Oral or intravenous administration of allethrin, a synthetic derivative of the pirethrin-based insecticides, produces neurotoxic symptoms consisting of mild salivation, hyperexcitability, tremors and convulsions which result in death. Intracerebroventricular injection of allethrin to mouse at about one-nineth the dose of intravenous administration, produced qualitatively identical but less prominent symptoms, indicating that at least some of the symptoms may be originated in the central nervous system. To investigate the mechanism of action of the compound, we studied the ability of agents which alter neurotransmission to prevent or potentiate the effect of convulsive doses of technical grade (15.5% cis, 84.5% trans) allethrin. Intraperitoneal pretreatment with drugs which block noradrenergic receptors or norepinephrine synthesis, such as pentobarbital, chlorpromazine, phentolamine, phenoxybenzamine and reserpine, depressed the tremor induced by allethrin. The inhibitory effect of reserpine was reversed by phenylephrine. Both the serotonergic blocker, methysergide, and the serotonin depletor, rho-chlorphenylalanine, potentiated the effect of allethrin. The potentiating effect of methysergide was antagonized by 5-hydroxytryptamine. However, intracerebroventricular administration of methysergide was ineffective in potentiating the effect of allethrin. alpha 2- and beta-adrenoceptor blockers, muscarinic antagonists, GABA mimenergics and morphine had no effect. These results suggest that allethrin produces its neurotoxic responses in mice by acting on the brain and spinal levels. Furthermore, adrenergic excitatory and serotonergic inhibitory mechanisms may be involved in the neural pathway through which the allethrin-induced tremor is evoked.
Release of acetylcholine (ACh) by prostaglandin E1 from the nerve terminals of the guinea‐pig longitudinal muscle strip was studied in order to reveal the effect of PGE1 on myenteric plexus activity. The ACh released was collected in the presence of physostigmine (2·1 μg ml−1) and choline (0·1 μg ml−1) at 38° C. Five to 100 ng ml−1 PGE1 enhanced the release dose‐dependently. The effect was maintained during the presence of PGE1 in the organ bath, while rapid tachyphylaxis was observed with the ACh‐releasing action of nicotine. Tetrodotoxin or morphine almost completely inhibited the effect of PGE1 on ACh release. Hexamethonium, in a concentration which completely blocked the effect of nicotine, partially inhibited the effect of PGE1. In the late phase of nicotine action, the tissue was still sensitive to PGE1 despite the continued exposure to nicotine. These data suggest the presence in the myenteric plexus of PG receptors which can increase ACh release.
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