Favoring inhibitory synaptic drive mediated by GABAA receptors in the basolateral nucleus of the amygdala efficiently reduces pain symptoms in neuropathic mice

Abstract

Pain is an emotion and neuropathic pain symptoms are modulated by supraspinal structures such as the amygdala. If the central nucleus of the amygdala is often named as the "nociceptive amygdala", little is known on the role of the basolateral amygdala. Here, we monitored the mechanical nociceptive thresholds in a mouse model of neuropathic pain and infused modulators of the glutamate/GABAergic transmission in the BLA via chronically-implanted cannulas. First, we found that NMDA-type glutamate receptor antagonist (MK-801) exerted a potent anti-allodynic effect whereas a transient allodynia was induced after perfusion of bicuculline, a GABAA receptor antagonist. Potentiating GABAA receptor function using diazepam (DZP) or etifoxine (EFX, a nonbenzodiazepine anxiolytic) fully but transiently alleviated mechanical allodynia. Interestingly, the anti-allodynic effect of EFX disappeared in animals incapable of producing 3alpha-steroids. DZP had a similar effect but of shorter duration. As indicated by patch-clamp recordings of BLA neurons, these effects were mediated by a potentiation of GABAAR-mediated synaptic transmission. Together with a presynaptic elevation of miniature IPSC frequency, the duration and amplitude of GABAA mIPSCs was also increased (postsynaptic effect). The analgesic contribution of endogenous neurosteroid seemed to be exclusively postsynaptic. This study highlights the importance of BLA and of the local inhibitory/excitatory neuronal network activity while setting the mechanical nociceptive threshold. Furthermore, it appears that promoting inhibition in this specific nucleus could fully alleviate pain symptoms. Therefore BLA could be a novel interesting target to develop pharmacological or non pharmacological therapies

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