Department of Physiological Sciences, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK, USA.
Toxicol Appl Pharmacol. 2013 Nov 1;272(3):608-15. doi: 10.1016/j.taap.2013.07.025. Epub 2013 Aug 7.
Parathion (PS) and chlorpyrifos (CPF) are organophosphorus insecticides (OPs) that elicit acute toxicity by inhibiting acetylcholinesterase (AChE). Endocannabinoids (eCBs, N-arachidonoylethanolamine, AEA; 2-arachidonoylglycerol, 2AG) can modulate neurotransmission by inhibiting neurotransmitter release. We proposed that differential inhibition of eCB-degrading enzymes (fatty acid amide hydrolase, FAAH, and monoacylglycerol lipase, MAGL) by PS and CPF leads to differences in extracellular eCB levels and toxicity. Microdialysis cannulae were implanted into hippocampus of adult male rats followed by treatment with vehicle (peanut oil, 2 ml/kg, sc), PS (27 mg/kg) or CPF (280 mg/kg) 6-7 days later. Signs of toxicity, AChE, FAAH and MAGL inhibition, and extracellular levels of AEA and 2AG were measured 2 and 4 days later. Signs were noted in PS-treated rats but not in controls or CPF-treated rats. Cholinesterase inhibition was extensive in hippocampus with PS (89-90%) and CPF (78-83%) exposure. FAAH activity was also markedly reduced (88-91%) by both OPs at both time-points. MAGL was inhibited by both OPs but to a lesser degree (35-50%). Increases in extracellular AEA levels were noted after either PS (about 2-fold) or CPF (about 3-fold) while lesser treatment-related 2-AG changes were noted. The cannabinoid CB1 receptor antagonist/inverse agonist AM251 (3mg/kg, ip) had no influence on functional signs after CPF but markedly decreased toxicity in PS-treated rats. The results suggest that extracellular eCBs levels can be markedly elevated by both PS and CPF. CB1-mediated signaling appears to play a role in the acute toxicity of PS but the role of eCBs in CPF toxicity remains unclear.
对硫磷 (PS) 和毒死蜱 (CPF) 是有机磷杀虫剂 (OPs)，通过抑制乙酰胆碱酯酶 (AChE) 引起急性毒性。内源性大麻素 (eCBs，N-花生四烯酸乙醇胺，AEA；2-花生四烯酸甘油，2AG) 可以通过抑制神经递质释放来调节神经递质传递。我们提出，PS 和 CPF 对 eCB 降解酶 (脂肪酸酰胺水解酶，FAAH 和单酰基甘油脂肪酶，MAGL) 的不同抑制导致细胞外 eCB 水平和毒性的差异。成年雄性大鼠海马内植入微透析套管，6-7 天后用载体 (花生油，2ml/kg，sc)、PS (27mg/kg) 或 CPF (280mg/kg) 处理。2 和 4 天后测量毒性体征、AChE、FAAH 和 MAGL 抑制以及细胞外 AEA 和 2AG 水平。PS 处理的大鼠出现体征，但对照大鼠或 CPF 处理的大鼠没有出现体征。PS (89-90%) 和 CPF (78-83%) 暴露后，海马中的胆碱酯酶抑制作用广泛。两种 OP 在两个时间点均显著降低 FAAH 活性 (88-91%)。两种 OP 均抑制 MAGL，但抑制程度较低 (35-50%)。PS 后 (约 2 倍) 或 CPF 后 (约 3 倍) 观察到细胞外 AEA 水平升高，而较少的治疗相关 2AG 变化。大麻素 CB1 受体拮抗剂/反向激动剂 AM251(3mg/kg，ip) 对 CPF 后的功能体征没有影响，但明显降低了 PS 处理大鼠的毒性。结果表明，PS 和 CPF 均可显著升高细胞外 eCBs 水平。CB1 介导的信号转导似乎在 PS 的急性毒性中起作用，但 eCBs 在 CPF 毒性中的作用尚不清楚。
