Oxidative Stress Contributes to Fracture/Cast-Induced Inflammation and Pain in a Rat Model of Complex Regional Pain Syndrome

Abstract

Clinical evidence suggests vitamin C (Vit C) may protect against the development of complex regional pain syndrome (CRPS) after fracture and/or surgery. Tibia fracture followed by 4 weeks cast immobilization (fracture/cast) in rats results in nociceptive, vascular, and bone changes resembling clinical CRPS. In the present study, fracture/cast rats were treated with the oxidative stress inhibitors Vit C, N-acetyl cysteine (NAC) or 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPOL) to examine their effects on CRPS-related nociceptive and vascular changes. Administration of these agents significantly reduced fracture/cast-induced cutaneous allodynia by 64–78%, muscle hyperalgesia by 34–40% and hindlimb unweighting by 48–89%. Treatments with Vit C and NAC reduced the oxidative stress markers malondialdehyde in the skin, muscle and sciatic nerve, and lactate in the gastrocnemius muscle of the fracture/cast limb. Furthermore, Vit C treatment inhibited the post fracture up-regulation of SP and CGRP in the sciatic nerve and the increased expression of the pain-related inflammatory mediators, including interleukin 6 (IL-6), and nerve growth factor (NGF) in the skin and interleukin 1β (IL-1β), and IL-6 in the muscle of the post fracture/cast limb. These data suggest that oxidative stress may contribute to the nociceptive features of the rat CRPS model. Perspective: Vit C reduced the CRPS-like signs, oxidative stress, and the up regulation of neuropeptide production and inflammatory mediators observed after tibia fracture and casting in rats. Limiting oxidative stress using Vit C or alternative strategies could reduce the risk of developing CRPS after surgery or other forms of trauma.

Dietary Interventions for Treatment of Chronic Pain: Oxidative Stress and Inflammation

“…Oxidative stress occurs when free radical compounds such as reactive oxygen species (ROS) or reactive nitrogen species (RNS) are imbalanced with antioxidant defense systems in the body [ 34 – 36 ]. When certain macronutrients are consumed in excess and are broken down, natural oxidative by-products of their metabolism triggers oxidative stress responses and production of more ROS when bound to their receptors – more so than the body is equipped to handle.…”

Autoinflammatory and autoimmune contributions to complex regional pain syndrome

“…Similar to the findings in humans, the keratinocyte layer was found to be responsible for generating most of the involved mediators, 41 , 56 though again deeper tissues such as muscle do seem to generate pain-related cytokines. 50 Mitogen-activated protein kinase (MAPK) activation within keratinocytes was functionally linked to the enhanced cytokine production. 56 Additional studies on CRPS model animals demonstrated the activation of inflammasomes in keratinocytes as a required step in the production of IL-1β in the tibial fracture/cast model consistent with established autoinflammatory pathways.…”

Electroacupuncture Alleviates Mechanical Allodynia in a Rat Model of Complex Regional Pain Syndrome Type-I via Suppressing Spinal CXCL12/CXCR4 Signaling

“…Several mechanisms have been proposed to contribute to CRPS-I, including peripheral/central pain sensitization, TRPA1 and reactive oxygen species. 13,16,21,38,39 Our recent work contributed to these efforts by identifying TRPV1 and spinal glial cells as important players involved in the pain response of CPIP model rats. 16 Electroacupuncture (EA) combines traditional manual acupuncture with modern electrotherapy.…”