Background. Curcumin, the active ingredient of turmeric (Curcuma longa), has a wide range of beneficial effects including anti-inflammation and analgesia. However, poor bioavailability ofcurcumin hinders its clinical application. To overcome this limitation, wemodified the structure of curcumin and synthesized new derivatives with favourable pharmacokinetic profiles. Recently,curcumin has been shown to have an antagonizing effect on transient receptor potential vanilloid type 1 (TRPV1) ion channels. We investigated the antinociceptive activity of KMS4034 which had themost favourable pharmacokinetics among the tested curcumin derivatives. Methods. To evaluate the mechanism of the antinociceptive effects of KMS4034, capsaicin (I CAP)- and heat (Iheat)-induced currents in TRPV1 expressing HEK293 cells were observed after the application of KMS4034. Nociceptive behavioural measurement using the hot-plate test, formalintest, and chronic constriction injury (CCI) model were evaluated in mice. Also, calcitonin generelated peptide (CGRP) was stained immunohistochemically in the L4/5 dorsal horns in micewith neuropathic pain.Results. ICAP (P<0.01) andIheat (P<0.05) of TRPV1were significantly blockedby 10μMKMS4034.Behaviourally, noticeable antinociceptive effects after 10 mg kg-1 of KMS4034 treatment wereobserved in the first (P<0.05) and second phases (P<0.05) of the formalin and hot-plate tests. The mechanical threshold of CCI mice treated with 10 mg kg-1 KMS4034 was significantly increased compared with control. Immunohistochemical CGRP expression was decreased in the lamina 1-2 of the lumbar dorsal horns in KMS4034-treated CCI mice compared with thecontrol (P<0.05). Conclusions. KMS4034 may be an effective analgesic for various pain conditions.
- Calcitonin gene-related peptide
- Curcuminoid synthesis
- TRPV1 receptor