Activation of corticostriatal circuitry relieves chronic neuropathic pain.

Neural circuits that determine the perception and modulation of pain remain poorly understood. The prefrontal cortex (PFC) provides top-down control of sensory and affective processes. While animal and human imaging studies have shown that the PFC is involved in pain regulation, its exact role in pain states remains incompletely understood. A key output target for the PFC is the nucleus accumbens (NAc), an important component of the reward circuitry. Interestingly, recent human imaging studies suggest that the projection from the PFC to the NAc is altered in chronic pain. The function of this corticostriatal projection in pain states, however, is not known. Here we show that optogenetic activation of the PFC produces strong antinociceptive effects in a rat model (spared nerve injury model) of persistent neuropathic pain. PFC activation also reduces the affective symptoms of pain. Furthermore, we show that this pain-relieving function of the PFC is likely mediated by projections to the NAc. Thus, our results support a novel role for corticostriatal circuitry in pain regulation.

Persistent neuropathic pain increases synaptic GluA1 subunit levels in core and shell subregions of the nucleus accumbens.

The nucleus accumbens (NAc) is a key component of the brain reward system, and it is composed of core and shell subregions. Glutamate transmission through AMPA-type receptors in both core and shell of the NAc has been shown to regulate reward- and aversion-type behaviors. Previous studies have additionally demonstrated a role for AMPA receptor signaling in the NAc in chronic pain states. Here, we show that persistent neuropathic pain, modeled by spared nerve injury (SNI), selectively increases the numbers of GluA1 subunits of AMPA receptors at the synapse of both core and shell subregions. Such increases are not observed, however, for the GluA2 subunits. Furthermore, we find that phosphorylation at Ser845-GluA1 is increased by SNI at both core and shell subregions. These results demonstrate that persistent neuropathic pain increases AMPA receptor delivery to the synapse in both NAc core and shell, implying a role for AMPA receptor signaling in these regions in pain states.