Abstract
In clinical practice, inflammatory pain is an important, unresolved health problem, despite the utilization of non-steroidal anti-inflammatory drugs (NSAIDs). In the last decade, different studies have proven that reactive oxygen species (ROS) and reactive nitrogen species (RNS) are involved in the development and maintenance of inflammatory pain and hyperalgesia via the post-translation modification of key proteins, such as manganese superoxide dismutase (MnSOD). It is well-known that inducible cyclooxygenase 2 (COX-2) plays a crucial role at the beginning of the inflammatory response by converting arachidonic acid into proinflammatory prostaglandin PGE2 and then producing other proinflammatory chemokines and cytokines. Here, we investigated the impact of oxidative stress on COX-2 and prostaglandin (PG) pathways in paw exudates, and we studied how this mechanism can be reversed by using antioxidants during hyperalgesia in a well-characterized model of inflammatory pain in rats. Our results reveal that during the inflammatory state, induced by intraplantar administration of carrageenan, the increase of PGE2 levels released in the paw exudates were associated with COX-2 nitration. Moreover, we showed that the inhibition of ROS with Mn (III) tetrakis (4-benzoic acid) porphyrin(MnTBAP) antioxidant prevented COX-2 nitration, restored the PGE2 levels, and blocked the development of thermal hyperalgesia.
Highlights
Inflammatory pain is considered a major health issue
We investigated the impact of oxidative stress on cyclooxygenase 2 (COX-2) and prostaglandin (PG) pathways in paw exudates, and we studied how this mechanism can be reversed by using antioxidants during hyperalgesia in a well-characterized model of inflammatory pain in rats
We showed that the inhibition of reactive oxygen species (ROS) with Mn (III) tetrakis (4-benzoic acid) porphyrin(MnTBAP) antioxidant prevented COX-2 nitration, restored the prostaglandin E2 (PGE2) levels, and blocked the development of thermal hyperalgesia
Summary
Inflammatory pain is considered a major health issue. Nowadays, non-steroidal anti-inflammatory drugs (NSAIDs) are the most common class of analgesics for moderate/severe inflammatory pain—in particular, non-selective cyclooxygenase 1/cyclooxygenase 2 (COX-1/COX-2) or more selective COX-2 inhibitors are the mostly used formulations, even if various side effects associated with their prolonged utilization are well-documented [1,2,3,4]. During acute/chronic inflammation, hyperalgesia is the result of a persistent state of peripheral afferent sensitization, which subsequently leads to spinal sensitization through the release of the excitatory amino acid glutamate and free radical production (reactive oxygen species (ROS) and reactive nitrogen species (RNS)) [5,6,7,8]. Nitric oxide (NO) seems to interfere directly with the activity of COX-2, and with the production of PGs; the metabolites of the arachidonic acid, would be able to modulate the biosynthesis of NO [10,20,21,24], generating a vicious circle mechanism. We investigated the impact of oxidative stress on COX-2 and PG pathways in paw exudates, and how this mechanism can be reversed by the utilization of widely employed antioxidants, such as MnTBAP, during hyperalgesia, in a well-characterized model of inflammatory pain in rats. We suggest that the chronicization of pain could depend on post-translational nitration of key enzymes and transporters linked to glutamatergic neuro-transmission
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