Roles of .Mu.-Opioid Receptors in Development of Tolerance to Diisopropylfluorophosphate (Dfp)

Abstract

-Anatomical evidence indicates that cholinergic and opioidergic systems are co-localized and acting on the same neuron. However, the regulatory mechanisms between cholinergic and opioidergic system have not been well characterized. In the present study, the potential involvement of µ-opioid receptors in mediating the changes of toxic signs and muscarinic receptor binding after administration of irreversible anti-acetylcholinesterase diisopropylfluorophosphate (DFP) was investigated. DFP (1 mg/kg/day, subcutaneous injection, s.c.)-induced tremors and chewing movements were monitored during the 28-day treatment period in µ-opioid receptor knockout and wild type mice. Autoradiographic studies of total, M1, and M2 muscarinic receptors were conducted using [ ]-AF-DX384 as ligands, respectively. DFP-induced tremors in both µ-opioid receptor knockout and wild type mice showed tolerance development. However, DFP-induced tremors in µ-opioid receptor knockout mice showed delayed tolerance development than that of DFP-treated wild type controls. DFPinduced chewing movements in both µ-opioid receptor knockout and wild type mice failed to show development of tolerance after four weeks of treatment. M2 muscarinic receptor binding of DFP-treated µ-opioid receptor knockout mice was significantly decreased than that of the DFP-treated wild type controls in the striatum, but not in the cortex and hippocampus. However, there were no significant differences in total and M1 muscarinic receptor binding between DFP-treated µ-opioid receptor knockout and wild type mice in the cortex, striatum and hippocampus. These studies indicate that µ-opioid receptors play an important role through the striatal M2 muscarinic receptors to regulate the development of tolerance to DFP-induced tremors.