The cannabinoid receptor antagonist AM251 increases paraoxon and chlorpyrifos oxon toxicity in rats

Abstract

Organophosphorus anticholinesterases (OPs) elicit acute toxicity by inhibiting acetylcholinesterase (AChE), leading to acetylcholine accumulation and overstimulation of cholinergic receptors. Endocannabinoids (eCBs, e.g., arachidonoyl ethanolamide [AEA] and 2-arachidonoyl glycerol [2-AG]) are neuromodulators that regulate neurotransmission by reducing neurotransmitter release. The eCBs are degraded by the enzymes fatty acid amide hydrolase (FAAH, primarily involved in hydrolysis of AEA) and monoacylglycerol lipase (MAGL, primarily responsible for metabolism of 2-AG). We previously reported that the cannabinoid receptor agonist WIN 55,212-2 reduced cholinergic toxicity after paraoxon exposure. This study compared the effects of the cannabinoid receptor antagonist AM251 on acute toxicity following either paraoxon (PO) or chlorpyrifos oxon (CPO). CPO was more potent in vitro than PO at inhibiting AChE (≈ 2 fold), FAAH (≈ 8 fold), and MAGL (≈ 19 fold). Rats were treated with vehicle, PO (0.3 and 0.6 mg/kg, sc.) or CPO (6 and 12 mg/kg, sc.) and subsets treated with AM251 (3 mg/kg, ip; 30 min after OP). Signs of toxicity were recorded for four hours and rats were then sacrificed. OP-treated rats showed dose-related involuntary movements, with AM251 increasing signs of toxicity with the lower dosages. PO and CPO elicited excessive secretions, but AM251 had no apparent effect with either OP. Lethality was increased by AM251 with the higher dosage of PO, but no lethality was noted with either dosage of CPO, with or without AM251. Both OPs caused extensive inhibition of hippocampal AChE and FAAH (>80–90%), but only CPO inhibited MAGL (37–50%). These results provide further evidence that eCB signaling can influence acute OP toxicity. The selective in vivo inhibition of MAGL by CPO may be important in the differential lethality noted between PO and CPO with AM251 co-administration.

Effects of low‐dose chlorpyrifos on neurobehavior and potential mechanisms: A review of studies in rodents, zebrafish, and Caenorhabditis elegans

“…It is, in part, comprised of (a) the CB1 receptor; (b) two principal endogenous ligands (2‐arachidonoylglycerol and anandamide [AEA]); (c) the serine hydrolases monoacylglycerol lipase; (d) and endocannabinoid metabolizing enzymes (fatty acid amide hydrolase [FAAH] and monoacylglycerol lipase) (Di Marzo et al, ), as well as other signaling pathways involved in neurodevelopment (Berghuis, ; Dalton & Howlett, ). CPF has been shown to disrupt this system in adult (Liu & Pope, ; Nomura et al, ; Nomura & Casida, ; Quistad, Klintenberg, Caboni, Liang, & Casida, ; Quistad, Nomura, Sparks, Segall, & Casida, ; Quistad, Sparks, & Casida, ) and preweaning rats (Buntyn et al, ; Carr, Adams, Kepler, Ward, & Ross, ; Carr et al, ; Carr, Graves, Mangum, Nail, & Ross, ). Furthermore, the endocannabinoid system is partly involved in anxiety responses (Carr et al, ; Ruehle, Rey, Remmers, & Lutz, ).…”

Comparative in vitro and in vivo effects of chlorpyrifos oxon in the outbred CD-1 mouse (Mus musculus) and great plains toad (Anaxyrus cognatus)

“…Liver homogenates were clarified by centrifugation at 1000 g at 4 8C for 10 min using an Avanti J-25I centrifuge (Beckman Coulter), and the supernatant was used for assays. Acetylcholinesterase, butyrylcholinesterase, and monoacylglycerol lipase were measured using the photometric method of Ellman et al (1961) as modified by Ulloa and Deutsch (2010) and Liu and Pope (2015). A cocktail (175 mL) of substrate (final concentrations: acetylthiocholine, 1 mM; butyrylthiocholine, 1 mM; 2arachidonoyl thioglycerol, 0.1 mM) along with 5,5 0 -dithiobis (2-nitrobenzoic acid) (0.1 mM final) in 10 mM Tris buffer containing 1 mM EDTA (pH 7.2; Tris-E) was added to tissue homogenates (25 mL) in a final reaction volume of 200 mL.…”

Comparative effects of parathion and chlorpyrifos on endocannabinoid and endocannabinoid-like lipid metabolites in rat striatum

“…Indeed, we previously reported that acute toxicity of both paraoxon (the active metabolite of parathion) and diisopropylfluorophosphate, is reduced by CB1 receptor agonists (Nallapaneni et al ., 2006, 2008; Wright et al ., 2010). More recently, the CB1 receptor antagonist AM251 was shown to increase the acute toxicity of paraoxon and chlorpyrifos oxon (the active metabolite of chlorpyrifos; Liu and Pope, 2015). …”