Increased diisopropylfluorophosphate-induced toxicity in mu-opioid receptor knockout mice.

Abstract

The potential involvement of mu-opioid receptors in mediating the changes of toxic signs and muscarinic receptor bindings after acute administration of irreversible antiacetylcholinesterase diisopropylfluorophosphate (DFP) was investigated. DFP-induced chewing movement and tremors were monitored for a period of 180 min in mu-opioid receptor knockout and wild-type mice. The autoradiographic studies of total, M1, and M2 muscarinic receptors were conducted using [(3)H]quinuclidinyl benzilate, [(3)H]pirenzepine, and [(3)H]AF-DX384 as ligands, respectively. Saline-treated mu-opioid receptor knockout and wild-type mice did not show chewing movement or tremors. Although DFP (1, 2, or 3 mg/kg, subcutaneous injection, s.c.)-induced chewing movement and tremors were shown in a dose-dependent manner, there were no significant differences in tremors induced by 1 or 2 mg/kg of DFP between mu-opioid receptor knockout and wild-type mice. There were also no significant differences in chewing movement induced by all doses of DFP between mu-opioid receptor knockout and wild-type mice. However, DFP (3 mg/kg)-induced tremors in mu-opioid receptor knockout mice were significantly increased over those in wild-type controls. Acetylcholinesterase activity in the striatum of saline-treated mu-opioid receptor knockout mice was significantly higher than that of the wild-type controls. After administration of DFP, acetylcholinesterase activity in the striatum of both mu-opioid receptor knockout and wild-type mice was significantly decreased (more than 36%, 58%, and 94% reduced at the doses of 1, 2, and 3 mg/kg, respectively) than that of their respective saline controls. M2 muscarinic receptor binding in saline-treated mu-opioid receptor knockout mice was significantly lower than that of the wild-type controls in the striatum. However, there were no significant differences in total, M1, or M2 muscarinic receptor binding in the cortex, striatum, or hippocampus of mu-opioid receptor knockout and wild-type mice after DFP administration. Our data show increased DFP-induced tremors, compensatory up-regulation of acetylcholinesterase activity, and compensatory down-regulation of M2 muscarinic receptors in the striatum of mice lacking mu-opioid receptor gene. These results suggest that the enhancement of DFP-induced tremors may be associated with the compensatory up-regulation of acetylcholinesterase activity and compensatory down-regulation of M2 muscarinic receptors in the striatum of mu-opioid receptor knockout mice.