Antinociceptive effect of diisopropylphosphofluoridate: development of tolerance and lack of cross-tolerance to morphine

The irreversible cholinesterase inhibitor diisopropylphosphofluoridate (DFP) causes a naloxone-sensitive antinociceptive effect in laboratory animals. Chronic treatment of male mice with DFP (2 mg/kg/day for fourteen days) rendered the animals tolerant to its antinociceptive effect. Animals tolerant to DFP were cross-tolerant to the antinociception induced by the cholinergic agonists oxotremorine and nicotine, but no cross-tolerance with morphine was observed. Similarly, mice made tolerant to morphine were not cross-tolerant to DFP, nor were they cross-tolerant to oxotremorine and nicotine. Binding of muscarinic and nicotinic cholinergic ligands was significantly decreased in the brain of DFP-tolerant mice, due to a reduction in receptor density. No change was observed in the binding of [3H]-dihydromorphine to opiate receptors. None of these three binding sites was altered in mice tolerant to morphine. Although there is evidence of an involvement of endogenous opioids in the antinociceptive action of DFP, the lack of cross-tolerance between DFP and morphine suggests the existence of a more complex interaction between DFP and the cholinergic and opiate systems.