Mode of action of insecticidal dihydropyrazoles: Selective block of impulse generation in sensory nerves

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Abstract
When injected into cockroaches (Periplaneta americana), dihydropyrazoles (pyrazolines), e.g. RH 3421, methyl 1‐(N‐(α,α,α‐trifluoro‐p‐tolyl)carbamoyl‐3‐(4‐chlorophenyl)‐4‐methyl‐2‐pyrazolin‐4‐ylcarboxylate, caused incoordination, followed by prostration and violent tremors. After several hours, prostrate cockroaches became very still, appearing paralyzed, but for several days they retained the ability to produce violent tremors when physically disturbed. The paralysis was associated with block of spontaneous activity in sensory nerves of cockroaches, tobacco hornworm larvae (Manduca sexta) and housefly larvae (Musca domestica). Block of spontaneous central nervous system activity was also seen in some cases.Current‐clamp experiments on the cell body of the crayfish slowly‐adapting stretch receptor neuron revealed that spike initiation in response to injected current was blocked by dihydropyrazoles, with no change in resting potential or input resistance, suggesting that the sodium current was suppressed. Hyperpolarization of blocked stretch receptors could reverse block, and crayfish giant axons, which were not normally sensitive to block by dihydropyrazoles, were rendered sensitive when artificially depolarized by elevation of extracellular potassium ion concentration, leading to the conclusion that the block of sodium current was strongly voltage dependent. The proposed mode of action, while similar to that of local anesthetics, class I anticonvulsants and class I antiarrhythmics, is novel for an insecticide.