Enhanced antinociceptive effects of morphine in histamine H2 receptor gene knockout mice

• Published in: Neuropharmacology 2006-09, Vol.51 (3), p.612-622
• Main Authors: Mobarakeh, Jalal Izadi, Takahashi, Kazuhiro, Sakurada, Shinobu, Kuramasu, Atsuo, Yanai, Kazuhiko
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Animals; Antinociception; Benzothiazoles - therapeutic use; Brain - drug effects; Brain - metabolism; Capsaicin; Drug Synergism; Ganglia, Spinal - drug effects; Ganglia, Spinal - metabolism; Gene knockout mice; Histamine H2 Antagonists - therapeutic use; Histamine H2 receptor; Hot Temperature; Hyperalgesia - chemically induced; Hyperalgesia - drug therapy; Hyperalgesia - genetics; Intracerebroventricular injection (i.c.v.); Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Morphine; Morphine - therapeutic use; Narcotics - therapeutic use; Pain Measurement - methods; Phenoxypropanolamines - therapeutic use; Piperidines - therapeutic use; Reaction Time - drug effects; Receptors, Histamine H2 - deficiency; Receptors, Histamine H2 - genetics; Reverse Transcriptase Polymerase Chain Reaction - methods; RNA, Messenger - biosynthesis; Time Factors; Touch
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2006.05.003

We have previously shown that antinociceptive effects of morphine are enhanced in histamine H1 receptor gene knockout mice. In the present study, involvement of supraspinal histamine H2 receptor in antinociception by morphine was examined using histamine H2 receptor gene knockout (H 2KO) mice and histamine H 2 receptor antagonists. Antinociception was evaluated by assays for thermal (hot-plate, tail-flick and paw-withdrawal tests), mechanical (tail-pressure test) and chemical (formalin and capsaicin tests) stimuli. Thresholds for pain perception in H 2KO mice were higher than wild-type mice. Antinociceptive effects of intracerebroventricularly administered morphine were enhanced in the H 2KO mice compared to wild-type mice. Intracerebroventricular co-administration of morphine and cimetidine produced significant antinociceptive effects in the wild-type mice when compared to morphine or cimetidine alone. Furthermore, zolantidine, a selective and hydrophobic H2 receptor antagonist, enhanced the effects of morphine in all nociceptive assays examined. These results suggest that histamine exerts inhibitory effects on morphine-induced antinociception through H2 receptors at the supraspinal level. Our present and previous studies suggest that H1 and H2 receptors cooperatively function to modulate pain perception in the central nervous system.