AMPAkines potentiate the corticostriatal pathway to reduce acute and chronic pain

Abstract

The corticostriatal circuit plays an important role in the regulation of reward- and aversion-types of behaviors. Specifically, the projection from the prelimbic cortex (PL) to the nucleus accumbens (NAc) has been shown to regulate sensory and affective aspects of pain in a number of rodent models. Previous studies have shown that enhancement of glutamate signaling through the NAc by AMPAkines, a class of agents that specifically potentiate the function of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, reduces acute and persistent pain. However, it is not known whether postsynaptic potentiation of the NAc with these agents can achieve the full anti-nociceptive effects of PL activation. Here we compared the impact of AMPAkine treatment in the NAc with optogenetic activation of the PL on pain behaviors in rats. We found that not only does AMPAkine treatment partially reconstitute the PL inhibition of sensory withdrawals, it fully occludes the effect of the PL on reducing the aversive component of pain. These results indicate that the NAc is likely one of the key targets for the PL, especially in the regulation of pain aversion. Furthermore, our results lend support for neuromodulation or pharmacological activation of the corticostriatal circuit as an important analgesic approach.

Presynaptic AMPA Receptors in Health and Disease

“…However, the most recent progresses in this field have shown that the modulation of the activity of AMPARs is effective in chronic pain therapy [94,95,104]. Worthy of notice is the recent literature showing that the enhancement of glutamate signaling by AM-PAkines, a class of agents that specifically potentiate the function of AMPAR, reduce acute and chronic pain [104][105][106]. In addition, recent studies indicate that AMPAkines may have an antidepressant effect [107][108][109] and that they may influence memory in a mouse model of intellectual disability [110].…”