Hiragata Shiro, Ogawa Teruyuki, Hayashi Yukio, Tyagi Pradeep, Seki Satoshi, Nishizawa Osamu, de Miguel Fernando, Chancellor Michael B, Yoshimura Naoki
Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
Urology. 2007 Jul;70(1):202-8. doi: 10.1016/j.urology.2007.02.069.
Ajulemic acid (IP-751) is a synthetic analog of tetrahydrocannabinol, which is a major ingredient of the plant Cannabis. IP-751 reportedly shows potent anti-inflammatory activity and is a powerful analgesic agent. Thus, we examined whether IP-751 can suppress urinary frequency induced by nociceptive stimuli in the bladder.
Continuous cystometry (infusion rate 0.04 mL/min) under urethane anesthesia was performed to evaluate the effect of intravenous injection of IP-751 with or without a cannabinoid-1 receptor antagonist (AM251) or a cannabinoid-2 receptor antagonist (AM630) on bladder function in normal rats and rats with urinary frequency induced by intravesical infusion with 0.25% acetic acid or cyclophosphamide (CYP) (150 mg/kg intraperitoneally, 48 hours before cystometrography).
When 10 mg/kg of IP-751 was injected in normal rats, the intercontraction interval (ICI) and pressure threshold increased. A 0.25% acetic acid infusion induced urinary frequency, as evidenced by a reduction in ICIs, which were suppressed by injection of IP-751 (10 mg/kg). Urinary frequency, indicated by significant ICI reductions, was also observed in the CYP-treated rats. Administration of IP-751 (10 mg/kg) significantly suppressed CYP-induced urinary frequency, as evidenced by the increase in the ICI. When AM251, but not AM630, was administered before IP-751, the IP-751-induced increases in the ICI and pressure threshold were prevented in all three groups. In addition, administration of AM251 alone decreased the ICIs in CYP-treated rats.
IP-751 can suppress normal bladder activity and urinary frequency induced by bladder nociceptive stimuli, probably by suppression of bladder afferent activity. These inhibitory effects of IP-751 are at least in part mediated by the cannabinoid-1 receptor.
阿居列米酸（IP - 751）是四氢大麻酚的合成类似物，四氢大麻酚是植物大麻的主要成分。据报道，IP - 751具有强大的抗炎活性，是一种强效镇痛剂。因此，我们研究了IP - 751是否能抑制膀胱中伤害性刺激诱导的尿频。
在氨基甲酸乙酯麻醉下进行连续膀胱测压（输注速率0.04 mL/分钟），以评估静脉注射IP - 751（有无大麻素-1受体拮抗剂（AM251）或大麻素-2受体拮抗剂（AM630））对正常大鼠以及膀胱内输注0.25%乙酸或环磷酰胺（CYP）（在膀胱测压前48小时腹腔注射150 mg/kg）诱导尿频的大鼠膀胱功能的影响。
在正常大鼠中注射10 mg/kg的IP - 751时，收缩间期（ICI）和压力阈值增加。0.25%乙酸输注诱导尿频，表现为ICI缩短，而注射IP - 751（10 mg/kg）可抑制这种缩短。在CYP处理的大鼠中也观察到了以ICI显著缩短为指标的尿频。给予IP - 751（10 mg/kg）可显著抑制CYP诱导的尿频，表现为ICI增加。当在IP - 751之前给予AM251而非AM630时，三组中IP - 751诱导的ICI和压力阈值增加均被阻止。此外，单独给予AM251可缩短CYP处理大鼠的ICI。
IP - 751可能通过抑制膀胱传入活动来抑制正常膀胱活动以及膀胱伤害性刺激诱导的尿频。IP - 751的这些抑制作用至少部分由大麻素-1受体介导。
