Neuropathic pain is a debilitating clinical condition with few efficacious treatments, warranting development of novel therapeutics. We hypothesized that dysregulated translation regulation pathways may underlie neuropathic pain. Peripheral nerve injury induced reorganization of translation machinery in the peripheral nervous system of rats and mice, including enhanced mTOR and ERK activity, increased phosphorylation of mTOR and ERK downstream targets, augmented eIF4F complex formation and enhanced nascent protein synthesis. The AMP activated protein kinase (AMPK) activators, metformin and A769662, inhibited translation regulation signaling pathways, eIF4F complex formation, nascent protein synthesis in injured nerves and sodium channel-dependent excitability of sensory neurons resulting in a resolution of neuropathic allodynia. Therefore, injury-induced dysregulation of translation control underlies pathology leading to neuropathic pain and reveals AMPK as a novel therapeutic target for the potential treatment of neuropathic pain.

Rest in the fruit fly Drosophila melanogaster has key characteristics of mammalian sleep and is thus considered as a fly version of sleep. Drosophila sleep has been studied extensively, with the aim of gaining fundamental insights into the evolutionarily conserved functions of sleep as well as the mechanisms that regulate it. An interesting question that has not yet been addressed is whether fly sleep can be classified into distinct sleep types, each having particular biological roles – like rapid eye movement (REM) and non-REM sleep in birds and mammals. Typically, Drosophila sleep displays a bimodal pattern, consisting of distinct daytime and nighttime components. Notably, daytime and nighttime sleep differ with respect to several qualities, such as sleep-bout lengths and arousal thresholds. In this short review, we describe several genetic and environmental factors that differentially affect daytime and nighttime sleep, highlighting the observations suggesting the notion that these temporally distinct components of Drosophila sleep may have unique biological functions and be regulated by different homeostatic regulatory mechanisms.

G-protein-coupled receptors (GPCRs) for steroid hormones mediate unconventional steroid signaling and play a significant role in the rapid actions of steroids in a variety of biological processes, including those in the nervous system. However, the effects of these GPCRs on overall neuronal activity remain largely elusive. Drosophila DopEcR is a GPCR that responds to both ecdysone (the major steroid hormone in insects) and dopamine, regulating multiple second messenger systems. Recent studies have revealed that DopEcR is preferentially expressed in the nervous system and involved in behavioral regulation. Here we utilized the bioluminescent Ca-indicator GFP-aequorin to monitor the nicotine-induced Ca-response within the mushroom bodies (MB), a higher-order brain center in flies, and examined how DopEcR modulates these Ca-dynamics. Our results show that in DopEcR knockdown flies, the nicotine-induced Ca-response in the MB was significantly enhanced selectively in the medial lobes. We then reveal that application of DopEcR's ligands, ecdysone and dopamine, had different effects on nicotine-induced Ca-responses in the MB: ecdysone enhanced activity in the calyx and cell body region in a DopEcR-dependent manner, whereas dopamine reduced activity in the medial lobes independently of DopEcR. Finally, we show that flies with reduced DopEcR function in the MB display decreased locomotor activity. This behavioral phenotype of DopEcR-deficient flies may be partly due to their enhanced MB activity, since the MB have been implicated in the suppression of locomotor activity. Overall, these data suggest that DopEcR is involved in region-specific modulation of Ca dynamics within the MB, which may play a role in behavioral modulation.

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