Pharmacological Research 54 (2006) 282–286 Oleanolic acid, a pentacyclic triterpene attenuates capsaicin-induced nociception in mice: Possible mechanisms Juliana L. Maia a , Roberto C.P. Lima-J´ unior a , Caroline M. Melo a , Juceni P. David b , Jorge M. David c , Adriana R. Campos a , Fl´ avia A. Santos a , Vietla S.N. Rao a,∗ a Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, POB-3157, 60430-270 Fortaleza, CE, Brazil b Pharmacy Faculty, Federal University of Bahia, 1401-70-250 Salvador, Brazil c Institute of Chemistry, Federal University of Bahia, 1401-70-250 Salvador, Brazil Accepted 13 June 2006 Abstract The anti-inflammatory pentacyclic triterpene, oleanolic acid (OA) was examined on acute nociception induced by intraplantar injection of capsaicin in mice. OA administered orally to mice at 10, 30 and 100 mg kg -1 , significantly attenuated the paw-licking response to capsaicin (1.6 g/paw) by 53%, 68.5% and 36.6%, respectively. Ruthenium red (3 mg kg -1 , s.c.), a non-competitive vanilloid receptor (V1, TRPV1)- antagonist also suppressed the capsaicin nociception by 38.6%. The maximal antinociception produced by 30 mg kg -1 OA was significantly blocked in animals pre-treated with naloxone (2 mg kg -1 , i.p.), the opioid antagonist; l-arginine (600 mg kg -1 , i.p.), the substrate for nitric oxide synthase; or glibenclamide (2 mg kg -1 , i.p.), the K ATP -channel blocker, but was unaffected by yohimbine (2 mg kg -1 , i.p.), an  2 -adrenoceptor antagonist. In open-field and rota-rod tests that detect motor deficits, mice received 30 mg kg -1 OA did not manifest any effect per se, indicating that the observed antinociception is not a consequence of motor abnormality. These data suggest that OA inhibits capsaicin-evoked acute nociception due to mechanisms possibly involving endogenous opioids, nitric oxide, and K ATP -channel opening. © 2006 Elsevier Ltd. All rights reserved. Keywords: Oleanolic acid; Pentacyclic triterpene; Capsaicin; Antinociceptive activity; Endogenous opioids; Nitric oxide; K ATP -channels 1. Introduction The capsaicin receptor TRPV1 (transient receptor potential vanilloid 1) is a Ca 2+ permeable non-specific cation channel that mediates chemical and thermal pain. TRPV1 receptors are expressed primarily in small sensory neurons type C and A fibers and to a less extent in other tissues and initiate a complex cascade of events, including neuronal excitation and release of pro-inflammatory mediators, desensitization of recep- tor, and neuronal toxicity [1–3]. These receptors are activated by vanilloids (capsaicin, resiniferatoxin, piperine, etc.) and non- vanilloid endogenous ligands (protons, anandamide, bradykinin and lipoxygenase products) as well [4,5]. The functional role of TRPV1 in acute and chronic nociception has been estab- lished by the use of TRPV1 antagonists, and TRPV1 knockout mice [6,2,7]. Currently, TRPV1 agonists and antagonists are ∗ Corresponding author. Tel.: +55 85 3366 8341; fax: +55 85 3366 8333. E-mail address: vietrao@ufc.br (V.S.N. Rao). both being developed for the treatment of pain. The desensi- tization induced after TRPV1 agonists points to the utility of these agents in the suppression of neuropathic pain, whereas, TRPV1 antagonists as valuable agents for the treatment of inflammatory, postoperative and arthritic pain [8,9]. Some of these antagonists like ruthenium red and capsazepine may fur- ther serve as molecular tools in drug investigations. However, the available compounds show only moderate potency, lim- ited selectivity, poor pharmacokinetics and species differences [7]. Therefore, the search for more potent and ideal TRPV1 antagonists effective for the treatment of painful neuropathy continues. A number of natural sources have been examined for the development of drugs acting as agonists or antagonists at vanil- loid receptors, which include compounds like polygodial, a full vanilloid agonist derived from marsh pepper; warburganal from the bark of warburgia trees; isovelleral with terpenoid structure isolated from fungi; scalaradial, an unsaturated dialde- hyde isolated from sponges; and scutigeral, isolated from edible mushrooms [10]. Oleanolic acid (OA) is a pentacyclic triterpene 1043-6618/$ – see front matter © 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.phrs.2006.06.003