Symptoms of SCBI Poisoning in Insects Pseudoparalysis

Pyrazolines and indoxacarb produce identical acute neurotoxic symptoms in the American cockroach Periplaneta americana, progressing through initial incoordination (5-20 min after 1-10 mg injection), then tremors and prostration, and finally a distinctive pseudoparalysis, so named because the apparently paralyzed insects produce violent convulsions when disturbed. This pseudoparalysis was maintained for 3-4 days, after which the ability to move when disturbed waned. By 4-6 days, the insects could be considered dead. Lower doses caused a similar progression of symptoms, but the time before appearance of symptoms was delayed. This unusual pseudoparalysis was key to unraveling the complex mode of action of this family in insects.

Irreversible pseudoparalysis was also observed in lepidopterous larvae, with disturbance during the pseudoparalyzed state leading to squirming, and tremors of legs and mandibles evident upon microscopic examination. Higher doses of pyrazolines, especially in lepidopterous larvae, led within a few hours to flaccid paralysis (Salgado, 1990). Injection of 10 mgg-1 indoxacarb into fifth instar Manduca sexta larvae produced excitatory neurotoxic symptoms leading to convulsions and then relatively rapidly to flaccid paralysis (Wing et al., 1998). As discussed above, indoxacarb itself is converted in vivo to DCMP by esterase-like enzymes. The pseu-doparalytic symptoms caused by indoxacarb have also been clearly observed in Spodoptera frugiperda larvae treated by injection of 20 mgg 1 indoxacarb or DCJW, and also in male P. americana injected with 1, 3, or 10 mg g_1 DCJW (Salgado, unpublished data).

Under field conditions, after ingesting or being directly sprayed with indoxacarb, insects will irreversibly stop feeding within a few minutes to 4 h; higher doses cause more rapid onset of symptoms.

Higher temperatures increase desiccation and speed of kill. Unlike the pyrethroids, indoxacarb exhibits a positive temperature coefficient. Uncoordinated insects may fall off the plant and desiccate, drown, or become subject to predation. Affected insects can stay alive for 4-96 h, depending on the dose of indoxacarb and susceptibility of the insect. Insects exposed to subparalytic doses eat much less than untreated larvae, develop more slowly, gain less weight, and pupate and emerge later than untreated insects.

6.2.4.2. Block of Spontaneous Activity in the Nervous System

RH-3421 and RH-1211, two highly active pyrazo-lines, were used as model compounds in an electro-physiological analysis of poisoned P. americana, together with RH-5529, which was useful for some experiments because of its ready reversibility (Figure 1). The upper panel in Figure 5 compares extracellular recordings from three parts of the nervous system before and shortly after paralysis with 5 mgg"1 RH-3421. The connectives between the second and third thoracic ganglia are major pathways for interneurons within the central nervous system (CNS); the crural nerve is the major leg nerve, with both sensory and motor traffic; and the cercal nerve is exclusively sensory. In all cases, the complete absence of neural activity upon dihy-dropyrazole poisoning is striking. It has likewise been shown that activity in the CNS connectives of M. sexta larvae is completely blocked after paralysis with indoxacarb or DCJW via injection (Wing et al., 1998). The lower panel in Figure 5 shows recordings from S. frugiperda larvae before and shortly after paralysis with both DCJW and indoxacarb. In the CNS connectives and also in the ventral nerve roots of the abdominal ganglia, which carry motor and sensory axons, there is no nerve activity in the paralyzed insects. The assessment of the state of the nervous system during poisoning is completed with Figure 6, which shows that even in a cockroach paralyzed for 24 h, tactile stimulation of the tro-chanter could elicit sensory spikes in the crural nerve that in turn initiate reflex motor activity in the same nerve. This is a clear demonstration that axonal conduction and synaptic transmission function more or less normally in paralyzed insects; the evident defect is that the nerves no longer generate action potentials spontaneously.

Normally, even in a quiescent insect, there is background or spontaneous action potential activity in the nervous system arising from pacemaker cells in the CNS and from tonic sensory receptors. Mechanoreceptors exist in many places on the cuticle to detect cuticular deformations or hair

Ventricular Fibrillation

Figure 5 SCBI poisoning inhibits all spike activity in the nervous system. Representative extracellular recordings from the central nervous system (CNS) and peripheral nerves of paralyzed insects and untreated DMSO-injected controls. Adult male cockroaches were treated by injection of 5mgg"1 RH-3421 and fifth instar Spodoptera larvae weighing 500 mg were treated with 5 mg g"1 DCJW or indoxacarb, 3-4 h before dissection of and recording from the paralyzed insects. (Cockroach data: reproduced with permission from Salgado, V.L., 1990. Mode of action of insecticidal dihydropyrazoles: selective block of impulse generation in sensory nerves. Pestic. Sci. 28, 389-411; © Society of Chemical Industry, permission is granted by John Wiley & Sons Ltd. on behalf of the SCI. Spodoptera data previously unpublished.)

