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 β-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.

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These results provide strong evidence that NA-3,4-DCM produces antihypernociception in mice at peripheral, spinal, and supraspinal sites, and that interaction with the group I metabotropic glutamate receptors and NMDA receptors contributes to the mechanisms underlying its effect.

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 B 1 and B 2 receptors (B 1 R and B 2 R) was confirmed using both knockout mice and mRNAs quantification in the injected nerve, DRG and spinal cord. The treatment with the B 2 R antagonist HOE 140 or with B 1 R antagonist des-Arg 9 -Leu 8 -BK reduced both BK-and DABKinduced hypersensitivity. The experiments using kinin receptor antagonists and CPM inhibitor (thiorphan) suggest that BK does not only activate B 2 R as an orthosteric agonist, but also seems to be converted into DABK that consequently activates B 1 R. These results indicate a connection between TNF and the kinin system, suggesting a relevant role for B 1 R and B 2 R 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.

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