| The insular cortex is one of the important parts of cortex network involved in pain perception. It is not only involved in physiological pain and takes part in thermal and acute pain, but also participates in chronic pain. Pain is a complicated perception including pain sensation, emotion and cognition.The insular cortex also contributes to emotion and cognition of pain perception as well. Tons of evidence has elucidated underlying mechanisms about the insular cortex involved in pain perception. For example, in the state of neuropathic pain, AMPA and NMDA receptor-mediated excitatory synaptic transmission efficiency are enhanced and long term potential is disappeared in the insular cortex. In addition, GABA receptors in the insular cortex were involved in physical pain and fibromyalgia. The above results suggest that bothexcitatory andinhibitory neurons in the insular cortex may undergo plastic changes in the generation and maintenance during chronic pain. The rostral agranularinsular cortex(RAIC) was associated with pain perception, emotion and cognition of pain. And the RAICundertakes a lot of important physiological functions of the insular cortex. Endocannabinoid system was confirmed to participate in algesthesia of physical, inflammatory and neuropathic pain. Taking advantage of activating the endogenous pain inhibiting factors provides one of important strategies for the treatment of chronic pain in clinic. And cannabinoid receptor 1(CB1R) which is expressed widely in central nervous system is activated by endocannabinoids(ECs) and takespart in pain regulation. Whether is the CB1 R in the RAIC associated with chronic pain?Stress-induced analgesia was increased by intrathecal activation of m Glu R5 induced by its agonist(S)-3,5-dihydroxyphenylglycine(DHPG)at the lumbar level. And this role of m Glu R5 was blocked by CB1 R inhibitor. Furtherstudies showed that m Glu R5 promoted the synthesis of ECs(2-AG). 2-AG induced the retrogradesuppression of nociceptive transmission at the spinal level by presynaptical CB1 R.ECs act as negative regulation on variety of neurotransmitters release via the short-term synaptic plasticity mediated by CB1 R. Depolarization-induced suppression of excitation in glutamatergic transmissionwas regarded as DSE. And depolarization-induced suppression of inhibitionin GABAergictransmission was considered as DSI. What do DSE and DSI undergo in the RAIC under chronic pain condition? DSI and DSE which are mediated by CB1 R might be affected by the level of ECs and activity of CB1 R. In neuropathic pain state, the level of CB1 R and ECs were both upregulated in the thalamus.Newly recent work showed that the synaptic axon protein(Nrx-1β) was involved in the regulation of CB1R-mediated functionand EC level. Prompting us to study whether abirritation of CB1 R in the RAIC were influenced by Nrx-1β following nerve injury? In addition, DSI and DSE have the characteristics of diffuse. ECs, which were released from the postsynaptic, diffused into the synaptic cleft and mediated the DSI and DSE via CB1 R. And at the same time, ECs could diffuse into the nearby synaptic structureto induce DSI and DSE. The activation of CB1 R could coordinate the larger synchronization of neurons of the central and affect the excitability of the neural network in the larger scope. In the physiological state, the balance of excitation-inhibition is kept an appropriate homeostasis and participates in cognitive and behavioral neural networks in the brain. Changes in GABA levels in the RAIC can raise or lower the pain threshold, resulting in analgesia or hyperalgesiain freely moving rats respectively. Is there any change of excitation-inhibition balance occured in the RAIC under neuropathic pain state.Previous studies showed that ECs affected excitation-inhibition balance via CB1 R and switched the direction to excitation in the prelimbic cortex and the hippocampus. ECs may act on the balance between excitatory and inhibitory neurons at the same time in the RAIC, and may affect the RAIC output ultimately in neuropathic pain state.Evidence of neuroanatomy suggested that the RAIC was connected to the ACC, contralateral RAIC, thalamus and other cortices. At the same time, RAIC and PAG, RⅤM which are associated with pain descending inhibitory pathway formed connection. Is there any relationship between the function of CB1 R in the RAIC and the pain descending inhibitory pathwayin neuropathic pain state? Thus, the effectof CB1 R on neuropathic pain behavior and whether its effect is involvedbypain descending inhibitory pathway were investigated inamice model with the ligation of unilateralcommon peroneal nerve(CPN). Changes of short-term synaptic plasticity mediated by CB1 R were also studied in the RAIC in CPN mice, and the expression of Nrx-1β in the RAICas well. Our study explored the effectsand mechanisms of CB1 R on CPN mice,and further provided an experimental basis for CB1 R participating in pain regulationin the RAIC under the neuropathic pain state.Main results:1. Bilateral injection of CB1 R agonist(ACEA) in the RAIC obviously increased the paw withdrawalthreshold and downregulated the positive pecentage induced by 0.008 g Ⅴon Frey filament of CPN mice. The analgesic action of ACEA was completely reversedin the presence of CB1 R antagonist(AM251).2. The amplitudes of both ECsmediated DSE and DSI in Layer Ⅱ/Ⅲ pyramidal neurons were significantly decreased in the RAIC of CPN mice, while the amplitude of ECs mediated DSE of Layer Ⅴ pyramidal neuron was not significantly changed.Furthermore the amplitude of ECsmediated DSI was significantly increased in the RAIC Layer Ⅴ pyramidal neurons of CPN mice.DSI amplitudewas not dependent on thedepolarized time(depolarization time: 1 s, 5 s, 10 s).3.m RNA and protein levels of Nrx-1β were not significently changed in the RAIC of CPN mice.4.E/I ratios of both Layer Ⅱ/Ⅲ and Layer Ⅴ pyramidal neurons were significantly increased in the RAIC of CPN mice.5. Motor function and mechanical paw withdrawal threshold were not affected by DLF lesion in control mice. However, the positive pecentages induced by 0.008 g Ⅴon Frey filament were significantly increased in control mice. Meanwhile, mechanical alodynia was not affected by DLF lesion in CPN mice. Analgesiceffect of ACEA in the RAIC on bilateral mechanical allodynia wasabolished after DLF lesionin CPN mice.Main conclusions:1. The activation of CB1 R in the RAIC effectively suppressed bilateral mechanical allodynia of neuropathic pain mice. The analgesic effect of CB1 R agonist was dependent onpain descending inhibitory pathway in neuropathic pain state.2.In neuropathic pain state, bothamplitudes of the inhibition mediated by ECs on excitatoryandinhibitory synaptic transmissions were decreased in the Layer Ⅱ/Ⅲpyramidal neurons. But theamplitude of theinhibition mediated by ECs on inhibitory synaptic transmission was meaningfully increasedin the Layer Ⅴ pyramidal neurons.3.Under neuropathic pain condition, Nrx-1β might not participate in the modulation of CB1 R in the RAIC.4.In neuropathic pain state, the excitability of Layer Ⅱ/Ⅲand Layer Ⅴpyramidal neurons wereincreasedin the RAIC;... |
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