Experts interpret Neuron. Li Xiaoming's team reveals new mechanisms for cannabis analgesia.

Professor Zhang Ya (Medical Department of Qingdao University / Medical School of University of Ottawa, Canada) chronic pain is a common disease, which affects about 20% of the world's population and brings heavy burden to families and society.at present, the exact mechanism of pain is still poorly understood.previous studies have shown that the posterior complex of the thalamus (PO) is a high-order somatosensory nucleus responding to pain. Its abnormal activity is the main cause of pain after spinal cord injury. However, the exact function of the Po nucleus in the pain response is still unclear.because the Po nucleus itself lacks GABAergic interneurons to regulate its projection neurons, it relies on GABAergic projections from other nuclei to play a regulatory role, including Zi, zone incerta.Zi has been reported to be involved in defensive behavior, fear memory, predatory behavior, and is closely related to pain.however, the types of neurons involved in pain response and the molecular mechanism of Zi Po loop involved in pain process still need to be further studied.on June 4, 2020, Professor Li Xiaoming Laboratory of Medical College of Zhejiang University published a research paper entitled "incerta thalamic circuit controls nocicensive behavior via cannabinoid type 1 receptors" in the journal Neuron, The GABAergic nerve circuit involved in pain response and revealed a new mechanism of pain relief by marijuana.this study not only helps people better understand the neural loop mechanism of pain, but also provides a new target for clinical treatment of pathological pain.in this latest study of Professor Li Xiaoming's team, we first found a new neural circuit involved in pain response, namely, the small albumin positive neurons in the ventral adventitious zone (Ziv) project to the glutamatergic neurons of Po, and further found that in various pain models, the activity of this circuit is significantly enhanced, and the activity of this neural circuit can be activated or inhibited by using photogenetic technology To reduce or increase the pain threshold of mice.secondly, they found that cannabinoid CB1 receptors were specifically expressed in this loop, and local activation of CB1 receptors in the Po region increased pain thresholds in mice.on the contrary, knockdown of CB1 receptor in this loop significantly reduced the pain threshold of mice.more importantly, local administration of CB1 receptor agonists in the Po region reversed the decrease of pain threshold caused by CB1 receptor knockdown.these findings not only reveal the molecular and loop mechanisms of cannabinoid analgesia, but also promote people's understanding of the neural mechanism of pain, and provide new molecular targets for clinical diagnosis and treatment of pathological pain.the research group first used the acute pain model induced by von Frey acupuncture and radiation heat to test the expression of c-fos in Zi nucleus in mice during pain response. It was found that parvalbumin was positive in Ziv when the mice felt pain, When the PV + neurons in Ziv were gradually apoptotic with tacasp3, the pain threshold of mice was significantly increased.the research group continued to use photogenetic technology for further verification, and obtained similar results. Activation of PV positive neurons in Ziv nucleus can reduce the pain threshold of mice, on the contrary, inhibition of this type of neurons can increase the threshold of mice.this indicates that the activity of PV positive neurons in Ziv nucleus affects the perception of pain response in mice.next, through retrograde tracking and calcium imaging technology, the research group further found that during the pain response process, PV positive neurons in Ziv nucleus could project to the downstream Po nucleus, forming synaptic connection with glutamatergic neurons in Po nucleus. the research group found that Ziv Po neural loop was involved in the pain response process and played a very important role in regulating the pain threshold. cannabinoid is a very effective analgesic, which can be used to treat pain, vomiting, epilepsy, etc. as early as a thousand years ago, the classic document of traditional medicine, Emperor's Canon, recorded the cases of ancient people using medical hemp to treat pain and other diseases. through single cell PCR and RNA scope in situ hybridization, we found that cannabinoid CB1 receptor co expressed with PV positive neurons in Ziv nucleus. through the whole cell recording technology of brain slices, CB1 receptor agonists and inhibitors further confirmed that CB1 receptor can regulate the synaptic transmission process of Ziv Po neural circuit. next, the research group confirmed that the activation of CB1 receptor in the circuit can significantly improve the pain threshold of mice; on the contrary, inhibition or knockdown of CB1 receptor will reduce the pain tolerance of mice, and activation of residual CB1 receptor in CB1 receptor knockdown mice can reverse this process, which fully indicates that CB1 receptor on Ziv Po neural loop can specifically regulate pain response 。 in conclusion, this study reveals the regulation of CB1 receptor on the zona thalamic neural circuit and its role in pain response, which not only deepens the understanding of pain central mechanism, but also reveals the brain mechanism of hemp analgesic effect, and provides theoretical guidance for clinical treatment of pain related diseases. Professor Li Xiaoming returned to China in 2008 and set up his own laboratory in Zhejiang University. In the past decade or so, he has focused on the role and mechanism of GABAergic circuits in affective and affective disorders and made a series of systematic breakthrough contributions. since 2012, they have mainly studied the role of PV positive GABAergic inhibitory neural circuits in neuropsychiatric diseases (Li et al. Nature Neuroscience, 2012; Yang et al. Journal of neuroscience, 2013; Ni, et al. ELife, 2015; Zhang, et al. Cell research, 2016; Geng, et al, Journal of neuroscience, 2017). in recent years, they have systematically studied the whole brain projections of GABAergic neurons, including PV neurons, by using the method of transcynaptic virus labeling. their neuron article (Li, et al, neuron, 2019) found that GABAergic neurons in VTA brain region have a new neural loop mechanism for the regulation of addiction behavior (neuron expert comments: Li Xiaoming group found a new pathway target for addiction treatment, which may effectively alleviate morphine addiction in the future). their nature neuroscience article (Dong, et al, Nature Neuroscience, 2019) found a new circuit of PV positive GABAergic neurons in TRN brain area regulating fear (expert comments on natural neuro Li Xiaoming's team found a new circuit of fear emotion). Nature Medicine (Shen et al, nature medicine, 2019) (nature medicine expert review Li Xiaoming team reveals the new mechanism of marijuana in the treatment of depression) has studied the magical function of CCK neural circuit in amygdala and found a new mechanism of marijuana anti depression. original link: