TRPA1, substance P, histamine and 5-hydroxytryptamine interact in an interdependent way to induce nociception

Inflamm Res. 2017 Apr;66(4):311-322. doi: 10.1007/s00011-016-1015-1. Epub 2016 Nov 30.


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.

Methods and 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 3 receptors 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 3 receptors.

Conclusion: 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.

Keywords: 5-Hydroxytryptamine (5-HT); Histamine; Nociception; Substance P; TRPA1.

MeSH terms

  • Acetanilides / pharmacology
  • Animals
  • Histamine / metabolism*
  • Histamine H1 Antagonists / pharmacology
  • Isothiocyanates
  • Male
  • Oligonucleotides, Antisense / pharmacology
  • Pain / chemically induced
  • Pain / metabolism*
  • Piperazines / pharmacology
  • Purines / pharmacology
  • Pyrilamine / pharmacology
  • Quinuclidines / pharmacology
  • Rats, Wistar
  • Receptor, Serotonin, 5-HT1A / metabolism
  • Receptors, Histamine H1 / metabolism
  • Receptors, Neurokinin-1 / metabolism
  • Receptors, Serotonin, 5-HT3 / metabolism
  • Serotonin / metabolism*
  • Serotonin Antagonists / pharmacology
  • Substance P / metabolism*
  • TRPA1 Cation Channel
  • TRPC Cation Channels / agonists
  • TRPC Cation Channels / antagonists & inhibitors
  • TRPC Cation Channels / genetics
  • TRPC Cation Channels / metabolism*
  • p-Methoxy-N-methylphenethylamine / pharmacology


  • 2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopropylphenyl)acetamide
  • Acetanilides
  • Histamine H1 Antagonists
  • Isothiocyanates
  • Oligonucleotides, Antisense
  • Piperazines
  • Purines
  • Quinuclidines
  • Receptors, Histamine H1
  • Receptors, Neurokinin-1
  • Receptors, Serotonin, 5-HT3
  • Serotonin Antagonists
  • TRPA1 Cation Channel
  • TRPC Cation Channels
  • Trpa1 protein, rat
  • Receptor, Serotonin, 5-HT1A
  • WAY 100135
  • L 703606
  • Serotonin
  • Substance P
  • p-Methoxy-N-methylphenethylamine
  • Histamine
  • allyl isothiocyanate
  • Pyrilamine