Insect Control: Biological and Synthetic Agents - Index of

and their primary site of action is the voltage-gated
sodium channels. However, there is controversy regarding
the precise mode of action of pyrethroids
and their binding site on the sodium channels.
Much of the work on the mode of action was
reported during the 1980s but investigations on sodium
channels have continued and a great deal of
progress made. Many in vitro and in vivo investigations
on mode of action and metabolism have been
carried out on mammalian systems because of the
interest in toxicology of these pesticides to mammals
including humans and the expertise present
in many laboratories for electrophysiology on mammalian
neurons and muscles. Experiments have also
used model systems such as squid and crustacean
giant nerve fibers because of their large size and
robustness. However, such studies may not be relevant
to insects since there is considerable variation,
not only in the metabolic capacities but also in the
amino-acid sequences of the sodium channel proteins
and thus their pharmacological properties. Another
complication is that, in mammals, several
genes express different sodium-channel isoforms,
which exhibit differential responses to the two
types of pyrethroids (Tatebayashi and Narahashi,
1994; Soderlund et al., 2002). Furthermore, each
gene can express channels (splice variants) with
varying pharmacological and biophysical properties
(Tan et al., 2002). In insects, the voltage-gated sodium
channels are encoded by only a single gene,
which can also express splice-variants. Such channels,
though having a common binding site, might
nevertheless exhibit differences in their responses to
pyrethroids. Such differences have been demonstrated
in mammals but not yet in insects, though
there is ample indirect evidence for this (see below).
These different factors give rise to the complex
nature of pyrethroid action and therefore difficulty
in defining in detail the mode of action. Early investigations
into their mode of action were conducted
on insect and mammalian nerve preparations but
the interpretation of these measurements is somewhat
controversial. Broad agreement has only been
possible with measurements from sodium channels
(see below) (Soderlund et al., 2002). Thus the summary
presented below is a brief personal overview
of the area.
1.4.2.1. Investigations based on nerve
preparations Of the various symptoms induced
by pyrethroids (hyperactivity, tremors, incoordination,
convulsions followed by paralysis and death),
only the initial toxicity symptoms can be linked to
neurophysiological measurements and then only for
Type I pyrethroids. They induce repetitive firing
1: Pyrethroids 11
(short bursts of less than 5 s duration) in axonal
nerve preparation in the sensory nerves accompanied
by occasional large bursts of action potential
in the ganglia (Nakagawa et al., 1982; Narahashi,
2002; Soderlund et al., 2002). Repetitive firing has
been correlated to hyperactivity and uncoordinated
movements leading to rapid knockdown in
insects. This is also thought to stimulate the neurosecretory
system causing an excessive release of
diuretic hormones which eventually results in the
disruption of the overall metabolic system in insects
(Naumann, 1990 and references therein). The initial
symptoms are manifested at very low concentrations
(0.1–0.001 LD50), it being estimated that
less than 1% of the sodium channels need to be
modified to induce repetitive firing (Song and
Narahashi, 1996). In contrast, Type II pyrethroids,
even at rather high concentrations, initially cause
much less visible activity in insects, convulsions and
rapid paralysis being the main symptoms. They cause
slow depolarization of nerve membranes leading
to block of nerve conduction. The concentration
required ultimately to kill insects is much lower for
Type II than for Type I compounds.
In general, Type I compounds have been viewed
as more active than Type II in producing both
visible symptoms and repetitive discharges in the
peripheral nerves, though exceptions are known,
especially when considering results from noninsect
nerve preparations. For example, repetitive firing
has been observed for both Type I and Type II
pyrethroids in frog-nerve preparations (Vijverberg
et al., 1986).
The first claimed correlation between a neurophysiological
response and the poisoning action of
pyrethroids related to the increased production of miniature
excitatory postsynaptic potentials (MEPSPs)
in response to depolarization of the nerve terminal
caused by both Type I and Type II compounds
(Salgado et al., 1983a, 1983b; Miller, 1998). This
increase in MEPSPs results in depletion of neurotransmitter
at the nerve-muscle synapses leading
to nerve depolarization (paralysis) and also blockage
of flight reflex responses. At low threshold
concentrations, Type I pyrethroids induce repetitive
firing and hyperactivity but not neurotransmitter
release so that these processes are not linked to the
toxic action of pyrethroids. These observations
thus accounted for the apparent contradiction that
though initial symptoms of Type I pyrethroids are
positively correlated with temperature, the toxic
action (release of neurotransmitter and conduction
block) is negatively correlated with temperature.
At high concentrations, Type I pyrethroids behave
similarly to Type II pyrethroids and elicit toxic