Involvement of adrenergic and serotonergic nervous mechanisms in allethrin-induced tremors in mice.

Abstract

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.

Neurobehavioral toxicology of pyrethroid insecticides in adult animals: A critical review

“…The behavioral observations conducted 20-30 years ago (e.g. [175,98,127]) support this assumption. The T(Type I)/CS (Type II)/TS(Type I/II) classification scheme established in these studies is still useful for systematic comparison of acute poisoning syndromes between older and "modern" pyrethroids and across different insecticide classes.…”

“…administration of pyrethroids, the time course for the development of poisoning signs in insects and mammals is comparable. A latency of seconds to minutes from dosing to the onset of poisoning signs is seen in both cases [98,62,127,13,139,39]. In rodents, the onset of poisoning signs correlates with the accumulation of an internal dose in nervous system tissue [180,70,66,74,146].…”

“…A detailed comparison of the clinical signs observed in small rodents following exposure to both types of pyrethroids is shown in Table 1. The key features of these syndromes are similar between rodent species regardless of the route of administration: i.c., i.v., i.p., or oral [175,98,127,36]. Generally, pyrethroids with a halogenated acid esterified to an αcyano-3-phenoxybenzyl alcohol produce the CS/Type II syndrome.…”

Evidence for Dose-Additive Effects of Pyrethroids on Motor Activity in Rats

“…Previous reports from studies using similar dosing protocols in rats demonstrated maximal decreases in figure-eight maze activity at 1–4 hr postdosing (Crofton et al 1995; Crofton and Reiter 1984, 1988; McDaniel and Moser 1993; Wolansky et al 2006). In addition, allethrin, S -bioallethrin, permethrin, fenvalerate, delta-methrin, and cypermethrin evoke alterations in motor-related end points in small rodents evident as early as 0.5–1.5 hr after systemic exposure (De Souza Spinosa et al 1999; Hoy et al 2000; McDaniel and Moser 1993; Nishimura et al 1984; Wolansky et al 2006). Likewise, the extended effect on activity through 8 hr is consistent with the prolonged syndromes evoked by resmethrin and bifenthrin (Crofton and Reiter 1984; Holton et al 1997; Soderlund et al 2002; White et al 1976; Wolansky et al 2006, 2007).…”

“…A proposed mechanism of action for all pyrethroids is the prolongation of the open state of neuronal voltage-dependent sodium channels (Narahashi 1971; Vijverberg and van den Bercken 1990). This action results in altered neuronal excitability characterized by in vitro and in vivo changes in neuronal firing rates (e.g., repetitive firing or depolarizing block of the neuron) (Narahashi 2000) that are associated with two high-dose neurologic syndromes, T syndrome and the CS syndrome (Aldridge 1990; Barnes and Verschoyle 1974; Lawrence and Casida 1982; Ray and Forshaw 2000; Ray and Fry 2006; Verschoyle and Aldridge 1980), and dose-dependent changes in motor and sensory behaviors at lower doses (Chanh et al 1984; Crofton and Reiter 1984 1988; Hornychova et al 1995; McDaniel and Moser 1993; Nishimura et al 1984; Wolansky et al 2006; Wolansky and Harrill 2008). …”