Peripheral Nerve Injury Induces Persistent Vascular Dysfunction and Endoneurial Hypoxia, Contributing to the Genesis of Neuropathic Pain

J Neurosci. 2015 Feb 25;35(8):3346-59. doi: 10.1523/JNEUROSCI.4040-14.2015.

Abstract

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.

Keywords: Na+/K+ ATPase ion transporter; drug development; hypoxia; nerve injury; neuropathic pain; vascular dysfunction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Cell Hypoxia
  • Endothelium, Vascular / metabolism*
  • Endothelium, Vascular / pathology
  • Glycolysis
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neuralgia / etiology
  • Neuralgia / metabolism*
  • Neuralgia / physiopathology
  • Oxygen / metabolism*
  • Oxygen Consumption
  • Peripheral Nerve Injuries / complications
  • Peripheral Nerve Injuries / metabolism*
  • Peripheral Nerve Injuries / physiopathology
  • Sciatic Nerve / blood supply
  • Sciatic Nerve / metabolism
  • Sciatic Nerve / pathology
  • Sodium-Potassium-Exchanging ATPase / genetics
  • Sodium-Potassium-Exchanging ATPase / metabolism

Substances

  • Adenosine Triphosphate
  • Sodium-Potassium-Exchanging ATPase
  • Oxygen