3 research outputs found
Photopharmacological manipulation of amygdala metabotropic glutamate receptor mGlu4 alleviates neuropathic pain
Neuropathic pain is a common health problem resulting in exacerbated response to noxious and non noxious stimuli, as well as impaired emotional and cognitive responses. Unfortunately, neuropathic pain is also one of the most difficult pain syndromes to manage, highlighting the importance of better understanding the brain regions and neuromodulatory mechanisms involved in its regulation. Among the many interconnected brain areas which process pain, the amygdala is known to play an important role in the integration of sensory and emotional pain signals. Here we questioned the ability of a recently identified neuromodulatory mechanism associated with the metabotropic glutamate receptors mGlu4 in the amygdala to modulate neuropathic pain. In a murine model of peripheral mononeuropathy, we demonstrate that pharmacological activation of amygdala mGlu4 efficiently alleviates sensory and depressive-like symptoms in both male and female mice. Moreover, we reveal a differential modulation of these symptoms. Activating mGlu4 in the contralateral amygdala relative to the side of the mononeuropathy, is necessary and sufficient to relieve both sensory and depressive-like symptoms, while ipsilateral activation solely reduces depressive-like symptoms. Furthermore, using photopharmacology, a recent strategy allowing precise photocontrol of endogenous proteins, we further demonstrate the dynamic alleviation of neuropathic pain through light-dependent facilitation of mGlu4 by a photoswitchable positive allosteric modulator. Finally, coupling photopharmacology and analgesic conditioned place preference, we show a significant pain-reducing effect of mGlu4 activation. Taken together, these data highlight the analgesic potential of enhancing amygdala mGlu4 activity to counteract neuropathy reinforcing its therapeutic interest for the treatment of pathological pain.This work was supported by the International Emerging Action (IEA) from the Centre National de la Recherche Scientifique (CNRS) to CG and AL and by grants from the French National Research Agency (ANR): ANR-16-CE16–0010 to CG and ANR-17-NEU3–0001 under the frame of Neuron Cofund to CG and AL.Peer reviewe
Gelatinase Biosensor Reports Cellular Remodeling During Epileptogenesis
International audienceEpileptogenesis is the gradual process responsible for converting a healthy brain into an epileptic brain. This process can be triggered by a wide range of factors, including brain injury or tumors, infections, and status epilepticus. Epileptogenesis results in aberrant synaptic plasticity, neuroinflammation and seizure-induced cell death. As Matrix Metalloproteinases (MMPs) play a crucial role in cellular plasticity by remodeling the extracellular matrix (ECM), gelatinases (MMP-2 and MMP-9) were recently highlighted as key players in epileptogenesis. In this work, we engineered a biosensor to report in situ gelatinase activity in a model of epileptogenesis. This biosensor encompasses a gelatinase-sensitive activatable cell penetrating peptide (ACPP) coupled to a TAMRA fluorophore, allowing fluorescence uptake in cells displaying endogenous gelatinase activities. In a preclinical mouse model of temporal lobe epilepsy (TLE), the intrahippocampal kainate injection, ACPPs revealed a localized distribution of gelatinase activities, refining temporal cellular changes during epileptogenesis. The activity was found particularly but not only in the ipsilateral hippocampus, starting from the CA1 area and spreading to dentate gyrus from the early stages throughout chronic epilepsy, notably in neurons and microglial cells. Thus, our work shows that ACPPs are suitable molecular imaging probes for detecting the spatiotemporal pattern of gelatinase activity during epileptogenesis, suggesting their possible use as vectors to target cellular reactive changes with treatment for epileptogenesis
Psychostimulant Drugs Activate Cell-type Specific and Topographic cFos Expression in the Lumbar Spinal Cord
International audiencePsychostimulant drugs, such as cocaine, d-amphetamine and methylphenidate, alter a wide range of behaviors including locomotor activity and somatosensory perception. These altered behaviors are accompanied by the activation of specific neuronal populations within reward-, emotion- and locomotion-related circuits. However, whether such regulation occurs at the level of the spinal cord, a key node for neural circuits integrating and coordinating sensory and motor functions has never been addressed. By evaluating the temporal and spatial expression pattern of the phosphorylated form of the immediate early gene cFos at Ser32 (pS32-cFos), used as a proxy of neuronal activation, we demonstrate that, in adult male mice, d-amphetamine increases pS32-cFos expression in both inhibitory and excitatory neurons in dorsal and ventral horns at the lumbar spinal cord level. Interestingly, a fraction of neurons activated by a first exposure to d-amphetamine can be re-activated following d-amphetamine re-exposure. Similar expression patterns were observed in response to cocaine and methylphenidate, but not following morphine and dozilcipine administration. Finally, the blockade of dopamine reuptake was sufficient to recapitulate the increase in pS32-cFos expression induced by psychostimulant drugs. Our work provides evidence that cFos expression can be activated in lumbar spinal cord in response to acute psychostimulants administration. Running title: Psychostimulant-evoked neuronal ensembles in spinal cord