title: Antinociceptive curcuminoid, KMS4034, effects on inflammatory and neuropathic pain likely via modulating TRPV1 in mice.
abstract: BACKGROUND
  Curcumin, the active ingredient of turmeric (Curcuma longa), has a wide range of beneficial effects including anti-inflammation and analgesia. However, poor bioavailability of curcumin hinders its clinical application. To overcome this limitation, we modified 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 the most favourable pharmacokinetics among the tested curcumin derivatives.
  
  
  METHODS
  To evaluate the mechanism of the antinociceptive effects of KMS4034, capsaicin (I(CAP))- and heat (I(heat))-induced currents in TRPV1 expressing HEK293 cells were observed after the application of KMS4034. Nociceptive behavioural measurement using the hot-plate test, formalin test, and chronic constriction injury (CCI) model were evaluated in mice. Also, calcitonin gene-related peptide (CGRP) was stained immunohistochemically in the L4/5 dorsal horns in mice with neuropathic pain.
  
  
  RESULTS
  I(CAP) (P<0.01) and I(heat) (P<0.05) of TRPV1 were significantly blocked by 10 μM KMS4034. Behaviourally, noticeable antinociceptive effects after 10 mg kg(-1) of KMS4034 treatment were observed 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 I-II of the lumbar dorsal horns in KMS4034-treated CCI mice compared with the control (P<0.05).
  
  
  CONCLUSIONS
  KMS4034 may be an effective analgesic for various pain conditions.
authors.affiliation: Department of Dental Anesthesiology and Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea.
authors.forename: J Y
authors.initials: JY
authors.lastname: Lee
authors.forename: T J
authors.initials: TJ
authors.lastname: Shin
authors.forename: J M
authors.initials: JM
authors.lastname: Choi
authors.forename: K S
authors.initials: KS
authors.lastname: Seo
authors.forename: H J
authors.initials: HJ
authors.lastname: Kim
authors.forename: T G
authors.initials: TG
authors.lastname: Yoon
authors.forename: Y S
authors.initials: YS
authors.lastname: Lee
authors.forename: H
authors.initials: H
authors.lastname: Han
authors.forename: H J
authors.initials: HJ
authors.lastname: Chung
authors.forename: Y
authors.initials: Y
authors.lastname: Oh
authors.forename: S J
authors.initials: SJ
authors.lastname: Jung
authors.forename: K J
authors.initials: KJ
authors.lastname: Shin
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002478:Cells, Cultured; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005557:Formaldehyde; D006358:Hot Temperature; D007249:Inflammation / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009437:Neuralgia / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010812:Physical Stimulation / Q000379:methods; D020671:Posterior Horn Cells / Q000378:metabolism; D011930:Reaction Time / Q000187:drug effects; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D018712:Analgesics, Non-Narcotic; C584523:KMS4034; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D005557:Formaldehyde; D003474:Curcumin; D015740:Calcitonin Gene-Related Peptide
keywords: calcitonin gene-related peptide, curcuminoid synthesis, pain; inflammatory; neuropathic, TRPV1 receptor; nociceptive