title: TRPA1, substance P, histamine and 5-hydroxytryptamine interact in an interdependent way to induce nociception.
abstract: BACKGROUND
  Although TRPA1, SP, histamine and 5-hydroxytryptamine (5-HT) have recognized contribution to nociceptive mechanisms, little is known about how they interact with each other to mediate inflammatory pain in vivo. In this study we evaluated whether TRPA1, SP, histamine and 5-HT interact, in an interdependent way, to induce nociception in vivo.
  
  
  RESULTS
  The subcutaneous injection of the TRPA1 agonist allyl isothiocyanate (AITC) into the rat's hind paw induced a dose-dependent and short lasting behavioral nociceptive response that was blocked by the co-administration of the TRPA1 antagonist, HC030031, or by the pretreatment with antisense ODN against TRPA1. AITC-induced nociception was significantly decreased by the co-administration of selective antagonists for the NK1 receptor for substance P, the H1 receptor for histamine and the 5-HT1A or 3receptors for 5-HT. Histamine- or 5-HT-induced nociception was decreased by the pretreatment with antisense ODN against TRPA1. These findings suggest that AITC-induced nociception depends on substance P, histamine and 5-HT, while histamine- or 5-HT-induced nociception depends on TRPA1. Most important, AITC interact in a synergistic way with histamine, 5-HT or substance P, since their combination at non-nociceptive doses induced a nociceptive response much higher than that expected by the sum of the effect of each one alone. This synergistic effect is dependent on the H1, 5-HT1A or 3receptors.
  
  
  CONCLUSIONS
  Together, these findings suggest a self-sustainable cycle around TRPA1, no matter where the cycle is initiated each step is achieved and even subeffective activation of more than one step results in a synergistic activation of the overall cycle.
authors.affiliation: Division of Biological Sciences, Department of Physiology, Federal University of Parana, Curitiba, Parana, Brazil. fischer@ufpr.br.
authors.forename: Luana
authors.initials: L
authors.lastname: Fischer
authors.affiliation: Division of Biological Sciences, Department of Physiology, Federal University of Parana, Curitiba, Parana, Brazil.
authors.forename: Maria Isabel
authors.initials: MI
authors.lastname: Lavoranti
authors.affiliation: Division of Biological Sciences, Department of Physiology, Federal University of Parana, Curitiba, Parana, Brazil.
authors.forename: Mariana
authors.initials: M
authors.lastname: de Oliveira Borges
authors.affiliation: Division of Biological Sciences, Department of Physiology, Federal University of Parana, Curitiba, Parana, Brazil.
authors.forename: Alana Farias
authors.initials: AF
authors.lastname: Miksza
authors.affiliation: Division of Biological Sciences, Department of Physiology, Federal University of Parana, Curitiba, Parana, Brazil.
authors.forename: Natalia Fantin
authors.initials: NF
authors.lastname: Sardi
authors.affiliation: Division of Biological Sciences, Department of Physiology, Federal University of Parana, Curitiba, Parana, Brazil.
authors.forename: Bruno Jacson
authors.initials: BJ
authors.lastname: Martynhak
authors.affiliation: Department Functional and Structural Biology, Institute of Biology, State University of Campinas-UNICAMP, Campinas, São Paulo, Brazil.
authors.forename: Claudia H
authors.initials: CH
authors.lastname: Tambeli
authors.affiliation: Department Functional and Structural Biology, Institute of Biology, State University of Campinas-UNICAMP, Campinas, São Paulo, Brazil.
authors.forename: Carlos Amílcar
authors.initials: CA
authors.lastname: Parada
mesh_terms: D000083:Acetanilides / Q000494:pharmacology; D000818:Animals; D006632:Histamine / Q000378:metabolism*; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D017879:Isothiocyanates; D008297:Male; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010146:Pain / Q000139:chemically induced / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D011738:Pyrilamine / Q000494:pharmacology; D011812:Quinuclidines / Q000494:pharmacology; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D011969:Receptors, Histamine H1 / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013373:Substance P / Q000378:metabolism*; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D003189:p-Methoxy-N-methylphenethylamine / Q000494:pharmacology
chemical_list: C552888:2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopropylphenyl)acetamide; D000083:Acetanilides; D006634:Histamine H1 Antagonists; D017879:Isothiocyanates; D016376:Oligonucleotides, Antisense; D010879:Piperazines; D011687:Purines; D011812:Quinuclidines; D011969:Receptors, Histamine H1; D018040:Receptors, Neurokinin-1; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; C480976:Trpa1 protein, rat; D044282:Receptor, Serotonin, 5-HT1A; C081293:WAY 100135; C076851:L 703606; D012701:Serotonin; D013373:Substance P; D003189:p-Methoxy-N-methylphenethylamine; D006632:Histamine; C004471:allyl isothiocyanate; D011738:Pyrilamine
keywords: 5-Hydroxytryptamine (5-HT); Histamine; Nociception; Substance P; TRPA1