Comparative effects of DDT,allethrin, dieldrin and aldrin-transdiol on sense organs of Xenopus laevis

The effects of DDT, allethrin, dieldrin and aldrin-transdiol were studied in two different sense organs of Xenopus laevis; the lateral-line organ and the cutaneous touch receptors. DDT and allethrin produced pronounced repetitive firing in both preparations. Dieldrin and aldrin-transdiol, on the other hand, failed to induce any sign of repetitive activity. Aldrin-transdiol, however, caused a marked increase in the rate of spontaneous firing of the lateral-line organ, later followed by a blockade. The repetitive activity in the cutaneous touch receptors, whether induced by DDT or allethrin, was not distinguishable from repetitive firing of the afferent nerve fibers and showed no marked dependence on temperature. This contrasts sharply with the know negative temperature coefficient of the DDT- or allethrin-induced repetitive activity in the lateral-line organ.     

Structure-related effects of pyrethroid insecticides on the lateral-line sense organ and on peripheral nerves of the clawed frog, Xenopus laevis

The effects of seven different pyrethroid insecticides on the lateral-line sense organ and on peripheral nerves of the clawed frog, Xenopus laevis, were investigated by means of electrophysiological methods. The results show that two classes of pyrethroid can be clearly distinguished. (i) Pyrethroids without an α-cyano group (permethrin, cismethrin, and bioresmethrin). These noncyano pyrethroids induce short trains of nerve impulses in the lateral-line sense organ. In peripheral nerve branches they induce a depolarizing afterpotential and repetitive firing. These effects are very similar to those previously reported for allethrin. (ii) Pyrethroids with an α-cyano-3-phenoxybenzyl alcohol (cypermethrin, fenpropathrin, deltamethrin, and fenvalerate). In the lateral-line sense organ these α-cyano pyrethroids induce very long trains of nerve impulses which may last for seconds and may contain hundreds or even thousands of impulses. The α-cyano compounds do not cause repetitive activity in peripheral nerves. Instead they induce a quickly reversible, stimulus frequency-dependent suppression of the action potential. Since the chemical structure of cypermethrin differs from that of permethrin only in the α-cyano group and because all four α-cyano compounds act in a very similar way, it is concluded that the α-cyano substituent is responsible for the large differences in neurotoxic effects. In the lateral-line sense organ the duration of nerve impulse trains induced by the noncyano as well as the α-cyano pyrethroids increases dramatically when the temperature is lowered. Further, in sensory fibers the effects of both classes of pyrethroid on the nerve action potential are more pronounced compared to their effects on motor fibers. It is argued that the different neurotoxic effects reported here originate from a common mechanism of action of pyrethroids, which is a prolongation of the transient increase of sodium permeability of the nerve membrane associated with excitation.It is concluded that the sodium channel in the nerve membrane is the major target site of noncyano and α-cyano pyrethroids.     

Nerve membrane as a target of pyrethroids

Nerve membrane is one of the most important target sites of pyrethroids. Changes in excitability of nerve fibres caused by allethrin can be satisfactorily accounted for in terms of ionic permeabilities of the membrane. Temperature has a profound effect on the allethrin-induced permeability changes.     

Neuropharmacological studies of an insecticidal trihaloimidazole derivative in the crayfish neuromuscular preparation

A trihaloimidazole derivative (S-377; 1-(4-chlorobutoxymethyl)-2,4,5-trichloroimidazole) caused giant excitatory junctional potentials by a single electrical stimulus to the excitatory nerves. Repetitive discharges were simultaneously induced in the nerve fibres. S-377 also caused repetitive firing in the inhibitory nerve fibres. Permethrin showed quite similar actions on both the junction and nerve fibres. It was supposed that S-377 inhibited the inactivating system of the sodium channel, like pyrethroids. However, S-377 reduced the number of spikes of the permethrin-induced repetitive discharges on the excitatory nerve fibres. These observations suggest that binding sites of S-377 on sodium channels are different from those of pyrethroids.     

