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.
Highlights
Acute pain is an important sensory event that protects us from physical harm and environmental danger
AMPAkine potentiation of the glutamatergic signaling in the nucleus accumbens (NAc) partially reconstituted the effect of optogenetic activation of the prelimbic cortex (PL) on nocifensive withdrawals, but it fully occluded the effect of PL activation on reducing pain aversion. These results indicate that the NAc is an important target for the PL in pain regulation, especially in the regulation of the affective component of pain, and that AMPAkines can strongly modulate the corticostriatal circuit to treat acute and chronic pain
AMPAkine treatment alone only produced approximately half of the antinociceptive effect of PL activation (YFP + AMPAkine vs. YFP + saline, ChR2 + AMPAkine vs. YFP + AMPAkine, Fig. 3c), whereas AMPAkine combined with PL activation produced similar anti-nociceptive effects as PL activation alone (ChR2 + AMPAkine vs. ChR2 + saline, Fig. 3c). These results indicate that potentiation of the amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor function in the NAc partially reconstitutes the anti-nociceptive effects of PL activation in the chronic pain state
Summary
Acute pain is an important sensory event that protects us from physical harm and environmental danger. Affects one in four adults worldwide and can lead to debilitation and functional impairment. A better understanding of the endogenous pain regulatory pathways can unlock new treatments for both severe acute pain and more importantly for chronic pain. The prefrontal cortex (PFC) is a highly evolved structure in the brain that provides top-down regulation of a number of sensory and affective behaviors [1,2,3]. Previous studies have shown that this region has the capacity to regulate both sensory and affective components of pain [4,5,6,7,8]. Recent studies have shown that activation of the prelimbic region of the PFC (PL) in rodents can
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