The Mechanism Of Placebo Analgesia In Chronic Neuropathic Pain

[Objective]The high prevalence rate and heavy financial burden of the chronic pain make it one of the main concerns of public health.However there is still no effective therapy method for it.Recently,placebo analgesia is using as a therapeutic method in clinic.However the underlying neural and molecular mechanisms in detail are still poorly understood.Understanding the mechanism of placebo analgesia can help us establish a suitable treatment context,improve analgesic drug effects and provide a new avenue for the development of analgesics and therapeutic method.To reveal the mechanism of placebo analgesia,we induced placebo analgesia in rats,and examined the involved neurochemical systems and central nervous nuclei.[Methods]Human research suggested placebo analgesia can be induced by both verbal instruction and Pavlovian conditioning.In our study,we established a placebo analgesic model in neuropathic pain rats by Pavlovian conditioning.Conditioned place preference was used to confirm the preference induced by gabapentin.The pharmacological methods were applied to examine the neurochemical systems involved in rat placebo analgesia.The regional brain activity that related to placebo analgesia was assessed by a small animal neuroimaging method combing 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography(PET)imaging with statistical parametric mapping analysis.Chemical lesion was applied to confirm the nucleus which was involved in imaging data.Microinfusion in brain was applied to study the neurochemical system in specific nucleus.[Results]After the continuous pairings of unconditioned stimulus and conditioned stimulus,we induced placebo analgesia in neuropathic pain rats by Pavlovian conditioning.Pharmacological studies indicate both opioid system and dopamine system were involved in our Pavlovian conditioning induced placebo analgesia by the systemic treatment μ opioid receptor antagonist and D2 dopamine receptor antagonist.The analysis results from comparing the placebo responders and placebo non-responders or pharmacological groups suggested the pain modulating related nuclei were activated in placebo responders or positively correlated with placebo score,including rostral anterior cingulate cortex,ventrolateral periaqueductal gray and anterior insular,whereas the pain processing related nuclei were depressed or negatively correlated with placebo score,including primary somatosensory and motor cortices.Instead of dorsolateral prefrontal cortex which is critically involved in human placebo analgesia,medial prefrontal cortex was activated in our gabapentin-based Pavlovian conditioning induced placebo analgesic model,and the functional coupling was enhanced among medial prefrontal cortex,rostral anterior cingulate cortex and ventrolateral periaqueductal gray.The μ opioid receptor antagonist naloxone can block the functional coupling among medial prefrontal cortex,rostral anterior cingulate cortex and ventrolateral periaqueductal gray.Chemical lesion in mPFC suppressed the establishment of placebo analgesia which suggested a critical role of medial prefrontal cortex in Pavlovian conditioning induced placebo analgesia.And inhibited μ opioid receptor in medial prefrontal cortex can suppress placebo analgesia,but not dopamine D2 receptor.[Conclusions]These results suggested that brain activity changes are quite similar in both human and rat placebo analgesia,and neurochemical systems involved in placebo analgesia are also similar,including opioid system and dopamine system.The medial prefrontal cortex,which is thought as a homolog of dorsolateral prefrontal cortex in human,was critically involved in Pavlovian conditioning induced placebo analgesic model.All of those indicated nearly the same mechanisms might underlie placebo analgesia in both human and rats,so our results provide important evidences to reveal the mechanism of placebo analgesia.