Action of pyrethroids on a nerve-muscle preparation of the clawed frog,Xenopus laevis

The effects of a range of pyrethroids on end-plate potentials and muscle action potentials were studied in the pectoralis nerve-muscle preparation of the clawed frog, Xenopus laevis. The noncyano pyrethroids allethrin, cismethrin, bioresmethrin, and IR-cisphenothrin caused moderate presynaptic repetitive activity only, resulting in the occurrence of multiple end-plate potentials (epps). Trains of repetitive muscle action potentials without presynaptic repetitive activity were observed after the α-ethynyl pyrethroid S-5655 and after the α-cyano pyrethroids cypermethrin, deltamethrin, FCR 1272, and FCR 2769. An intermediate group of pyrethroids consisting of the non-cyano compounds 1R-permethrin, des-cyano-deltamethrin, NAK 1901 and NAK 1963, and the α-cyano pyrethroids cyphenothrin and fenvalerate caused both types of effect. The insecticidally inactive S-enantiomers of permethrin had no effect on the nerve-muscle preparation. Trains of repetitive action potentials in pyrethroid-treated muscle fibers were followed by a depolarizing afterpotential which in general decayed more rapidly for the non-cyano pyrethroids than for the α-cyano pyrethroids. The rate of decay of the depolarizing afterpotential decreased gradually as the temperature was lowered, whereas the pre- and postsynaptic repetitive activity remained largely unaffected over a large temperature range. It is concluded that in muscle membrane like in nerve membrane the pyrethroid-induced repetitive activity is due to a prolongation of the sodium current and that a clear distinction between non-cyano pyrethroids on the one hand and α-cyano compounds on the other cannot be made on the basis of the present results.     

Temperature dependence of allethrin-induced repetitive discharges in nerves

The action of allethrin in inducing repetitive discharges by a single stimulus has been studied with squid giant axons at various temperatures. Repetitive discharges are evoked in the allethrin-poisoned axon at optimal temperatures ranging from 20 to 28°C. A single action potential is produced below and above this temperature range. The negative (depolarizing) after-potential is increased markedly by allethrin, and it exceeds the threshold membrane potential for excitation only at the optimal temperatures, thereby accounting for the temperature dependence of repetitive responsiveness.     

Some effects of cismethrin on the rabbit nervous system

The effects of cismethrin, 5-benzyl-3-furylmethyl (1 R)-cis-chrysanthemate, in the spinal rabbit have been investigated at the level of the sensory receptors, in an afferent nerve, and in the spinal cord. Cismethrin causes a lowering of the threshold of some sensory receptors and the appearance of spontaneous activity, which may be in bursts, in some afferent fibres that were previously silent. When recordings were made from the afferent nerve, in addition to phenomena arising from the effects on sensory receptors, there was repetitive firing in the nerve when action potentials were evoked by electrical stimulation. The effects on the spinal cord were such as to increase the excitability of reflex arcs. There was also a change in the normal pattern of facilitation and inhibition as measured by the amplitude of the second of two suitably spaced monosynaptic responses and it is suggested that this is an indirect effect of cismethrin intoxication. The cumulative effect of the changes brought about in nervous activity in the system described here could account at least in part for the convulsions observed in intoxicated animals.     

Neural effects of allethrin on the free walking cockroach Periplaneta Americana: An investigation using defined doses at 15 and 32°C

The action of allethrin has been studied in the free-walking cockroach, Periplaneta americana (L) using implanted electrodes, at 15 and 32°C, following topical application of an LD₉₅ dose (that at 32°C being approximately ten times the LD₉₅ at 15°C). At both temperatures there was marked hyperexcitation of the peripheral nervous system. At 32°C there was also hyperexcitation of the central nervous system but central effects at 15°C were probably secondary. Likewise, nerve blockage often did not occur until many hours after paralysis and could thus be a secondary consequence of allethrin poisoning.     

Quantitative structure-activity relationships of insecticidal diphenyldichlorocyclopropanes

Neurophysiological activity of a series of aromatic-substituted 1,1-diphenyl-2,2-dichlorocyclopropanes (DCC analogs) in the induction of repetitive discharges in excised central nerve cords of the American cockroach was determined by an extracellular recording technique. Quantitative analysis using physicochemical parameters showed that variations in the activity were parabolically correlated with the van der Waals volume of aromatic substituents. Insecticidal activity of these compounds in the American cockroach under conditions where oxidative metabolic activity was inhibited by piperonyl butoxide was also determined. This was related to the repetitive nerve discharge activity, when transport factors were separated by using a hydrophobicity parameter. The analyses showed that the aromatic substituent effects on the neurophysiological activity as well as the relationship between insecticidal and neurophysiological activities are very close to those observed previously for DDT analogs including DDT, DDD, and prolan derivatives.     

