Opioidergic activation of the descending pain inhibitory system underlies placebo analgesia

Placebo analgesia is caused by inactive treatment, implicating endogenous brain function involvement. However, the neurobiological basis remains unclear. In this study, we found that μ-opioid signals in the medial prefrontal cortex (mPFC) activate the descending pain inhibitory system to initiate placebo analgesia in neuropathic pain rats. Chemogenetic manipulation demonstrated that specific activation of μ-opioid receptor–positive (MOR⁺) neurons in the mPFC or suppression of the mPFC–ventrolateral periaqueductal gray (vlPAG) circuit inhibited placebo analgesia in rats. MOR⁺ neurons in the mPFC are monosynaptically connected and directly inhibit layer V pyramidal neurons that project to the vlPAG via GABA_A receptors. Thus, intrinsic opioid signaling in the mPFC disinhibits excitatory outflow to the vlPAG by suppressing MOR⁺ neurons, leading to descending pain inhibitory system activation that initiates placebo analgesia. Our results shed light on the fundamental neurobiological mechanism of the placebo effect that maximizes therapeutic efficacy and reduces adverse drug effects in medical practice.