title: Citral: a monoterpene with prophylactic and therapeutic anti-nociceptive effects in experimental models of acute and chronic pain.
abstract: Citral (3,7-dimethyl-2,6-octadienal) is an open-chain monoterpenoid present in the essential oils of several medicinal plants. The aim of this work was to evaluate the effects of orally administered citral in experimental models of acute and chronic nociception, inflammation, and gastric ulcers caused by non-steroidal anti-inflammatory drugs (NSAIDs). Oral treatment with citral significantly inhibited the neurogenic and inflammatory pain responses induced by intra-plantar injection of formalin. Citral also had prophylactic and therapeutic anti-nociceptive effects against mechanical hyperalgesia in plantar incision surgery, chronic regional pain syndrome, and partial ligation of sciatic nerve models, without producing any significant motor dysfunction. In addition, citral markedly attenuated the pain response induced by intra-plantar injection of glutamate and phorbol 12-myristate 13-acetate (PMA, a protein kinase C activator), as well as by intrathecal (i.t.) injection of ionotropic and metabotropic glutamate receptor agonists (N-methyl-D-aspartic acid [NMDA] and 1-amino-1,3-dicarboxycyclopentane [trans-ACPD], respectively), substance P, and cytokine tumour necrosis factor-α. However, citral potentiated behaviours indicative of pain caused by i.t., but not intra-plantar, injection of a transient receptor potential vanilloid receptor type 1 (TRPV1) agonist. Finally, the anti-nociceptive action of citral was found to involve significant activation of the 5-HT2A serotonin receptor. The effect of citral was accompanied by a gastro-protective effect against NSAID-induced ulcers. Together, these results show the potential of citral as a new drug for the treatment of pain.
authors.affiliation: Natural Products Laboratory, Department of Physiology, Bioscience Institute, Universidade Estadual Paulista 'Júlio de Mesquita Filho', Botucatu, São Paulo 18618-970, Brazil. Electronic address: cat.nishi@ig.com.br.
authors.forename: Catarine M
authors.initials: CM
authors.lastname: Nishijima
authors.affiliation: Natural Products Laboratory, Department of Physiology, Bioscience Institute, Universidade Estadual Paulista 'Júlio de Mesquita Filho', Botucatu, São Paulo 18618-970, Brazil. Electronic address: ellen_gg@yahoo.com.br.
authors.forename: Ellen G
authors.initials: EG
authors.lastname: Ganev
authors.affiliation: Laboratory of Neurobiology of Pain and Inflammation, Department of Physiological Sciences, Centre of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis 88040-900, Santa Catarina, Brazil. Electronic address: leidiane2001@yahoo.com.br.
authors.forename: Leidiane
authors.initials: L
authors.lastname: Mazzardo-Martins
authors.affiliation: Laboratory of Neurobiology of Pain and Inflammation, Department of Physiological Sciences, Centre of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis 88040-900, Santa Catarina, Brazil. Electronic address: danielmartinsfisio@hotmail.com.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Martins
authors.affiliation: Natural Products Laboratory, Department of Physiology, Bioscience Institute, Universidade Estadual Paulista 'Júlio de Mesquita Filho', Botucatu, São Paulo 18618-970, Brazil. Electronic address: lrocha@ibb.unesp.br.
authors.forename: Lúcia R M
authors.initials: LR
authors.lastname: Rocha
authors.affiliation: Laboratory of Neurobiology of Pain and Inflammation, Department of Physiological Sciences, Centre of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis 88040-900, Santa Catarina, Brazil. Electronic address: adair.santos@ufsc.br.
authors.forename: Adair R S
authors.initials: AR
authors.lastname: Santos
authors.affiliation: Natural Products Laboratory, Department of Physiology, Bioscience Institute, Universidade Estadual Paulista 'Júlio de Mesquita Filho', Botucatu, São Paulo 18618-970, Brazil. Electronic address: hiruma@ibb.unesp.br.
authors.forename: Clelia A
authors.initials: CA
authors.lastname: Hiruma-Lima
mesh_terms: D059787:Acute Pain / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D000080462:Acyclic Monoterpenes; D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002211:Capsaicin; D059350:Chronic Pain / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D018846:Excitatory Amino Acids; D005557:Formaldehyde; D018698:Glutamic Acid; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism; D007511:Ischemia / Q000150:complications; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D051379:Mice; D039821:Monoterpenes / Q000494:pharmacology / Q000627:therapeutic use*; D009437:Neuralgia / Q000188:drug therapy / Q000378:metabolism; D010149:Postoperative Pain / Q000188:drug therapy / Q000378:metabolism; D017208:Rats, Wistar; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology; D013276:Stomach Ulcer / Q000188:drug therapy / Q000378:metabolism; D013373:Substance P; D013755:Tetradecanoylphorbol Acetate; D014409:Tumor Necrosis Factor-alpha
chemical_list: D000080462:Acyclic Monoterpenes; D000700:Analgesics; D018846:Excitatory Amino Acids; D039821:Monoterpenes; D044402:Receptor, Serotonin, 5-HT2A; D058830:Serotonin 5-HT2 Receptor Antagonists; D014409:Tumor Necrosis Factor-alpha; D005557:Formaldehyde; D013373:Substance P; D018698:Glutamic Acid; D007650:Ketanserin; D013755:Tetradecanoylphorbol Acetate; D002211:Capsaicin; C007076:citral
keywords: Chronic pain; Chronic regional pain syndrome; Citral; Gastro-protective effect; Neuropathic pain; Postoperative pain