Effects of the pyrethroids bioallethrin,deltamethrin and RU-15525 on the electrical activity of a cuticular mechanoreceptor of the cockroach Periplaneta americana

A study has been made of the effects of bioallethrin, RU-15525 [5-benzyl-3-furylmethyl (1R)-cis-2,2-dimethyl-3-(tetrahydro-2-oxo-3-thienylidenemethyl)-cyclopropanecarboxylate, ‘Kadethrin’], and deltamethrin on the electrical activity, measured in vivo, of a cuticular mechanoreceptor of Periplaneta americana. The modifications induced by these pyrethroids on the membrane excitability can be classified into two groups: Type I effects (bioallethrin) are characterised by a substantial increase in the number of action potentials triggered at the initiation site by a given mechanical stimulation, by an electrical activity persisting after mechanical stimulus has been stopped (repetitive activity), and possibly, by an inhibition of excitability of the cell membrane. Type II effects (RU-15525 and deltamethrin), are characterised by an inhibition of the excitability of the initiation site. In the case of RU-15525, there was a transient spontaneous electrical activity. Both types of effects have been linked to an action on the sodium channel, particularly at the initiation site. The preparation studied, which possessed no synapses, was shown to be more sensitive to deltamethrin (which is also the most insecticidal of the three pyrethroids) than to either allethrin or RU-15525. These results suggest that it is unnecessary to envisage a main target (sodium channel) that is different for the two types of pyrethroid.     

The pyrethrins and related compounds. Part xxxi: Alkoxyimino-substituted esters

Esters derived from pyrethroidal acids and benzyl and furylmethyl alcohols bearing a wide range of side-chains each containing at least one oxime ether group, and related derivatives of allethrin and benzylnorthrin, were synthesised and tested for insecticidal activity. Of the benzyl esters, the most insecticidal were those with the methoxyimino-methyl or -ethyl side-chains at C-3 or C-4, and with E configuration. Changing the alkoxy group, the configuration or the chain length resulted in lower activity. Introducing an occyano group increased activity if the side-chain was at C-3, but lowered it drastically if the substituent was at C-4. In the case of allethrin, the methoxime derivative was less active than the parent ketone, but with benzylnorthrin conversion to the methoxime markedly increased activity against one of the test species.     

羟丙基-β-环糊精对烯丙菊酯的增溶作用及其包合物的表征

为了开发水溶性好、运输方便、对环境威胁小的高效拟除虫菊酯的控制释放制剂,研究了羟丙基-β-环糊精(HP-β-CD)对烯丙菊酯的包合作用。通过相溶解度图法研究了HP-β-CD对烯丙菊酯的增溶作用,并用共蒸法制备了烯丙菊酯/HP-β-CD包合物,经差示扫描量热法(DSC)、红外光谱法(IR)、热重分析法(TG)和核磁共振法(NMR)对其结构进行了表征。结果表明:HP-β-CD对烯丙菊酯有明显的增溶作用,相溶解度曲线为线性AL型,烯丙菊酯与HP-β-CD形成了物质的量之比为1:1的包合物;DSC和TG分析均证明了该包合物的形成,IR和NMR分析显示烯丙菊酯的五元环部分已深入HP-β-CD空腔内部,且重心位于内腔H-5附近。     

Quantitative structure-activity studies of substituted benzyl chrysanthemates: 7. Relationship between induction of repetitive discharges and effects on the action potential

The effects of substituted benzyl (1R)-trans-chrysanthemates and related compounds on the action potential of the crayfish giant axon were investigated using an intracellular microelectrode. The effects are broadly classified into three types: deceleration of the falling-phase of the action potential (type A), elevation of the depolarizing after-potential (type B), and the combination type (type C). The potency of the type A compounds to decelerate the rate of the falling-phase was determined in terms of the concentration required for reducing the rate to a specified degree. This potency was shown to correlate with the potency to induce repetitive discharges in the cockroach central nerve cord in terms of minimum effective concentration, which was determined previously. The potency of the types B and C compounds to elevate the after-potential was, however, not related directly with the cockroach nerve repetitive activity. The elevation of the after-potential is one of the critical factors but other effects such as a depolarization of the resting potential may be involved in determining the repetitive activity.     