Figure 5 SCBI poisoning inhibits all spike activity in the nervous system. Representative extracellular recordings from the central nervous system (CNS) and peripheral nerves of paralyzed insects and untreated DMSO-injected controls. Adult male cockroaches were treated by injection of 5mgg"1 RH-3421 and fifth instar Spodoptera larvae weighing 500 mg were treated with 5 mg g"1 DCJW or indoxacarb, 3-4 h before dissection of and recording from the paralyzed insects. (Cockroach data: reproduced with permission from Salgado, V.L., 1990. Mode of action of insecticidal dihydropyrazoles: selective block of impulse generation in sensory nerves. Pestic. Sci. 28, 389-411; © Society of Chemical Industry, permission is granted by John Wiley & Sons Ltd. on behalf of the SCI. Spodoptera data previously unpublished.)

Figure 6 Sensory and motor nerve activity could still be elicited long after the onset of paralysis. These recordings, from nerve 5 (crural nerve) of a cockroach injected 24 h earlier with 5|mgg~1 RH-3421, show that although there was no background activity (trace a), tactile stimulation of the ipsilateral trochanter elicited activity in several axons (trace b). Furthermore, cutting nerve 5 proximal to the recording site abolished the larger spikes (trace c), showing that the remaining smaller spikes were in primary sensory neurons while the larger ones in trace (b) were reflexly evoked motor spikes. (Reproduced with permission from Salgado, V.L., 1990. Mode of action of insecticidal dihydropyrazoles: selective block of impulse generation in sensory nerves. Pestic. Sci. 28, 389-411; © Society of Chemical Industry, permission is granted by John Wiley & Sons Ltd. on behalf of the SCI.)

Figure 6 Sensory and motor nerve activity could still be elicited long after the onset of paralysis. These recordings, from nerve 5 (crural nerve) of a cockroach injected 24 h earlier with 5|mgg~1 RH-3421, show that although there was no background activity (trace a), tactile stimulation of the ipsilateral trochanter elicited activity in several axons (trace b). Furthermore, cutting nerve 5 proximal to the recording site abolished the larger spikes (trace c), showing that the remaining smaller spikes were in primary sensory neurons while the larger ones in trace (b) were reflexly evoked motor spikes. (Reproduced with permission from Salgado, V.L., 1990. Mode of action of insecticidal dihydropyrazoles: selective block of impulse generation in sensory nerves. Pestic. Sci. 28, 389-411; © Society of Chemical Industry, permission is granted by John Wiley & Sons Ltd. on behalf of the SCI.)

deflections resulting from stresses due to the body's own movements or to external stimuli, and internally in the form of chordotonal organs or muscle stretch receptor organs to report on joint angles. Mechanoreceptors in general have both phasically and tonically responding sensory cells or units. The phasic units respond with a burst of activity at the start or end of a stimulus, but rapidly adapt in the presence of constant stimuli, because their function is to sensitively detect changes in stimulus level. The tonic units maintain a steady firing rate during stimulus presentation and give rise to slowly adapting sensations. In insect muscle stretch receptor organs, both phasic and tonic functions are subserved by a single neuron. A sudden elongation of this receptor induces firing initially at a high rate, which then declines to a constant rate that is proportional to static elongation, so that both velocity and position are encoded (Finlayson and Lowenstein, 1958).

The complete absence of neural activity in poisoned insects indicates that SCBIs block not only tonic sensory activity, but also pacemaker activity in the CNS. Both of these effects involve action potential generation in regions of neurons that are able to generate action potentials repetitively in response to constant stimuli. The ability of phasic receptors to respond long after paralysis at a high dose (Figure 6), suggests that phasic receptors are not as sensitive as the tonic ones, although they may also be affected at higher doses in Lepidoptera, when insects are completely paralyzed, as mentioned earlier. At this point in the electrophysiological analysis, the pseudoparalysis resulting from SCBI poisoning is apparently due to inhibition of spontaneous activity in tonic sensory receptors and pacemaker neurons. However, excitatory symptoms are also seen during the course of poisoning; a plausible hypothesis is that early in poisoning, before the compound reaches the CNS, sensory receptors in the periphery become blocked. In the absence of adequate sensory feedback to the CNS in response to attempted movements, there would be a tendency to overaccentuate these movements, resulting in the altered posture and gait that is observed. The quiet periods that predominate later in pseudoparalysis may be due to block of pacemaker activity in the CNS. An explanation of the tremors will be proposed below, after the cellular effects of the compounds that cause the observed block are considered. What is noteworthy, however, about the excitatory symptoms arising from a blocking action is the long time period over which apparent excitatory effects can be seen. Compounds with primary excitatory effects on neurons lead to continuous excitation, and within a few hours to complete paralysis due to, among other things, neuromuscular block, as seen for example with pyrethroids (Schouest et al., 1986) or spino-sad (Salgado, 1998). Insects poisoned with SCBIs, alternatively, do not suffer this pysiological exhaustion, and can therefore show strong tremors intermittently for several days after poisoning.

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