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.

Forced swim stress exacerbates inflammation-induced hyperalgesia and oxidative stress in the rat trigeminal ganglia

“…Nox4 is distinct from other Nox enzymes in that it generates predominantly H 2 O 2 rather than O2 − due to its unique molecular structure ( 57 ). It contributes to chronic pain conditions through specific signaling mechanisms along nociceptive pathways ( 58 ). In rats with cancer-induced bone pain, Nox4 expression significantly increases, and downregulating Nox4 protein at the spinal cord level alleviates bone cancer pain ( 59 ) Nerve injury-induced mechanical hypersensitivity is significantly attenuated in mice with both global and inducible knockout of Nox4 ( 60 , 61 ).…”

Alpha-Lipoic Acid as an Antioxidant Strategy for Managing Neuropathic Pain

“…A wide range of molecules, enzymes, transcription factors, and other mediators are involved in redox homeostasis. Among these components, the mitochondrial respiratory chain as well as enzymes NADPH oxidases (Nox) are important sources of ROS implicated in nociceptive sensitization/transmission during NP [ 20 , 32 ].…”

“…They also play critical roles in cardiovascular regulation and innate immunity [ 41 ]. Nevertheless, the Nox family can also be involved in pathological conditions including neurodegeneration, epilepsy [ 42 ], thrombosis [ 43 ], and chronic pain [ 32 ]. Isoforms Nox1, Nox2, and Nox4 are involved in pain processing and several studies point to their functional role on the pathophysiology of NP [ 32 ].…”

“…Nox2-positive macrophages amplify oxidative stress and contribute to the upregulation of TNF-α, hence increasing the painful response [ 44 , 45 ]. Corroborating this mechanism, preclinical studies have shown that Nox2-deficient mice submitted to the sciatic nerve ligation model of NP develop less mechanical and thermal hypernociception and exhibit reduced production of ROS and proinflammatory cytokines as well as reduced microglia activation [ 32 ].…”

“…This isoform is responsible for promoting TNF-α signaling [ 46 ], inducing apoptosis in dorsal root ganglia (DRG) neurons [ 47 ], and upregulating TRPA1 in the spinal cord of oxaliplatin-induced neuropathic mice [ 48 ]. Numerous studies have shown that Nox4 is involved in different mechanisms that contribute to neuropathic pain [ 32 ], but not to acute nociceptive or inflammatory pain [ 49 ]. Nox4 plays a part in structural changes and in the degradation of peripheral myelin proteins in the injured nerve [ 49 ].…”