The kinin B 1 and B 2 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 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 DABK-induced 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.