METHODS: We evaluated KBP-336\'s effect on pain-like symptoms in Sprague Dawley (SD) rats on high-fat diet (HFD) that underwent meniscectomy using the von Frey test to measure the 50% paw withdrawal threshold (PWT) and analyzed using one-way ANOVA. Short in vivo studies and in vitro cell receptor expression systems were used to illustrate receptor pharmacology.
RESULTS: After 30 weeks on HFD, including an 8-week treatment, female MNX animals receiving KBP-336 4.5 nmol/Kg/72 h had lower body weight and smaller adipose tissues than their vehicle-treated counterparts. After 20 weeks on HFD, including an 8-week treatment, male rats receiving KBP-336 had lower body weight than the vehicle group. In both the female and male rats, the MNX groups on KBP-336 treatment had a higher PWT than the vehicle-treated MNX group. Aiming to identify the receptor influencing pain alleviation, KBP-336 was compared to the long-acting human calcitonin (hCTA). Single-dose studies on 12-week-old male rats showed that hCTA lowers CTX-I without affecting food intake, confirming its calcitonin receptor selectivity. On the metabolic OA model with 18 weeks of HFD, including 6-week treatment, hCTA at 100 nmol/Kg/24 h and KBP-336 at 0.5, 1.5, and 4.5 nmol/Kg/72 h produced significantly higher PWT in MNX animals compared to MNX animals on vehicle treatment. hCTA and KBP-336 at 0.5 nmol/Kg did not affect body weight and fat tissues.
CONCLUSIONS: Overall, KBP-336 improved the pain observed in the metabolic OA model. Calcitonin receptor activation proved to be essential in this antinociceptive effect.
方法:我们使用vonFrey测试评估了KBP-336对接受半月板切除术的高脂饮食(HFD)的SpragueDawley(SD)大鼠疼痛样症状的影响。测量50%的爪退缩阈值(PWT),并使用单向ANOVA进行分析。短体内研究和体外细胞受体表达系统用于说明受体药理学。
结果:进行HFD30周后,包括8周的治疗,接受KBP-3364.5nmol/Kg/72小时的雌性MNX动物的体重较低,脂肪组织较小。在HFD上20周后,包括8周的治疗,接受KBP-336的雄性大鼠的体重低于载体组。在雌性和雄性老鼠中,接受KBP-336治疗的MNX组的PWT高于接受载体治疗的MNX组.为了确定影响疼痛缓解的受体,将KBP-336与长效人降钙素(hCTA)进行比较。对12周龄雄性大鼠的单剂量研究表明,hCTA降低CTX-I而不影响食物摄入,证实其降钙素受体选择性。在18周HFD代谢OA模型上,包括6周的治疗,与媒介物处理的MNX动物相比,100nmol/Kg/24小时的hCTA和0.5、1.5和4.5nmol/Kg/72小时的KBP-336在MNX动物中产生显著更高的PWT。0.5nmol/Kg的hCTA和KBP-336不影响体重和脂肪组织。
结论:总体而言,KBP-336改善了在代谢OA模型中观察到的疼痛。降钙素受体激活被证明是这种抗伤害作用必不可少的。