The kinin B1 and B2 receptors and TNFR1/p55 axis on neuropathic pain in the mouse brachial plexus.

Tumour necrosis factor (TNF) and kinins have been associated with neuropathic pain-like behaviour in numerous animal models. However, the way that they interact to cause neuron sensitisation remains unclear. This study assessed the interaction of kinin receptors and TNF receptor TNFR1/p55 in mechanical hypersensitivity induced by an intraneural (i.n.) injection of rm-TNF into the lower trunk of brachial plexus in mice. The i.n. injection of rm-TNF reduced the mechanical withdrawal threshold of the right forepaw from the 3rd to the 10th day after the injection, indicating that TNF1/p55 displays a critical role in the onset of TNF-elicited neuropathic pain. The connection between TNF1/p55 and kinin B1 and B2 receptors (B1R and B2R) was confirmed using both knockout mice and mRNAs quantification in the injected nerve, DRG and spinal cord. The treatment with the B2R antagonist HOE 140 or with B1R antagonist des-Arg9-Leu8-BK reduced both BK- and DABK-induced hypersensitivity. The experiments using kinin receptor antagonists and CPM inhibitor (thiorphan) suggest that BK does not only activate B2R as an orthosteric agonist, but also seems to be converted into DABK that consequently activates B1R. These results indicate a connection between TNF and the kinin system, suggesting a relevant role for B1R and B2R in the process of sensitisation of the central nervous systems by the cross talk between the receptor and CPM after i.n. injection of rm-TNF.

Biological and Toxicological Evaluation of N-(4methyl-phenyl)-4-methylphthalimide on Bone Cancer in Mice.

BACKGROUND: It was recently demonstrated that the phthalimide N-(4-methyl-phenyl)-4- methylphthalimide (MPMPH-1) has important effects against acute and chronic pain in mice, with a mechanism of action correlated to adenylyl cyclase inhibition. Furthermore, it was also demonstrated that phthalimide derivatives presented antiproliferative and anti-tumor effects. Considering the literature data, the present study evaluated the effects of MPMPH-1 on breast cancer bone metastasis and correlated painful symptom, and provided additional toxicological information about the compound and its possible metabolites. METHODS: In silico toxicological analysis was supported by in vitro and in vivo experiments to demonstrate the anti-tumor and anti-hypersensitivity effects of the compound. RESULTS: The data obtained with the in silico toxicological analysis demonstrated that MPMPH-1 has mutagenic potential, with a low to moderate level of confidence. The mutagenicity potential was in vivo confirmed by micronucleus assay. MPMPH-1 treatments in the breast cancer bone metastasis model were able to prevent the osteoclastic resorption of bone matrix. Regarding cartilage, degradation was considerably reduced within the zoledronic acid group, while in MPMPH-1, chondrocyte multiplication was observed in random areas, suggesting bone regeneration. Additionally, the repeated treatment of mice with MPMPH-1 (10 mg/kg, i.p.), once a day for up to 36 days, significantly reduces the hypersensitivity in animals with breast cancer bone metastasis. CONCLUSION: Together, the data herein obtained show that MPMPH-1 is relatively safe, and significantly control the cancer growth, allied to the reduction in bone reabsorption and stimulation of bone and cartilage regeneration. MPMPH-1 effects may be linked, at least in part, to the ability of the compound to interfere with adenylylcyclase pathway activation.

Chemical composition and evaluation of the anti-hypernociceptive effect of the essential oil extracted from the leaves of Ugni myricoides on inflammatory and neuropathic models of pain in mice.

The study analyzes the chemical composition of the essential oil obtained from the leaves of Ugni myricoides (Kunth) O. Berg (U. myricoides EO). The composition of the essential oil was characterized by GC-FID and GC-MS analysis, showing at least six major constituents: α-pinene (52.1%), 1,8-cineole (11.9%), α-humulene (4.6%), caryophyllene oxide + globulol (4.5%), humulene epoxide II (4.2%) and ß-caryophyllene (2.9%). It demonstrates for the first time the systemic anti-hypernociceptive properties of this orally administered oil in inflammatory and neuropathic models of hypernociception in mice. The effects of U. myricoides EO and its major constituent, α-pinene, were compared with those of indomethacin or gabapentin, drugs used clinically to treat inflammatory and neuropathic processes. Like indomethacin (5 or 10 mg/kg, p.o.), U. myricoides EO (5-50 mg/kg, p.o.) was able to significantly prevent mechanical hypernociception induced by carrageenan or complete Freund's adjuvant (CFA) in mice. These effects were observed for up to 48 h after i.pl. injection of flogistic agents. Repeated treatment with U. myricoides EO (5-25 mg/kg, p.o.), α-pinene (5-50 mg/kg, p.o.), or gabapentin (70 mg/kg, p.o.) also abolished the mechanical sensitization induced by CFA, or following the partial ligation of the sciatic nerve (PLSN). The present results indicate that U. myricoides EO produces marked anti-hypernociceptive effects in carrageenan and CFA mechanical sensitization models, and also inhibited neuropathic pain-like behavior after PLSN with efficacy similar to that observed for indomethacin or gabapentin. The relevant effects shown by U. myricoides EO are related, at least in part, to the presence of α-pinene and may be of potential interest for the management of inflammatory and neuropathic pain.