AUTHOR=Hayashi Takafumi , Watanabe Chizuko , Katsuyama Soh , Agatsuma Yasuyuki , Scuteri Damiana , Bagetta Giacinto , Sakurada Tsukasa , Sakurada Shinobu 

TITLE=Contribution of Histamine to Nociceptive Behaviors Induced by Intrathecally Administered Cholecystokinin-8

JOURNAL=Frontiers in Pharmacology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2020.590918

DOI=10.3389/fphar.2020.590918

ISSN=1663-9812

ABSTRACT=<p>The involvement of spinal release of histamine in the nociceptive behaviors induced by cholecystokinin-8 (CCK-8) was investigated in mice. Intrathecal (i.t.) injection of CCK-8 elicited the nociceptive behaviors consisting of biting and licking. The nociceptive behaviors induced by i.t. treatment with CCK-8 showed two bell-shaped patterns. The histamine H<sub>3</sub> receptor antagonist significantly promoted the nociceptive behaviors induced by CCK-8 at doses of 1–100 fmol and 100 pmol. The nociceptive behaviors elicited by CCK-8 was inhibited by i.t. administration of the CCK-B receptor antagonist in a dose-dependent manner, but not by the CCK-A receptor antagonist. The nociceptive behaviors induced by CCK-8 were markedly suppressed by i.t. pretreatment with antiserum against histamine and were abolished in histidine decarboxylase-deleted gene mice. In histamine H<sub>1</sub> receptor-deleted gene mice, the nociceptive behaviors induced at both 10 amol and 10 pmol of CCK-8 were not affected. The tachykinin neurokinin-1 (NK<sub>1</sub>) receptor antagonists inhibited CCK-8 (10 pmol)-induced nociceptive behaviors in a dose-dependent manner. CCK-8 (10 amol)-induced nociceptive behaviors was not antagonized by co-administration with the tachykinin NK<sub>1</sub> receptor antagonists. The nociceptive behaviors elicited by CCK-8 were inhibited by i.t. administration of the antagonist for the <italic>N</italic>-methyl-D-aspartate (NMDA) receptor in a dose-dependent manner. Our results suggest that the nociceptive behaviors induced by i.t. administration of CCK-8 (10 pmol) are mediated through the spinal release of histamine and are elicited via activation of the tachykinin NK<sub>1</sub> and NMDA receptors, whereas the nociceptive behaviors induced by i.t. administration of CCK-8 (10 amol) are mediated through the spinal release of histamine and elicited via NMDA receptor activation.</p>