Hyperbaric oxygen therapy ameliorates TNBS-induced acute distal colitis in rats.

BACKGROUND: This study investigated the therapeutic effects of hyperbaric oxygen in experimental acute distal colitis focusing on its effect on the production of pro-inflammatory cytokines, nitric oxide and hypoxia-inducible factor 1alpha. METHODS: Colitis was induced with a rectal infusion of 150 mg/kg of TNBS under anesthesia with Ketamine (50 mg/kg) and Xylazine (10 mg/kg). Control animals received only rectal saline. After colitis induction, animals were subjected to two sessions of hyperbaric oxygen and were then euthanized. The distal intestine was resected for macroscopic analysis, determination of myeloperoxidase activity, western-blotting analyses of inducible nitric oxide synthase and cyclooxygenase-2 expression and immunohistochemical analysis of hypoxia-inducible factor 1alpha and cyclooxygenase-2. Cytokines levels in the distal intestine were measured using an enzyme-linked immunosorbent assay. RESULTS: Hyperbaric oxygen therapy attenuated the severity of acute distal colitis, with reduced macroscopic damage score. This effect was associated with prevention in the increase of pro-inflammatory cytokine production; myeloperoxidase activity, in the expression of inducible nitric oxide synthase and cyclooxygenase-2. Finally, hyperbaric oxygen inhibited the acute distal colitis-induced up-regulation of hypoxia-inducible factor 1alpha. CONCLUSIONS: The results indicate that hyperbaric oxygen attenuates the severity of acute distal colitis through the down-regulation of pro-inflammatory events.

Stimulation of peripheral kappa opioid receptors inhibits inflammatory hyperalgesia via activation of the PI3Kγ/AKT/nNOS/NO signaling pathway.

BACKGROUND: In addition to their central effects, opioids cause peripheral analgesia. There is evidence showing that peripheral activation of kappa opioid receptors (KORs) inhibits inflammatory pain. Moreover, peripheral µ-opioid receptor (MOR) activation are able to direct block PGE(2)-induced ongoing hyperalgesia However, this effect was not tested for KOR selective activation. In the present study, the effect of the peripheral activation of KORs on PGE(2)-induced ongoing hyperalgesia was investigated. The mechanisms involved were also evaluated. RESULTS: Local (paw) administration of U50488 (a selective KOR agonist) directly blocked, PGE(2)-induced mechanical hyperalgesia in both rats and mice. This effect was reversed by treating animals with L-NMMA or N-propyl-L-arginine (a selective inhibitor of neuronal nitric oxide synthase, nNOS), suggesting involvement of the nNOS/NO pathway. U50488 peripheral effect was also dependent on stimulation of PI3Kγ/AKT because inhibitors of these kinases also reduced peripheral antinociception induced by U50488. Furthermore, U50488 lost its peripheral analgesic effect in PI3Kγ null mice. Observations made in vivo were confirmed after incubation of dorsal root ganglion cultured neurons with U50488 produced an increase in the activation of AKT as evaluated by western blot analyses of its phosphorylated form. Finally, immunofluorescence of DRG neurons revealed that KOR-expressing neurons also express PI3Kγ (≅ 43%). CONCLUSIONS: The present study indicates that activation of peripheral KORs directly blocks inflammatory hyperalgesia through stimulation of the nNOS/NO signaling pathway which is probably stimulated by PI3Kγ/AKT signaling. This study extends a previously study of our group suggesting that PI3Kγ/AKT/nNOS/NO is an important analgesic pathway in primary nociceptive neurons.