ROLES OF μ-OPIOID RECEPTORS IN DEVELOPMENT OF TOLERANCE TO DIISOPROPYLFLUOROPHOSPHATE (DFP)

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- 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 [³H]-quinuclidinyl benzilate, [³H]-pirenzepine, and [³H]-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. DFP-induced 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.