P2X3-mediated peripheral sensitization of neuropathic pain in resiniferatoxin-induced neuropathy.

Abstract

Patients suffering from sensory neuropathy due to skin denervation frequently have paradoxical manifestations of reduced nociception and neuropathic pain. However, there is a lack of satisfactory animal models to investigate these phenomena and underlying mechanisms. We developed a mouse system of neuropathy induced by resiniferatoxin (RTX), a capsaicin analog, and examined the functional significance of P2X3 receptor in neuropathic pain. From day 7 of RTX neuropathy, mice displayed mechanical allodynia (p<0.0001) and thermal hypoalgesia (p<0.0001). After RTX treatment, dorsal root ganglion (DRG) neurons of the peripherin type were depleted (p=0.012), while neurofilament (+) DRG neurons were not affected (p=0.62). In addition, RTX caused a shift in neuronal profiles of DRG: (1) increased in P2X3 receptor (p=0.0002) and ATF3 (p=0.0006) but (2) reduced TRPV1 (p=0.036) and CGRP (p=0.015). The number of P2X3(+)/ATF3(+) neurons was linearly correlated with mechanical thresholds (p=0.0017). The peripheral expression of P2X3 receptor in dermal nerves was accordingly increased (p=0.016), and an intraplantar injection of the P2X3 antagonists, A-317491 and TNP-ATP, relieved mechanical allodynia in a dose-dependent manner. In conclusion, RTX-induced sensory neuropathy with upregulation of P2X3 receptor for peripheral sensitization of mechanical allodynia, which provides a new therapeutic target for neuropathic pain after skin denervation.

• Authors: Yu-Lin Hsieh, Hao Chiang, June-Horng Lue, Sung-Tsang Hsieh
• Journal: Experimental neurology (Exp Neurol) Vol. 235 Issue 1 Pg. 316-25 (May 2012) ISSN: 1090-2430 [Electronic] United States
• PMID: 22391132 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Crown Copyright © 2012. Published by Elsevier Inc. All rights reserved.

Chemical References

• Diterpenes
• Receptors, Purinergic P2X3
• resiniferatoxin

Topics

• Animals
• Diterpenes
• Ganglia, Spinal (metabolism, physiopathology)
• Hyperalgesia (chemically induced, metabolism, physiopathology)
• Male
• Mice
• Mice, Inbred ICR
• Neuralgia (chemically induced, metabolism, physiopathology)
• Neurons (metabolism)
• Pain Measurement
• Peripheral Nervous System Diseases (chemically induced, metabolism, physiopathology)
• Receptors, Purinergic P2X3 (metabolism)
• Skin (innervation, metabolism, physiopathology)