目的:2-(4-氯苯基)-5-苯并恶唑乙酸甲酯(MCBA),一种合成的苯并恶唑衍生物,具有既定的抗银屑病功效,研究了潜在的抗伤害作用。本研究采用小鼠的各种伤害性试验来阐明MCBA的镇痛机制。
方法:针对福尔马林诱导的各种伤害感受模型,测试了MCBA的抗伤害感受潜能,谷氨酸,辣椒素,一种瞬时受体电位香草酸1(TRPV1)受体激动剂,和佛波醇12-肉豆蔻酸酯13-乙酸酯,蛋白激酶C(PKC)激活剂。然后使用热板测试对其进行评估,并在乙酸诱导的扭体测试中进行检查。在乙酸引起的扭体试验中,MCBA受到选择性受体拮抗剂如纳洛酮的预先攻击,咖啡因,阿托品,育亨宾,昂丹司琼,和氟哌啶醇.还接受了ATP敏感性钾通道抑制剂(格列本脲)的挑战,以进一步阐明其抗伤害感受机制。
结果:结果显示,在60、120和240mg/kg的剂量下,在所有评价的模型中,MCBA的口服给药导致对伤害感受作用的剂量依赖性和显著抑制(p<0.05)。此外,MCBA的抗伤害潜能的功效被特异性拮抗剂显著抵消(p<0.0001):(i)针对腺苷,α-2肾上腺素能,和使用咖啡因的胆碱能受体,育亨宾,还有阿托品,分别靶向ATP敏感性钾通道,使用格列本脲.针对阿片能和5-羟色胺能受体的拮抗剂(纳洛酮和昂丹司琼,分别)在抑制抗伤害感受活性方面的效用较差。相反,多巴胺能受体拮抗剂氟哌啶醇增强了与MCBA治疗相关的运动异常。
结论:MCBA诱导的抗伤害感受涉及谷氨酸调节-,TRVP1受体和PKC信号通路。它影响腺苷能,α-2肾上腺素能,和胆碱能受体,并打开ATP敏感性钾通道。
OBJECTIVE: Methyl-2-(4-chloro- phenyl)-5-benzoxazoleacetate (MCBA), a synthetic benzoxazole derivative with established antipsoriatic efficacy, was investigated for potential antinociceptive effects. This study employs various nociceptive assays in mice to elucidate MCBA\'s antinociceptive mechanisms.
METHODS: MCBA\'s antinociceptive potential was tested against various nociception models induced by formalin, glutamate, capsaicin, a transient receptor potential vanilloid 1 (TRPV1) receptor agonist, and phorbol 12-myristate 13-acetate, a protein kinase C (PKC) activator. It was then assessed using the hot plate test and examined within the acetic acid-induced writhing test. During the acetic acid-induced writhing test, MCBA was pre-challenged against selective receptor antagonists such as naloxone, caffeine, atropine, yohimbine, ondansetron, and haloperidol. It was also pre-challenged with ATP-sensitive potassium channel inhibitor (glibenclamide) to further elucidate its antinociceptive mechanism.
RESULTS: The results showed that oral administration of MCBA led to a dose-dependent and significant inhibition (p < 0.05) of nociceptive effects across all evaluated models at doses of 60, 120, and 240 mg/kg. Moreover, the efficacy of MCBA\'s antinociceptive potential was significantly counteracted (p < 0.0001) by specific antagonists: (i) directed at adenosinergic, alpha-2 adrenergic, and cholinergic receptors using caffeine, yohimbine, and atropine, respectively; and (ii) targeting ATP-sensitive potassium channels, employing glibenclamide. Antagonists aimed at opioidergic and serotoninergic receptors (naloxone and ondansetron, respectively) had poor utility in inhibiting antinociceptive activity. Conversely, the dopaminergic receptor antagonist haloperidol potentiated locomotor abnormalities associated with MCBA treatment.
CONCLUSIONS: MCBA-induced antinociception involves modulation of glutamatergic-, TRVP1 receptors- and PKC-signaling pathways. It impacts adenosinergic, alpha-2 adrenergic, and cholinergic receptors and opens ATP-sensitive potassium channels.