End-plate potentials in frog muscle exposed to a synthetic pyrethroid

Isolated sartorius nerve-muscle preparations from Rana temporaria were irrigated in a chamber. Resting muscle membrane potentials and evoked end-plate potentials were recorded via intracellular microelectrodes. Multiple end-plate potentials appeared after the preparation had been exposed to a suspension, in Ringer's solution, of the toxic synthetic pyrethroid: 5-benzyl-3-furylmethyl (+)-cis-chrysanthemate (NRDC 119). It is thought that this effect was due to repetitive activity arising in the motor nerve fibers. The pyrethroid had no effect on the muscle resting potential nor on the amplitude or time course of the initial evoked end-plate potential.     

The effects of two pyrethroids,cismethrin and deltamethrin,on skeletal muscle and the trigeminal reflex system in the rat

The actions of a cyano pyrethroid (deltamethrin) and a non-cyano pyrethroid (cismethrin) upon trigeminal motor reflexes and isolated muscle responses were studied in the rat. Deltamethrin caused a marked facilitation of the muscle response to nerve stimulation in pithed rats at 2.5 μmol kg⁻¹. In intact anaesthetised rats this was associated with abnormal repetitive EMG discharges and, at 4 μmol kg⁻¹ with a suppression of late components of the reflex response to sensory stimuli in the spinal trigeminal nucleus and trigeminal motor nucleus. In contrast cismethrin had no effect on the muscle response to direct nerve stimulation at up to 15 μmol kg⁻¹, but produced abnormal extra responses to sensory stimuli in the trigeminal ganglion, spinal and motor nuclei, and jaw muscles at 9 μmol kg⁻¹. It is concluded that whilst deltamethrin produces reflex excitation within the trigeminal system at a primarily muscular site, cismethrin produces excitation at all stages of the reflex loop. This contrast is consistent with the known difference in duration of sodium current prolongation produced by the two pyrethroids. These findings, together with other known central actions of deltamethrin suggest that it has multiple sites of action in the intact animal, both central and peripheral, whilst most of the simpler symptoms produced by cismethrin may adequately be explained by action at a reflex level.     

Neural and behavioral correlates of pyrethroid and DDT-type poisoning in the house fly, Musca domestica L

Intact house flies were observed during poisoning caused by several pyrethroid and DDT-type insecticides. The two insecticide classes could be generally distinguished from each other based on differences in symptoms and several physiological correlates. Both insecticide types caused motor unit repetitive backfiring, but the temporal development and stability of repetitiveness were distinctly different between the two classes. Repetitive backfiring always disappeared at low temperatures, but DDT-type backfiring disappeared at lower temperatures than the pyrethroids. trans-Tetramethrin caused a threshold increase in flight motor nerve endings which did not occur in DDT or trans-Barthrin poisoning. Pyrethroids caused “uncoupling” of the flight motor pattern, while DDT-types did not. trans-Barthrin, a methylenedioxyphenyl pyrethroid, was unique in causing both symptoms and physiological aberrations which more closely resembled those of the DDT-types than the pyrethroids.     

Pyrethroid resistance in a strain of Spodoptera littoralis is correlated with decreased sensitivity of the CNS in vitro

The effects of permethrin and cypermethrin on the isolated abdominal nerve cord of insecticide-resistant [R] and -susceptible [S] strains of Spodoptera littoralis larvae have been studied. Above ca. 19°C, permethrin at 10^?7M caused a prolonged spike train to follow electrical stimulation of the nerve cord. The time of onset of this repetitive firing was significantly greater for the [R] strain. Moreover, cypermethrin, to which this strain shows negligible resistance, did not cause such repetitive discharges. Thus, resistance to permethrin but not to cypermethrin appears to be based on a qualitative difference between the pyrethroids. Nerve blockage by the two pyrethroids was also investigated, with particular reference to temperature. Once again, differences were apparent: when considered relative to untreated controls, permethrin caused quicker nerve blockage as temperature was reduced whereas the blocking action of cypermethrin was not affected by temperature. However, the times taken to cause nerve blockage by permethrin in [R] and [S] larvae were not significantly different, making it unlikely that nerve blockage plays a major role in this resistance. Two methods were employed to reduce the resistance factor in vitro. The synergist dodecyl imidazole failed to significantly reduce the time taken for permethrin to cause either repetitive firing or nerve blockage. However, reducing the calcium concentration in the saline did significantly reduce the latency of repetitive firing caused by permethrin in [R] larvae, thus increasing the nerve sensitivity to approximately the same level as normal calcium, [S] insects.     

