Abstract
Cortical mechanisms that regulate acute or chronic pain remain poorly understood. The prefrontal cortex (PFC) exerts crucial control of sensory and affective behaviors. Recent studies show that activation of the projections from the PFC to the nucleus accumbens (NAc), an important pathway in the brain’s reward circuitry, can produce inhibition of both sensory and affective components of pain. However, it is unclear whether this circuit is endogenously engaged in pain regulation. To answer this question, we disrupted this circuit using an optogenetic strategy. We expressed halorhodopsin in pyramidal neurons from the PFC, and then selectively inhibited the axonal projection from these neurons to neurons in the NAc core. Our results reveal that inhibition of the PFC or its projection to the NAc, heightens both sensory and affective symptoms of acute pain in naïve rats. Inhibition of this corticostriatal pathway also increased nociceptive sensitivity and the aversive response in a chronic neuropathic pain model. Finally, corticostriatal inhibition resulted in a similar aversive phenotype as chronic pain. These results strongly suggest that the projection from the PFC to the NAc plays an important role in endogenous pain regulation, and its impairment contributes to the pathology of chronic pain.
Highlights
Pain protects us from injury and harm
We found that inactivation of the PL-prefrontal cortex (PFC) substantially decreased latency to withdrawal to the thermal stimulus, suggesting that this region produces endogenous nociceptive control (Figure 1D)
One of the chambers was paired with repeated noxious mechanical stimulations in the form of a pin prick (PP) to the hind paw, coupled with simultaneous optogenetic inactivation of the prelimbic region of the PFC (PL-PFC)
Summary
Pain protects us from injury and harm. In some cases, pain can become magnified, giving rise to exaggerated emotional responses (Melzack and Casey, 1968). The prefrontal cortex (PFC) is a highly evolved structure that projects to other cortical and subcortical regions to regulate a host of sensory and affective processes (Ressler and Mayberg, 2007; Fuster, 2009; Arnsten et al, 2012). Exogenous activation of the PFC has long been known to inhibit nociceptive withdrawal responses (Cooper, 1975; Hardy, 1985). Optogenetic activation of Corticostriatal Inhibition Enhances Pain the prelimbic region of the PFC (PL-PFC) in rodents has been shown to reduce nociceptive withdrawals, and affective or aversive responses to pain (Lee et al, 2015; Zhang et al, 2015; Martinez et al, 2017)
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