title: Transient Receptor Potential Cation Channel Subfamily M Member 8 channels mediate the anti-inflammatory effects of eucalyptol.
abstract: Eucalyptol (1,8-cineol), the major ingredient in the essential oil of eucalyptus leaves and other medicinal plants, has long been known for its anti-inflammatory properties. Eucalyptol interacts with the TRP cation channels among other targets, but it is unclear which of these mediates its anti-inflammatory effects.
  
  
  
  Effects of eucalyptol were compared in wild-type and TRPM8 channel-deficient mice in two different models: footpad inflammation elicited by complete Freund's adjuvant (CFA) and pulmonary inflammation following administration of LPS. Oedema formation, behavioural inflammatory pain responses, leukocyte infiltration, enzyme activities and cytokine and chemokine levels were measured.
  
  
  
  In the CFA model, eucalyptol strongly attenuated oedema and mechanical allodynia and reduced levels of inflammatory cytokines (IL-1β, TNF-α and IL-6), effects comparable with those of ibuprofen. In the LPS model of pulmonary inflammation, eucalyptol treatment diminished leukocyte infiltration, myeloperoxidase activity and production of TNF-α, IL-1β, IFN-γ and IL-6. Genetic deletion of TRPM8 channels abolished the anti-inflammatory effects of eucalyptol in both models. Eucalyptol was at least sixfold more potent on human, than on mouse TRPM8 channels. A metabolite of eucalyptol, 2-hydroxy-1,8-cineol, also activated human TRPM8 channels.
  
  
  
  Among the pharmacological targets of eucalyptol, TRPM8 channels were essential for its anti-inflammatory effects in mice. Human TRPM8 channels are more sensitive to eucalyptol than rodent TRPM8 channels explaining the higher potency of eucalyptol in humans. Metabolites of eucalyptol could contribute to its anti-inflammatory effects. The development of more potent and selective TRPM8 agonists may yield novel anti-inflammatory agents.
authors.affiliation: Department of Anesthesiology, Duke University School of Medicine, Durham, NC, USA.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Caceres
authors.affiliation: Department of Anesthesiology, Duke University School of Medicine, Durham, NC, USA.|Department of Neurobiology and Acupuncture Research, The 3rd Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China.
authors.forename: Boyi
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, Duke University School of Medicine, Durham, NC, USA.
authors.forename: Sairam V
authors.initials: SV
authors.lastname: Jabba
authors.affiliation: Department of Anesthesiology, Duke University School of Medicine, Durham, NC, USA.
authors.forename: Satyanarayana
authors.initials: S
authors.lastname: Achanta
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, CT, USA.
authors.forename: John B
authors.initials: JB
authors.lastname: Morris
authors.affiliation: Department of Anesthesiology, Duke University School of Medicine, Durham, NC, USA.|Yale Tobacco Center of Regulatory Science (TCORS), Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Sven-Eric
authors.initials: SE
authors.lastname: Jordt
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology / Q000627:therapeutic use; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D003511:Cyclohexanols / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000077591:Eucalyptol; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D039821:Monoterpenes / Q000494:pharmacology* / Q000627:therapeutic use; D011897:Random Allocation; D050053:TRPM Cation Channels / Q000502:physiology*; D050051:Transient Receptor Potential Channels / Q000502:physiology
chemical_list: D000890:Anti-Infective Agents; D000893:Anti-Inflammatory Agents; D003511:Cyclohexanols; D018836:Inflammation Mediators; D039821:Monoterpenes; D050053:TRPM Cation Channels; C492297:TRPM8 protein, mouse; D050051:Transient Receptor Potential Channels; D000077591:Eucalyptol