Abstract
The potential involvement of μ‐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 μ‐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 μ‐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 μ‐opioid receptor knockout and wild‐type mice. There were also no significant differences in chewing movement induced by all doses of DFP between μ‐opioid receptor knockout and wild‐type mice. However, DFP (3 mg/kg)‐induced tremors in μ‐opioid receptor knockout mice were significantly increased over those in wild‐type controls. Acetylcholinesterase activity in the striatum of saline‐treated μ‐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 μ‐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 μ‐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 μ‐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 μ‐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 μ‐opioid receptor knockout mice. © 2004 Wiley‐Liss, Inc.