain conditions.

Keywords::

• acid-sensing ion channels
• central sensitization
• chronic pain
• degradation
• dorsal root ganglion
• EP4
• externalization
• internalization
• NMDA receptor
• nociception
• nociceptor
• P2X3
• P2X4
• pain mediators
• peripheral sensitization
• receptor trafficking
• recycling
• spinal dorsal horn
• transient receptor potential ankyrin-1
• transient receptor potential vanilloid-1
• voltage-gated sodium channel 1.8
• α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor
• α2δ subunits of voltage-gated calcium channel

Acknowledgements

We wish to thank Bruno St-Jacques for his editorial assistance with this manuscript.

Notes

This box summarizes key points contained in the article.