NADPH Oxidases in Pain Processing

Abstract

Inflammation or injury to the somatosensory nervous system may result in chronic pain conditions, which affect millions of people and often cause major health problems. Emerging lines of evidence indicate that reactive oxygen species (ROS), such as superoxide anion or hydrogen peroxide, are produced in the nociceptive system during chronic inflammatory and neuropathic pain and act as specific signaling molecules in pain processing. Among potential ROS sources in the somatosensory system are NADPH oxidases, a group of electron-transporting transmembrane enzymes whose sole function seems to be the generation of ROS. Interestingly, the expression and relevant function of the Nox family members Nox1, Nox2, and Nox4 in various cells of the nociceptive system have been demonstrated. Studies using knockout mice or specific knockdown of these isoforms indicate that Nox1, Nox2, and Nox4 specifically contribute to distinct signaling pathways in chronic inflammatory and/or neuropathic pain states. As selective Nox inhibitors are currently being developed and investigated in various physiological and pathophysiological settings, targeting Nox1, Nox2, and/or Nox4 could be a novel strategy for the treatment of chronic pain. Here, we summarize the distinct roles of Nox1, Nox2, and Nox4 in inflammatory and neuropathic processing and discuss the effectiveness of currently available Nox inhibitors in the treatment of chronic pain conditions.

Keywords: NADPH oxidase; Nox; Nox inhibition; inflammation; neuropathy; nociception; pain; peripheral injury.

Figure 1

Suggested contributions of Nox2 to pain processing in response to peripheral nerve injury (PNI), spinal cord injury (SCI) and diabetic neuropathy. Nox2 activity is increased in the spinal cord, DRGs and the sciatic nerve after up-regulation of Nox2 expression in microglial cells or through recruitment of Nox2-positive macrophages. This leads for example to enhanced ROS production and enhanced release of proinflammatory cytokines, resulting in enhanced mechanical and thermal hypersensitivity. Activation of Nox2 in response to PNI has been suggested to be mediated by TLR2 and Sig-1R. In addition, SCI and diabetic conditions also lead to enhanced Nox2 expression and activity in the spinal cord.

Figure 2

Nox1 affects inflammatory pain processing by redox regulation and translocation of PKCε to the plasma membrane. This subsequently modulates TRPV1-mediated signaling, glia activation, cFos upregulation, and phosphorylation of ERK1/2 in DRGs and/or in the spinal cord. In addition, Nox1 expressed in Schwann cells affects neuropathic pain signaling in response to peripheral nerve injury through activation of TRPA1 in sensory neurons.

Figure 3

Contribution of Nox4 to neuropathic pain signaling. Nox4 is expressed in primary afferent neurons and Nox4-derived ROS induce the degradation of peripheral myelin proteins in peripheral nerves after injury, leading to mechanical hypersensitivity. Similar effects are observed in diabetic models. Furthermore, Nox4 promotes ROS production and proinflammatory cytokine release in DRGs and the sciatic nerve. CIPN: chemotherapy-induced peripheral neuropathy; PNI: peripheral nerve injury.

Figure 4

Chemical structures of potential Nox inhibiting compounds (abstracted from [125,133]).