Hayashi Takafumi, Watanabe Chizuko, Katsuyama Soh, Agatsuma Yasuyuki, Scuteri Damiana, Bagetta Giacinto, Sakurada Tsukasa, Sakurada Shinobu
Laboratory of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai, Japan.
Department of Physiology and Anatomy, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai, Japan.
Front Pharmacol. 2020 Oct 29;11:590918. doi: 10.3389/fphar.2020.590918. eCollection 2020.
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 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 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) 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 receptor antagonists. The nociceptive behaviors elicited by CCK-8 were inhibited by i.t. administration of the antagonist for the -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 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.
在小鼠中研究了脊髓组胺释放参与胆囊收缩素-8（CCK-8）诱导的伤害性反应行为。鞘内注射CCK-8引发了包括咬和舔在内的伤害性反应行为。鞘内注射CCK-8诱导的伤害性反应行为呈现出两种钟形模式。组胺H受体拮抗剂在1 - 100飞摩尔和100皮摩尔剂量时显著促进了CCK-8诱导的伤害性反应行为。CCK-8引发的伤害性反应行为可被鞘内注射CCK-B受体拮抗剂以剂量依赖的方式抑制，但不受CCK-A受体拮抗剂的影响。CCK-8诱导的伤害性反应行为可被鞘内预先注射抗组胺血清显著抑制，且在组氨酸脱羧酶基因敲除小鼠中消失。在组胺H受体基因敲除小鼠中，10飞摩尔和10皮摩尔CCK-8诱导的伤害性反应行为不受影响。速激肽神经激肽-1（NK）受体拮抗剂以剂量依赖的方式抑制CCK-8（10皮摩尔）诱导的伤害性反应行为。CCK-8（10飞摩尔）诱导的伤害性反应行为不会因与速激肽NK受体拮抗剂共同给药而被拮抗。CCK-8引发的伤害性反应行为可被鞘内注射N-甲基-D-天冬氨酸（NMDA）受体拮抗剂以剂量依赖的方式抑制。我们的结果表明，鞘内注射CCK-8（10皮摩尔）诱导的伤害性反应行为是通过脊髓组胺释放介导的，并通过速激肽NK和NMDA受体的激活引发，而鞘内注射CCK-8（10飞摩尔）诱导的伤害性反应行为是通过脊髓组胺释放介导的，并通过NMDA受体激活引发。