Actions of formamidines,local anesthetics,octopamine and related compounds upon the electrical activity of neurohaemal organs of the stick insect (Carausius morosus) and sense organs of fly larvae (Musca domestica; Calliphora erythrocephala)

The pesticides, chlordimeform and amitraz, and their metabolites, demethylchlordimeform, N¹-(2,4-dimethylphenyl)-N-methylformamidine, and 2,4-dimethylformanilide, are effective at concentrations as low as 3 μM in raising the firing rate of endogenously active neurosecretory fibres in the isolated neurohaemal organs of Carausius morosus. Molecules such as bunamidine and cetrimide, with cationic detergent properties, produced sporadic bursting which did not elevate the overall firing rate to any great extent. Indeed, bunamidine could induce complete block of action potentials at concentrations as low as 30 μM. The local anesthetics, procaine, lidocaine, and benzocaine, do not induce block of activity at least up to a level of 1 mM. They have no effect at concentrations lower than 100 μM. Between 100 μM and 1 mM lidocaine and benzocaine produce a small increase in firing rate. Procaine produced a pronounced increase in the frequency of firing. The phenolic amines, octopamine, synephrine, and tyramine, markedly increased electrical activity. The catecholamines, dopamine, noradrenaline, and adrenaline, by contrast, only produced a weak excitation. Neither α- nor β-adrenergic blocking agents were effective in antagonizing the electrical activity induced by chlordimeform or phenolic amines until relatively high concentrations of about 1 mM were used. Chlordimeform was able to induce high-frequency bursts from sense organs associated with the epidermis and body-wall musculature in larvae of Musca domestica and Calliphora erythocephala. Octopamine did not induce any similar bursting activity in these sense organs. These results are discussed in relationship to current views on the mode of action of the N-aryl amidines. It is concluded that the excitatory effects of these compounds upon neurohaemal organs and sense organs are more likely to result from a direct action upon voltage sensitive channels of the nerve membranes, rather than by an effect mediated by interactions with octopamine receptors.     

Effectiveness of the (+)-trans-chrysanthemic acid ester of (±)-allethrolone (bioallethrin) against four insect species

The activity of the (+)-trans-chrysanthemic acid ester of (±)-allethrolone (Bio-allethrin) is shown to be superior to that of the (±)-cis, trans-isomers (allethrin), against houseflies, two species of grain beetle and larvae of the yellow fever mosquito. The efficiency of the (+)-trans-isomer compares favourably with that of pyrethrins when each is used alone or with piperonyl butoxide.     

The importance of nerve terminal depolarization in pyrethroid poisoning of insects

The effects of several pyrethroids and DDT were examined on neuromuscular preparations from larvae of Musca domestica, Culex quinquefasciatus, Anopheles stephensi, and Trichoplusia ni, in order to determine the importance of the type I effect (repetitive firing) and the type II effect (increased miniature excitatory postsynaptic potential (mepsp) rate, indicating nerve terminal depolarization) in the poisoning process. α-Cyano pyrethroids were very potent in increasing mepsp rate, and although DDT and non-α-cyano compounds were more potent at inducing repetitive firing, all these compounds increased mepsp rate at higher concentrations. A variety of evidence showed that the mepsp rate-increasing activity could be an important factor in toxicity: among all of the compounds, there was a positive correlation between toxicity and mepsp rate-increasing activity; mepsp rate-increasing activity had a negative temperature dependence; nerves of kdr larvae in vitro were resistant to the mepsp rate-increasing activity, commensurate with resistance level; and finally, increased mepsp rate and neuromuscular block were observed in poisoned insects, associated with paralysis. Among type I compounds, repetitive firing activity was correlated negatively with toxicity, but positively with knockdown activity.