of poisoning in mammals and invertebrate animals. In vitro studies of their mechanism of action on the nervous system have used nerve preparations isolated from insects, crayfish, and squid and cultured mouse neuroblastoma cells (Narahashi, 1971, 1985, 1989; Ruigt, 1984; Wouters and van den Bercken, 1978).

Pyrethroid poisoning is associated with an increase in electric activity of the central and peripheral nervous systems: a single presynaptic stimulation in the presence of pyrethroids causes repetitive excitation of presynaptic nerve and nerve terminals, thereby evoking repetitive postsynaptic discharges. This can be demonstrated by exposing isolated nerve fiber preparations, such as crayfish giant axons and frog myelinated nerve fibers, to low concentrations of pyrethroids (especially type I pyrethroids). Intracellular potential recording experiments reveal that the depolarizing after-potential is gradually increased in amplitude and prolonged after application of pyrethroids, until it finally generates repetitive after-discharges (Lund and Narahashi, 1983).

How the depolarizing after-potential is increased by pyrethroids is best studied by voltage-clamp techniques, whereby membrane ionic currents can be recorded. The sodium current that generates action potentials is markedly prolonged after the preparation is exposed to pyrethroids, and that causes a sustained depolarization after an action potential (Narahashi and Lund, 1980). However, the sodium current thus recorded represents an algebraic sum of currents passing through a large number of open sodium channels. The activity of individual ion channels can be studied by patch-clamp techniques, which allow measurements of ionic currents flowing through individual open channels. Pyrethroids have been found usually long periods (Yamamoto et al., 1983). A sodium channel normally is kept open during a depolarizing step for only a few milliseconds, whereas a sodium channel exposed to pyrethroids can remain open much longer—even up to several seconds, depending on the pyrethroid in question. Type I and type II pyrethroids have similar effects, but the increase in open time is more pronounced with type II pyrethroids.

Pyrethroids exert another effect on sodium channels. A pyrethroid-exposed sodium channel can be opened at negative membrane potentials near the resting potential. Prolonged opening of many sodium channels near the resting membrane potential leads to the nerve-membrane depolarization observed in the presence of pyrethroids. Membrane depolarization produces several changes in nervous function: depolarization in sensory neurons sends massive discharges to the central nervous system, causing hypersensitivity to external stimuli and paresthesia or a tingling sensation in the facial skin; depolarization of presynaptic terminals increases transmitter release, thereby disturbing synaptic transmission; and depolarization beyond some magnitude blocks nerve conduction and results in paralysis. In addition to the modified electric behavior of the sodium channels, all the more readily detected changes are biologic markers of exposure to pyrethroids.

During the last several years, it has been hypothesized that the γ-aminobutyric acid (GABA) receptor-channel complex, rather than the sodium channels, might be the target site of type II pyrethroids. That was based on several observations, including pyrethroid inhibition of ligand binding to the GABA receptor channel (Lawrence and Casida, 1983). However, recent patch-clamp experiments with rat dorsal root ganglion neurons in culture have unequivocally demonstrated that, whereas sodium channel current undergoes drastic and characteristic prolongation during exposure to the type II pyrethroid deltamethrin, the GABA-induced chloride channel current remains unaffected (Ogata et al., 1988). The GABA receptor-channel system thus plays a negligible role in poisoning with type II pyrethroids.

Pyrethroids thus seem to modify the