When applied 20 min after injection of histamine into human forearm skin, tea tree oil (TTO) reduces the developingcutaneous vascular response. In this study, the effect of TTO on inflammatory microvascular changes was dissectedat the base of an experimental blister on rat skin. 1,8-Cineole, representing 2% of TTO, reduced vascularchanges induced by sensory neuropeptides released when the distal portion of a cut sciatic nerve was electricallystimulated. 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 extravasationby a direct nitric oxide-mediated effect on the microvasculature, without sensory nerve involvement. a-Terpineol (3% of TTO) regulated both pre- and post-sensory nerve terminals. In human skin, terpinen-4-ol applied10 min after histamine injection, but not a-terpineol or 1,8-cineole, regulated the developing wheal and flare suggestingthat the histamine-induced responses in humans (at the dose used in this study, 50 lL of 330 lM histamine)are in large part determined by histamine directly affecting the vasculature via post-terminal-mediated events. Theunderlying strength of these studies is the use of a well-established rat physiologic model to differentiate themechanism of regulation of microvascular changes by modulatory agents.