Regulation of wheal and flare by tea tree oil: complementary human and rodent studies

J Invest Dermatol. 2004 Oct;123(4):683-90. doi: 10.1111/j.0022-202X.2004.23407.x.


When applied 20 min after injection of histamine into human forearm skin, tea tree oil (TTO) reduces the developing cutaneous vascular response. In this study, the effect of TTO on inflammatory microvascular changes was dissected at the base of an experimental blister on rat skin. 1,8-Cineole, representing 2% of TTO, reduced vascular changes induced by sensory neuropeptides released when the distal portion of a cut sciatic nerve was electrically stimulated. The pre-terminal modulatory effect of 1,8-Cineole was confirmed in tests in sensory-denervated rats. Terpinen-4-ol (approximately 40% TTO) reduced substance P-induced microvascular changes and protein extravasation by a direct nitric oxide-mediated effect on the microvasculature, without sensory nerve involvement. alpha-Terpineol (3% of TTO) regulated both pre- and post-sensory nerve terminals. In human skin, terpinen-4-ol applied 10 min after histamine injection, but not alpha-terpineol or 1,8-cineole, regulated the developing wheal and flare suggesting that the histamine-induced responses in humans (at the dose used in this study, 50 microL of 330 microM histamine) are in large part determined by histamine directly affecting the vasculature via post-terminal-mediated events. The underlying strength of these studies is the use of a well-established rat physiologic model to differentiate the mechanism of regulation of microvascular changes by modulatory agents.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Outbred Strains
  • Anti-Inflammatory Agents / administration & dosage*
  • Cyclohexane Monoterpenes
  • Cyclohexanols / administration & dosage
  • Cyclohexenes
  • Denervation
  • Dermatitis / drug therapy*
  • Eucalyptol
  • Histamine / administration & dosage
  • Humans
  • Male
  • Monoterpenes / administration & dosage
  • Neurons, Afferent / drug effects
  • Nitric Oxide Synthase / metabolism
  • Nitric Oxide Synthase Type III
  • Rats
  • Rats, Sprague-Dawley
  • Skin / blood supply
  • Skin / drug effects*
  • Skin / innervation
  • Substance P / pharmacology
  • Tea Tree Oil / administration & dosage*
  • Terpenes / administration & dosage


  • Anti-Inflammatory Agents
  • Cyclohexane Monoterpenes
  • Cyclohexanols
  • Cyclohexenes
  • Monoterpenes
  • Terpenes
  • alpha-terpineol
  • Substance P
  • terpinenol-4
  • Tea Tree Oil
  • Histamine
  • NOS3 protein, human
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type III
  • Nos3 protein, rat
  • Eucalyptol