Possible involvement of tachykinin NK1 and NMDA receptors in histamine-induced hyperalgesia in mice

Shinobu Sakurada, Tohru Orito, Chikai Sakurada, Takumi Sato, Takafumi Hayashi, Jalal Izadi Mobarakeh, Kazuhiko Yanai, Kenji Onodera, Takehiko Watanabe, Tsukasa Sakurada

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27 Citations (Scopus)


Intrathecal (i.t.) injection of histamine elicited a significant hyperalgesic response as assayed by the tail-flick test. This hyperalgesic effect peaked at 15 min following i.t. administration of histamine (800 pmol) and returned to control level with 30 min. Hyperalgesia produced by histamine was inhibited dose-dependently by i.t. co-administration of the histamine H1 receptor antagonist, d-chlorpheniramine, but not the histamine H2 receptor antagonist, ranitidine. The tachykinin NK1 receptor antagonists, (+)-[(2S,3S)-3-(2-methoxy-benzyl-amino)-2-phenylpiperidine] (CP-99,994), and [Tyr6, d-Phe7, d-His9]substance P-(6-11) (sendide), inhibited histamine-induced hyperalgesic response in a dose-dependent manner. A significant antagonistic effect of [d-Phe7, d-His9]substance P-(6-11), a selective antagonist for substance P receptors, was observed against histamine-induced hyperalgesic response. The tachykinin NK2 receptor antagonist, Asp-Tyr-d-Trp-Val-d-Trp-d-Trp-Lys-NH2 (MEN-10,376), had no effect on hyperalgesia elicited by histamine. The competitive N-methyl-d-aspartate (NMDA) receptor antagonists, and d-(-)-2-amino-5-phosphonovaleric acid (d-APV), (±)-3-(2-carboxypiperazin-yl)propyl-1-phosphoric acid (CPP), the noncompetitive NMDA receptor antagonist dizocilpine (MK-801), and l-NG-nitro arginine methyl ester (l-NAME), a nitric oxide (NO) synthase inhibitor, markedly inhibited histamine-induced hyperalgesic response. The present results suggest that hyperalgesic response induced by i.t. injection of histamine may be mediated by tachykinin NK1 receptors, but not NK2 receptors in the spinal cord. In addition, spinal NMDA receptor-NO system may also contribute to elicitation of hyperalgesia following i.t. injection of histamine.

Original languageEnglish
Pages (from-to)29-34
Number of pages6
JournalEuropean Journal of Pharmacology
Issue number1-2
Publication statusPublished - 2002 Jan 2


  • Histamine H receptor
  • Hyperalgesia
  • NMDA receptor
  • Nitric oxide (NO)
  • Tachykinin NK receptor

ASJC Scopus subject areas

  • Pharmacology


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