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 mu-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 mu-opioid receptor knockout and wild type mice. 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. DFP-induced tremors in both mu-opioid receptor knockout and wild type mice showed tolerance development. However, DFP-induced tremors in mu-opioid receptor knockout mice showed delayed tolerance development than that of DFP-treated wild type controls. DFP-induced chewing movements in both mu-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 mu-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 mu-opioid receptor knockout and wild type mice in the cortex, striatum and hippocampus. These studies indicate that mu-opioid receptors play an important role through the striatal M2 muscarinic receptors to regulate the development of tolerance to DFP-induced tremors.

• Authors: Lu-Tai Tien, Lir-Wan Fan, Tangeng Ma, Horace H Loh, Ing Kang Ho
• Journal: The Journal of toxicological sciences (J Toxicol Sci) Vol. 30 Issue 1 Pg. 43-59 (Feb 2005) ISSN: 0388-1350 [Print] Japan
• PMID: 15800401 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Receptors, Muscarinic
• Receptors, Opioid, mu
• Isoflurophate
• Acetylcholinesterase

Topics

• Acetylcholinesterase (metabolism)
• Animals
• Behavior, Animal (drug effects)
• Body Weight (drug effects)
• Corpus Striatum (drug effects)
• Drug Tolerance
• Isoflurophate (toxicity)
• Male
• Mice
• Mice, Inbred C57BL
• Receptors, Muscarinic (drug effects)
• Receptors, Opioid, mu (physiology)
• Tremor (chemically induced)