Journal
JOURNAL OF NEUROSCIENCE
Volume 35, Issue 8, Pages 3346-3359Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.4040-14.2015
Keywords
drug development; hypoxia; Na plus /K plus ATPase ion transporter; nerve injury; neuropathic pain; vascular dysfunction
Categories
Funding
- Louise and Alan Edwards Foundation
- Canadian Institutes for Health Research Neuroinflammation Training Program
- Canadian Institutes for Health Research [MOP-111129]
- Canada Foundation for Innovation
- Dr. John R. and Clara M. Fraser Memorial Trust
- Terry Fox Foundation Oncometabolism Team Grant [116128]
- McGill University
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Nerve injury is associated with microvascular disturbance; however, the role of the vascular system has not been well characterized in the context of neuropathic pain. Furthermore, ischemia is thought to play a role in a number of neuropathic pain conditions, and yet the role of hypoxia has also not been characterized in neuropathic pain conditions. In this study, we observed the presence of persistent endoneurial hypoxia in a mouse model of traumatic peripheral nerve injury, causing painful mononeuropathy. We attribute the ongoing hypoxia to microvascular dysfunction, endoneurial fibrosis, and increased metabolic requirements within the injured nerve. Increased lactate levels were observed in injured nerves, as well as increased oxygen consumption and extracellular acidification rates, suggesting that anaerobic glycolysis is required to maintain cellular ATP levels. Hypoxia causes a reduction in levels of the Na+/K+ ATPase ion transporter in both cultured primary dorsal root ganglion neurons and injured peripheral nerve. A reduction of Na+/K+ ATPase ion transporter levels likely contributes to the hyperexcitability of injured nerves. Physiological antagonism of hypoxia with hyperbaric oxygen alleviated mechanical allodynia in nerve-injured animals. These results suggest that hypoxia and the Na+/K+ ATPase ion transporter may be a novel mechanistic target for the treatment of neuropathic pain. In addition, the findings support the possibility of using hypoxia activated pro-drugs to localize treatments for neuropathic pain and nerve injury to injured nerves.
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