Reactive Oxygen Species Derived from NOX1/NADPH Oxidase Enhance Inflammatory Pain

Abstract

The involvement of reactive oxygen species (ROS) in an augmented sensitivity to painful stimuli (hyperalgesia) during inflammation has been suggested, yet how and where ROS affect the pain signaling remain unknown. Here we report a novel role for the superoxidegenerating NADPH oxidase in the development of hyperalgesia. In mice lacking Nox1 (Nox1 Ϫ/Y ), a catalytic subunit of NADPH oxidase, thermal and mechanical hyperalgesia was significantly attenuated, whereas no change in nociceptive responses to heat or mechanical stimuli was observed.

Reactive oxygen species and vascular biology: implications in human hypertension

“…However, induction of Nox mRNA expression is observed in response to physical stimuli, (shear stress, pressure), growth factors (plateletderived growth factor, epidermal growth factor and transforming growth factor b), cytokines (tumor necrosis factor-a, interleukin-1 and platelet aggregation factor), mechanical forces (cyclic stretch, laminar and oscillatory shear stress), metabolic factors (hyperglycemia, hyperinsulinemia, free fatty acids, advanced glycation end products and G protein-coupled receptor agonists (serotonin, thrombin, bradykinin, endothelin and Ang II). [107][108][109] Nox enzymes are also regulated by ClC-3, Poldip2 and protein disulfide isomerase. Poldip2 associates with p22phox to activate Nox4, leading to regulation of focal adhesion turnover and vascular smooth muscle cell migration, thus linking ROS production and cytoskeletal remodeling.…”

Involvement of NOX1/NADPH Oxidase in Morphine-Induced Analgesia and Tolerance

“…Intriguingly, phosphorylation of the RGS protein by various kinases including PKC has been documented to regulate GAP activity (Willars, 2006). In preceding communication, we reported that activation of PKC by ROS derived from NOX1 was the key mechanism underlying the development of hyperalgesia (Ibi et al, 2008). As a logical extension of these findings, a possible correlation may exist between NOX1/NADPH oxidase and desensitization of MOR.…”

“…؊/Y Previously, no difference in locomotor activity and coordinated movement was found between Nox1 ϩ/Y and Nox1 Ϫ/Y (Ibi et al, 2008). In untreated mice, no significant difference in the threshold for thermal (9.64 Ϯ 0.52 s latency in Nox1 ϩ/Y vs 8.43 Ϯ 0.34 s in Nox1 Ϫ/Y , N ϭ 9 -10) and mechanical (107.32 Ϯ 7.55 g in Nox1 ϩ/Y vs 99.30 Ϯ 6.45 g in Nox1 Ϫ/Y , N ϭ 10) nociceptive stimuli was observed between the two genotypes.…”

“…Mechanical nociception and thermal nociception were evaluated as described previously (Ibi et al, 2008). In brief, thermal nociception was determined as the latency to paw licking and tapping in the hot plate test (54°C).…”

“…NOX1 is not well understood, and although its role in some organs is being elucidated (Matsuno et al, 2005, Cui et al, 2011, its function in the nervous system is still unclear. Previously, we demonstrated the involvement of NOX1 in hyperalgesia using mice lacking the Nox1 gene (Nox1 Ϫ/Y ) (Ibi et al, 2008). While the molecular mechanisms underlying the development of opioid-induced tolerance have not been fully clarified, desensitization appears to contribute to tolerance.…”