Differential reduction of neuropathic pain symptoms by mGlu4-mediated neuromodulation of amygdala circuits

Abstract

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 of 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 mechanisms associated to the metabotropic glutamate receptors mGlu4 in the amygdala to modulate neuropathic pain. In a murine model of peripheral mononeuropathy induced by a chronic constriction of the sciatic nerve, we demonstrate that pharmacological activation of amygdala mGlu4 receptors efficiently alleviates sensory and depressive-like symptoms in both male and female mice. Moreover, we reveal a differential modulation of those symptoms, activating mGlu4 receptors in the controlateral amygdala, relatively 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 a precise spatiotemporal photocontrol of deep brain endogenous targets, we further demonstrate the rapid and reversible action of mGlu4-mediated neuromodulation on neuropathic pain symptoms. Finally, coupling photopharmacology and analgesic conditioned place preference, we show an important pain-reducing effect of mGlu4 activation. Taken together, these data highlight the analgesic potential of enhancing amygdala mGlu4 activity to counteract neuropathy in the hope of improving existing treatments.