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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., (Crown Copyright © 2012. Published by Elsevier Inc. All rights reserved.)

This study was aimed to determine whether axotomy coupled with hypoxia would exert a more profound effect on injury-induced neuronal nitric oxide synthase (NOS) expression. In this connection, the vagus and the hypoglossal nerves of adult rats were transected unilaterally in the same animal, and half of the operated animals were subjected to hypoxia treatment. Both the neuronal NOS immunohistochemistry and the nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) histochemistry were used to assess the neuronal NOS expression. The present results have shown that the number of NADPH-d/NOS-positive [NADPH-d/NOS(1)] neurons in the hypoglossal nucleus (HN) peaked at 14 days after axotomy, while that in dorsal motor nucleus of vagus (DMN) and nucleus ambiguus (NA) was progressively increased up to 60 days. The up-regulation of NADPH-d/NOS in HN and DMN was more pronounced in hypoxic than in normoxic animals, a feature that was not evident in the NA. Quantitative analysis showed that the number of surviving motoneurons in normoxic animals was significantly higher than those subjected to hypoxia at 14 days postaxotomy in HN and at all postaxotomy time points in DMN. The difference may be attributed to their different functional components. Since O2 deprivation leads to poor cellular function, the stronger expression of NADPH-d/NOS and the more drastic neuronal loss following nerve transection in the hypoxic animals compared with the controls suggest that hypoxia plays an important role in peripheral neuropathies in which NO is implicated., (Copyright 2001 Academic Press.)