A voxel-based analysis of neurobiological mechanisms in placebo analgesia in rats

Placebo analgesia is the beneficial effect that follows despite a pharmacologically inert treatment. Modern neuroimaging studies in humans have delineated the hierarchical brain regions involved in placebo analgesia. However, because of the lack of proper approaches to perform molecular and cellular manipulations, the detailed molecular processes behind it have not been clarified. To address this issue, we developed an animal model of placebo analgesia in rats and analyzed the placebo analgesia related brain activity using small-animal neuroimaging method. We show here that gabapentin-based Pavlovian conditioning successfully induced placebo analgesia in neuropathic pain model rats and hierarchical brain regions are involved in placebo analgesia in rats, including the prelimbic cortex (PrL) of the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), ventrolateral periaqueductal gray matter (vlPAG), etc. The functional couplings in placebo responders between the mPFC and vlPAG was interrupted by naloxone, an antagonist of μ opioid receptor. Moreover, both local chemical lesion and microinfusion of naloxone in the mPFC suppressed the placebo analgesia. These results suggest that the intrinsic μ opioid system in the mPFC causally contribute to placebo analgesia in rats, and the small-animal neuroimaging approach could provide important insights toward understanding the placebo effect in great detail.