Role of TrkA signalling and mast cells in the initiation of osteoarthritis pain in the monoiodoacetate model.

OBJECTIVE: Aiming to delineate novel neuro-immune mechanisms for NGF/TrkA signalling in osteoarthritis (OA) pain, we evaluated inflammatory changes in the knee joints following injection of monoiodoacetate (MIA) in mice carrying a TrkA receptor mutation (P782S; TrkA KI mice). METHOD: In behavioural studies we monitored mechanical hypersensitivity following intra-articular MIA and oral prostaglandin D2 (PGD2) synthase inhibitor treatments. In immunohistochemical studies we quantified joint mast cell numbers, calcitonin gene-related peptide expression in synovia and dorsal root ganglia, spinal cord neuron activation and microgliosis. We quantified joint leukocyte infiltration by flow cytometry analysis, and PGD2 generation and cyclooxygenase-2 (COX-2) expression in mast cell lines by ELISA and Western blot. RESULTS: In TrkA KI mice we observed rapid development of mechanical hypersensitivity and amplification of dorsal horn neurons and microglia activation 7 days after MIA. In TrkA KI knee joints we detected significant leukocyte infiltration and mast cells located in the vicinity of synovial nociceptive fibres. We demonstrated that mast cells exposure to NGF results in up-regulation of COX-2 and increase of PGD2 production. Finally, we observed that a PGD2 synthase inhibitor prevented MIA-mechanical hypersensitivity in TrkA KI, at doses which were ineffective in wild type (WT) mice. CONCLUSION: Using the TrkA KI mouse model, we delineated a novel neuro-immune pathway and suggest that NGF-induced production of PGD2 in joint mast cells is critical for referred mechanical hypersensitivity in OA, probably through the activation of PGD2 receptor 1 in nociceptors: TrkA blockade in mast cells constitutes a potential target for OA pain.

Phospholipid fatty acid and lipid peroxidation in liver microsomes from guinea pigs fed oil related to the toxic oil syndrome.

The potential effects of oil specimens both related and unrelated to cases of Toxic Oil Syndrome (TOS) on the phospholipid fatty acid composition, some antioxidant enzyme activities, and lipid peroxidation in guinea pig liver microsomes were investigated. For 4 weeks, animals were fed diets supplemented with either oil related to cases of TOS or control oil, previously heated or not. In all cases, the fat diet produced the incorporation of approximately 7% of linoleic acid exclusively in the phosphatidylethanolamine (PE) of liver microsomes. A pronounced increase in lipid peroxidation products, measured as malondialdehyde (MDA) and 4-hydroxyalkenals, was detected in animals fed nonheated control oil. Heated oil diets produced significant increases in superoxide dismutase and glutathione peroxidase activities with concomitant decreases in the lipid peroxidation status. Heated oils also increased the oleic/stearic acid ratio in the phosphatidylserine plus phosphatidylinositol (PS + PI) fraction. This ratio was also increased in the same fraction from animals fed non heated case oil. The study shows that case oil produces a decrease in the lipid peroxidation products with minimal alterations in phospholipid fatty acid composition of liver microsomes, which is dependent rather on the composition of dietary fat than on toxic effects.