Chronic pain is a major medical issue which reduces the quality of life of millions and inflicts a significant burden on health authorities worldwide. Currently, management of chronic pain includes first-line pharmacological therapies that are inadequately effective, as in just a portion of patients pain relief is obtained. Furthermore, most analgesics in use produce severe or intolerable adverse effects that impose dose restrictions and reduce compliance. As the majority of analgesic agents act on the central nervous system (CNS), it is possible that blocking pain at its source by targeting nociceptors would prove more efficient with minimal CNS-related side effects. The development of such analgesics requires the identification of appropriate molecular targets and thorough understanding of their structural and functional features. To this end, plant and animal toxins can be employed as they affect ion channels with high potency and selectivity. Moreover, elucidation of the toxin-bound ion channel structure could generate pharmacophores for rational drug design while favorable safety and analgesic profiles could highlight toxins as leads or even as valuable therapeutic compounds themselves. Here, we discuss the use of plant and animal toxins in the characterization of peripherally expressed ion channels which are implicated in pain.

Alzheimer’s disease (AD) is the most common form of dementia. One of the neuropathological hallmarks of AD is the accumulation of amyloid-β plaques. Overexpression of human amyloid precursor protein in transgenic mice induces hippocampal and neocortical amyloid-β accumulation and plaque deposition that increases with age. The impact of these effects on neuronal population responses and network activity in sensory cortex is not well understood. We used Voltage Sensitive Dye Imaging, to investigate at high spatial and temporal resolution, the sensory evoked population responses in the barrel cortex of aged transgenic (Tg) mice and of age-matched non-transgenic littermate controls (Ctrl) mice. We found that a whisker deflection evoked abnormal sensory responses in the barrel cortex of Tg mice. The response amplitude and the spatial spread of the cortical responses were significantly larger in Tg than in Ctrl mice. At the network level, spontaneous activity was less synchronized over cortical space than in Ctrl mice, however synchronization during evoked responses induced by whisker deflection did not differ between the two groups. Thus, the presence of elevated Aβ and plaques may alter population responses and disrupts neural synchronization in large-scale networks, leading to abnormalities in sensory processing.

Schizophrenia is a mental disease that results in decreased life expectancy and well-being by promoting obesity and sedentary lifestyles. Schizophrenia is treated by antipsychotic drugs. Although the second-generation antipsychotics (SGA), Olanzapine and Aripiprazole, are more effective in treating schizophrenia, they display a higher risk of metabolic side effects, mostly by development of diabetes and insulin resistance, weight gain, and dyslipidemia. Endoplasmic reticulum (ER) stress is induced when ER homeostasis of lipid biosynthesis and protein folding is impaired. This leads to the activation of the unfolded protein response (UPR), a signaling cascade that aims to restore ER homeostasis or initiate cell death. Chronic conditions of ER stress in the liver are associated with diabetes and perturbed lipid metabolism. These metabolic dysfunctions resemble the pharmacological side effects of SGAs. We therefore investigated whether SGAs promote the UPR in human and mouse hepatocytes. We observed full-fledged activation of ER stress by Aripiprazole not by Olanzapine. This occurred at low micromolar concentrations and to variable intensities in different cell types, such as hepatocellular carcinoma, melanoma, and glioblastoma. Mechanistically, Aripiprazole caused depletion of ER calcium, leading to activation of inositol-requiring enzyme 1 (IRE1)and protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), two major transducers of the UPR. Cells underwent apoptosis with Aripiprazole treatment, which coincided with UPR induction, and this effect was reduced by adding glutathione without affecting UPR itself. Deletion of IRE1 from HepG2, a human liver cancer cell line, protected cells from Aripiprazole toxicity. Our study reveals for the first time a cytotoxic effect of Aripiprazole that involves the induction of ER stress. SIGNIFICANCE STATEMENT The antischizophrenic drug Aripiprazole exerts cytotoxic properties at high concentrations. This study shows that this cytotoxicity is associated with the induction of endoplasmic reticulum (ER) stress and IRE1 activation, mechanisms involved in diet-induced obesity. Aripiprazole induced ER stress and calcium mobilization from the ER in human and mouse hepatocytes. Our study highlights a new mechanism of Aripiprazole that is not related to its effect on dopamine signaling.