Pyrethroid insecticides interact with a variety of neurochemical processes, but not all of these actions are likely to be involved in the disruption of nerve function. Several lines of evidence suggest that the voltage-sensitive sodium channel is the single principal molecular target site for all pyrethroids and DDT analogs in both insects and mammals. The alterations of sodium channel functions identified in both biophysical and biochemical studies are directly related to the effects of these compounds on intact nerves. The pyrethroid recognition site of the sodium channel exhibits the stringent stereospecificity predicted by in vivo estimates of intrinsic neurotoxicity in both insects and mammals. Type I and Type II compounds produce qualitatively different effects on sodium channel tail currents, divergent actions on intact nerves, and different effects on the excitability of vertebrate skeletal muscle. Moreover, compounds that are defined as intermediate in the Type I/Type II classification scheme are also intermediate in their effects on sodium channel kinetics. The range of different actions on sensory and motor nerve pathways arising from these qualitatively different effects at the level of the sodium channel appear to be sufficient to explain the distinct poisoning syndromes that have been identified in both insects and mammals. Thus, it does not appear necessary to invoke different primary target sites for Type I and Type II compounds to explain their actions in whole animals. Although the voltage-sensitive sodium channel is likely to be the principal site of pyrethroid action, it is probably not the only site involved in intoxication. Insect neurosecretory neurons are sensitive to very low concentrations of pyrethroids, and disruption of the neuroendocrine system has been implicated as a factor contributing to the irreversible effects of pyrethroid intoxication in insects. Since action potentials in these nerves are carried by calcium ions through TTX-insensitive voltage-gated cation channels, these findings provide evidence that pyrethroids can alter neuronal excitability through an action on voltage-sensitive channels other than the sodium channel. Actions on voltage-sensitive calcium channels may also be involved in the effects of pyrethroids on neurotransmitter release in mammals. The proconvulsant actions of pyrethroids mediated through the peripheral-type benzodiazepine receptor may also contribute to pyrethroid intoxication. Both Type I and Type II compounds are potent proconvulsants in vivo at doses well below those required to produce pyrethroid-dependent intoxication.(ABSTRACT TRUNCATED AT 400 WORDS)

By 2014, huanglongbing (HLB), the most destructive disease of citrus, and its insect vector, the Asian citrus psyllid (ACP), Diaphorina citri (Kuwayama), became established in all major citrus-growing regions of the world, including the United States, with the exception of California. At present, application of insecticides is the most widely followed option for reducing ACP populations, while application of antibiotics for suppressing HLB disease/symptoms is being practiced in some citrus-growing regions. Application of insecticides during the dormant winter season, along with cultivation of HLB-free seedlings and early detection and removal of symptomatic and asymptomatic trees, has been very effective in managing ACP. Area-wide management of ACP by application of insecticides at low volume in large areas of citrus cultivation has been shown to be effective in managing HLB and reducing management costs. As insecticide resistance is a major problem in sustainable management of ACP, rotation/alternation of insecticides with different chemistries and modes of action needs to be followed. Besides control of the insect vector, use of antibiotics has temporarily suppressed the symptoms of HLB in diseased trees. Recent efforts to discover and screen existing as well as new compounds for their antibiotic and antimicrobial activities have identified some promising molecules for HLB control. There is an urgent need to find a sustainable solution to the HLB menace through chemical control of ACP populations and within HLB-infected trees through the judicious use of labeled insecticides (existing and novel chemistries) and antibiotics in area-wide management programs with due consideration to the insecticide resistance problem.

Ion channels are the primary target sites for several classes of natural and synthetic insecticidal compounds. The voltage-sensitive sodium channel is the major target site for DDT and pyrethroids, the veratrum alkaloids, and N-alkylamides. Recently, neurotoxic proteins from arthropod venoms, some of which specifically attack insect sodium channels, have been engineered into baculoviruses to act as biopesticides. The synthetic pyrazolines also primarily affect the sodium channel, although some members of this group target neuronal calcium channels as well. The ryanoids have also found use as insecticides, and these materials induce muscle contracture by irreversible activation of the calcium-release channel of the sarcoplasmic reticulum. The arylheterocycles (e.g. endosulfan and fipronil) are potent convulsants and insecticides that block the GABA-gated chloride channel. In contrast, the avermectins activate both ligand- and voltage-gated chloride channels, which leads to paralysis. At field-use rates, a neurotoxic effect of the ecdysteroid agonist RH-5849 is observed that involves blockage of both muscle and neuronal potassium channels. The future use of ion channels as targets for chemical and genetically engineered insecticides is also discussed.

The avermectins represent a group of natural compounds with potent pesticidal activities. Because of their novel mode of action, they represent an important resource for pest control and resistance management. In the Colorado potato beetle, the house fly, and the two-spotted spider mite, resistance to abamectin is usually autosomal, recessive, and polygenic. Although these aspects are beneficial in resistance management, the fact that resistance could be readily selected for suggests that abamectin needs to be used in moderation. Furthermore, several major resistance mechanisms (e.g. excretion, oxidative metabolism, penetration) and minor factors (e.g. altered target site, conjugation, hydrolysis/sequestration) have been implicated in abamectin resistance. Thus, the question is not whether resistance to abamectin will occur but is simply when and how it will occur. To address this problem, we have gathered information on the genetics, biochemical mechanisms, effectiveness of synergists, and cross-resistances to other insecticides from three abamectin-resistant insects. Judicious implementation of this information may prove useful in the resistance management of this natural pesticide.

Insecticide resistance is a growing threat to mosquito control programs around the world, thus creating the need to discover novel target sites and target-specific compounds for insecticide development. Emerging evidence suggests that mosquito inward rectifier potassium (Kir) channels represent viable molecular targets for developing insecticides with new mechanisms of action. Here we describe the discovery and characterization of VU041, a submicromolar-affinity inhibitor of Anopheles (An.) gambiae and Aedes (Ae.) aegypti Kir1 channels that incapacitates adult female mosquitoes from representative insecticide-susceptible and -resistant strains of An. gambiae (G3 and Akron, respectively) and Ae. aegypti (Liverpool and Puerto Rico, respectively) following topical application. VU041 is selective for mosquito Kir channels over several mammalian orthologs, with the exception of Kir2.1, and is not lethal to honey bees. Medicinal chemistry was used to develop an analog, termed VU730, which retains activity toward mosquito Kir1 but is not active against Kir2.1 or other mammalian Kir channels. Thus, VU041 and VU730 are promising chemical scaffolds for developing new classes of insecticides to combat insecticide-resistant mosquitoes and the transmission of mosquito-borne diseases, such as Zika virus, without harmful effects on humans and beneficial insects.