A photoswitchable inhibitor of TREK channels controls pain in wild-type intact freely moving animals.

By endowing light control of neuronal activity, optogenetics and photopharmacology are powerful methods notably used to probe the transmission of pain signals. However, costs, animal handling and ethical issues have reduced their dissemination and routine use. Here we report LAKI (Light Activated K+ channel Inhibitor), a specific photoswitchable inhibitor of the pain-related two-pore-domain potassium TREK and TRESK channels. In the dark or ambient light, LAKI is inactive. However, alternating transdermal illumination at 365 nm and 480 nm reversibly blocks and unblocks TREK/TRESK current in nociceptors, enabling rapid control of pain and nociception in intact and freely moving mice and nematode. These results demonstrate, in vivo, the subcellular localization of TREK/TRESK at the nociceptor free nerve endings in which their acute inhibition is sufficient to induce pain, showing LAKI potential as a valuable tool for TREK/TRESK channel studies. More importantly, LAKI gives the ability to reversibly remote-control pain in a non-invasive and physiological manner in naive animals, which has utility in basic and translational pain research but also in in vivo analgesic drug screening and validation, without the need of genetic manipulations or viral infection.

Hypothalamic bile acid-TGR5 signaling protects from obesity.

Bile acids (BAs) improve metabolism and exert anti-obesity effects through the activation of the Takeda G protein-coupled receptor 5 (TGR5) in peripheral tissues. TGR5 is also found in the brain hypothalamus, but whether hypothalamic BA signaling is implicated in body weight control and obesity pathophysiology remains unknown. Here we show that hypothalamic BA content is reduced in diet-induced obese mice. Central administration of BAs or a specific TGR5 agonist in these animals decreases body weight and fat mass by activating the sympathetic nervous system, thereby promoting negative energy balance. Conversely, genetic downregulation of hypothalamic TGR5 expression in the mediobasal hypothalamus favors the development of obesity and worsens established obesity by blunting sympathetic activity. Lastly, hypothalamic TGR5 signaling is required for the anti-obesity action of dietary BA supplementation. Together, these findings identify hypothalamic TGR5 signaling as a key mediator of a top-down neural mechanism that counteracts diet-induced obesity.

Animal models of pain: Diversity and benefits.

Chronic pain is a maladaptive neurological disease that remains a major health problem. A deepening of our knowledge on mechanisms that cause pain is a prerequisite to developing novel treatments. A large variety of animal models of pain has been developed that recapitulate the diverse symptoms of different pain pathologies. These models reproduce different pain phenotypes and remain necessary to examine the multidimensional aspects of pain and understand the cellular and molecular basis underlying pain conditions. In this review, we propose an overview of animal models, from simple organisms to rodents and non-human primates and the specific traits of pain pathologies they model. We present the main behavioral tests for assessing pain and investing the underpinning mechanisms of chronic pathological pain. The validity of animal models is analysed based on their ability to mimic human clinical diseases and to predict treatment outcomes. Refine characterization of pathological phenotypes also requires to consider pain globally using specific procedures dedicated to study emotional comorbidities of pain. We discuss the limitations of pain models when research findings fail to be translated from animal models to human clinics. But we also point to some recent successes in analgesic drug development that highlight strategies for improving the predictive validity of animal models of pain. Finally, we emphasize the importance of using assortments of preclinical pain models to identify pain subtype mechanisms, and to foster the development of better analgesics.