Sensitivity of the cat to delayed neurotoxicity induced by O-ethyl O-4-nitrophenyl phenylphosphonothioate.

Delayed neurotoxicity was produced in cats following the administration of either a single dermal dose of 22.5 to 225 mg/kg (0.2 to 5.0 times the LD50) or subchronic (90 days) administration of 0.5 to 2.0 mg/kg of technical grade O-ethyl O-4-nitrophenyl phenylphosphonothioate (EPN). The study showed three differences from the condition produced in the chicken: difficulty to protect from acute poisoning, slower progression of delayed neurotoxicity, and propensity for improvement. These animals received atropine sulfate and pyridine-2-aldoxime methyl chloride (PAM) to protect them against acute poisoning, but most developed signs of acute cholinergic neurotoxicity, the degree of severity being dose dependent. Also cats given small single doses of EPN showed only leg weakness, while those treated with large doses progressed to severe ataxia and death. In cats treated with subchronic dermal daily doses of EPN, the extent and permanence of injury and progression or improvement of neurologic deficit also depended on the dose size and duration of exposure. Histopathologic changes were present in the most distal portion of the longest tracts in both the central and peripheral nervous system. Ascending tracts were most affected in the cervical spinal cord, while change in the descending tracts was concentrated in the lumbosacral spinal cord. Recovery to a varying degree from delayed neurotoxicity was seen in all surviving cats. The recovery was demonstrated as improvement in clinical signs, increase in body weight, and regeneration of peripheral nerves.

Physiological disposition and metabolism of O-ethyl-O-4-nitrophenyl phenylphosphonothioate in male cats following a single dermal administration.

The pharmacokinetics and metabolism of a single dermal 20.0 mg/kg of uniformly phenyl-labeled [14C]EPN (O-ethyl O-4-nitrophenyl [14C]phenylphosphonothioate) were investigated in adult male cats. Three treated cats were killed at each time interval: 0.5, 2, 4, 8, and 12. Radioactivity disappeared exponentially from administration site at a rate constant of 0.46 day-1, corresponding to a half-life of 1.5 days. Most of the absorbed radioactivity was excreted in the urine (29.9%). Only 3.2% of the 14C was recovered in the feces. No radioactivity was detected in expired CO2. Only traces of EPN were detected in the urine and feces. Most of the excreted 14C materials were identified as O-ethyl phenylphosphonothioic acid (EPPTA), O-ethyl phenylphosphonic acid (EPPA), and phenylphosphonic acid (PPA). The disposition studies showed that EPN was the major compound identified 0.5 day after administration in the brain, spinal cord, sciatic nerve, adipose tissue, plasma, muscle, liver, and kidney. Most of the radioactivity in the liver and kidney was identified after 4 days as EPPTA, EPPA, and PPA. Kinetic and distribution studies showed that EPN was eliminated from the tissues and plasma according to exponential kinetics. The half-life of the elimination of EPN from plasma was 9.1 days corresponding to a constant rate value of 0.076 day-1. Relative residence (RR) of EPN relative to plasma was longest in the sciatic nerve and shortest in the kidney.

Monosynaptic reflex depression in cats with organophosphorus neuropathy: effects of tri-o-cresyl phosphate.

The electrophysiology of organophosphorus induced delayed neurotoxicity was studied to determine the extent peripheral nerve changes affect monosynaptic reflex responses of the spinal cord. Cats were given a single dermal dose of 1500 mg/kg or two dermal doses of 500 mg/kg of tri-o-cresyl phosphate. Animals were observed for 60 days after which monosynaptic reflex (MSR) responses were recorded from L7 and S1 ventral roots after stimulation of the tibial or common peroneal nerves. Post-tetanic potentiated responses as well as ventral and dorsal root compound action potentials were also recorded. There was a significant decrease from control in the unconditioned MSR. The post-tetanic potentiated response was significantly decreased in the S1 ventral root, however, when expressed as a factor of potentiation of the unconditioned MSR, it was found to be increased, although not significantly. The dorsal and ventral root compound action potentials were also significantly decreased from control with their conduction velocities being no different from control The decrease in the unconditioned MSR as well as the dorsal and ventral root compound action potentials were attributed to peripheral nerve damage. The absence of any significant change in the post-tetanic potentiated response expressed as a factor of potentiation of the unconditioned MSR was attributed to a decrease in both the discharge zone as well as the subliminal fringe. The absence of any change in the conduction velocity indicates at least some of the large myelinated peripheral fibers were spared from significant damage.

The effects of convulsant doses of penicillin on primary afferents, dorsal root ganglion cells, and on 'presynaptic' inhibition in the spinal cord.

Intracellular recordings were made from neurons in dorsal root ganglia (DRG) of rats, isolated in vitro. The depolarization of DRG cells caused by the application of gamma-aminobutyric acid (GABA) diminished reversibly when penicillin (0.08--2.0 mM) was added to the bathing fluid. The decrease of the input resistance of DRG cells measured during GABA perfusion was also depressed in the presence of penicillin, but no evidence of a shift of the reversal potential of the GABA-induced depolarization was found. Nor did penicillin (up to 10 mM) cause a change in the voltage-current function, in electrical excitability, in the inclination to repetitive firing, bursting discharge, or after discharge. In decapitate cat preparation the amplitude of the negative dorsal root potential (DRP or DR V) diminished by 0--50% after the i.v. administration of 0.5--1.0 X 10(6) I.U./kg (the convulsant dose) of penicillin. Post-tetanic depression of the DRP was aggravated by penicillin. The degree of depression of the DRP bore no relationship to the promptness of the eruption, and to the intensity, of the seizure activity induced by penicillin. The rates of rise and fall of the negative DRP (DR V) were consistently slowed, the positive DRP (DR VI) reduced, and the dorsal root reflex (DRR) blocked by penicillin. Inhibitory reflex effects presumed to be presynaptic were either enhanced or unchanged, never depressed by penicillin. This was seen when inhibitory function was gauged by monosynaptic reflex amplitude, and also from the inhibition of ventral root electrotonic excitatory postsynaptic potentials (VP EPSPs). Possible explanations of these seemingly paradoxical findings are discussed, with arguments in favor and against each.