Pyrethroids interact with neurons causing them to become hyperexcitable and even spontaneously active. This incapacitates insects and is termed ‘‘knock down’’, which also underlies the pyrethroid poisoning syndromes in mammals.
Studying the specific binding of pyrethroids is difficult due to their high lipophilicity. It has been proposed that on displacement from a binding site pyrethroids merely move to the adjacent membrane lipid, where they are most thermodynamically stable, ready to re-attach if not destroyed by metabolism [Motomura & Narahashi, 2001]. What specific binding has been done suggests that interactions between pyrethroids and sodium channels is proportional to toxicity [Ghiasuddin & Soderlund, 1985].
Through inteference with voltage-sensitive sodium channels pyrethroids can cause neuronal signalling to go awry. The ubiquitous nature of voltage-sensitive sodium channels, combined with the tissue-penetrating properties of pyrethroids, makes the entire nervous system vulnerable to dysfunction. There are other targets beside voltage-sensitive sodium channels that are affected by pyrethroids, although the sodium channel seems to be crucial for most of the toxic effects.
Mechanisms contributing to pyrethroid-induced hyperexcitability |
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Sodium channels |
Delayed inactivation → repetitive firing |
all pyrethroids |
Chloride channels |
Decreased open time → increased excitability |
some type II pyrethroids |
Calcium channels |
Block → decreased excitability |
types I and II pyrethroids |
GABAa channels |
Antagonism → decreased synaptic inhibition |
type II pyrethroids |
All of these mechanisms probably contribute to the effects of lethal level exposures of some pyrethroids, but evidence is strongest for the former two – adapted from Ray and Fry 2006 – in press |
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Voltage-sensitive sodium channels (VSSCs) are crucial for generating the inward sodium current that produces an action potential in excitable cells. Positively charged domains in the channel are thought to be shifted across the lipid layer in response to a change in potential, in turn transposing the electrostatic energy into a conformational shift in the channel's structure. Shortly after opening of the channel, it closes again, becoming insensitive to the membrane depolarisation. By rapidly stopping the sodium flow after full depolarisation, the total sodium current into the cell remains small, and there is a minimal loss of ionic gradient across the membrane.
Normal current flows through a cell membrane during an action potential. Notice the short inrush of sodium peaking within a milisecond (purple line). Potassium efflux is slower in onset but greater in volume, and acts to repolarise the cell.
The specific action of pyrethroids on VSSCs is to slow of both the activation and inactivation phases of channel gating. By retarding the channel’s kinetics in this way, sodium current is increased during single openings. This additional flow of sodium through modified channels can prolong the depolarisation of the membrane, adding a lagging sodium current behind the precise injections affored by unaffected VSSCs. The high level of expression of sodium channels in excitable cells means that modification of merely 1% by a pyrethroid can facilitate sodium current enough to render a cell hyperexcitable [Motomura & Narahashi, 2001].
Characteristic sodium conductance through single VSSCs before and after pyrethroid administration. The black bars show the activation and deactivation phases of the channel’s gating. The filled area represents the total charge moved through the membrane, which is clearly much more per channel when affected by pyrethroid.
Pyrethroids slow the kinetics of sodium channels, but the activation phase of the action potential remains normal as long as sufficient unmodified channels are present; the high density of sodium channels means there is an ample supply. It is by retarding the inactivation phase that pyrethroids cause toxic effects. In the inactivation, or falling, phase of the action potential just a small proportion of modified channels can generate enough extra current to disrupt the excitability of a cell.
The amplitude and duration of a pyrethroid-extended tail current are quite independent. The current amplitude is dependent only on the proportion of sodium channels modified, and hence it shows a sigmoidal relationship with pyrethroid concentration, increasing with the recruitment of channels. The current duration is dependent only on the particular pyrethroid. Type I pyrethroids, such as permethrin, typically hold the channel open for relatively short times, whilst type II pyrethroids, such as deltamethrin, hold it open for much longer.
Individual pyrethroids generate a characteristic time constant for prolongation of the sodium channel tail current, virtually independent of dose [Brown & Narahashi, 1992]. There is a continuous distribution of time constants across the range of pyrethroid structures, with type I pyrethroids producing shorter time constants and type II pyrethroids producing longer time constants.
Typical effects of type I and type II pyrethroids on whole-neuron currents. Both classes have little effect on the activation of channels and current flow, but prolong the inactivation, creating tail currents, which are substantially longer for type II pyrethroids.
Significantly, after modification by pyrethroids, sodium channels retain many of their normal functions, such as selectivity for sodium ions and conductance. Their link with membrane potential is also retained but shifted so as to increase excitability [Narahashi et al, 1998]. This means that, after exposure to moderate levels of pyrethroids, cells can continue to function in a new and relatively stable state of abnormal hyperexcitability.
Through slowing the rate of inactivation of VSSCs pyrethroids create prolonged depolarizing tail currents that follow normal action potentials. The tail currents can trigger subsequent action potentials if the current is both large enough and lasts for 0.5–2 milliseconds, the time needed for neighbouring, unmodified sodium channels to recover excitability. So under the influence of pyrethroids what would normally be a single action potential can trigger multiple discharges from a cell. Pyrethroids ‘short circuit’ the finely balanced sodium ion dynamics of excitable tissues, making them hyperexcitable.
[Motomura & Narahashi, 2001], [Ghiasuddin & Soderlund, 1985], [Brown & Narahashi, 1992],
[Narahashi et al, 1998]
