| Neuropathic pain is defined as a pain caused by injury, disease or dysfunction of peripheral or central nervous system. Neuropathic pain is a high incidence of chronic pain, the incidence is about 7% in general population, about 100 million patients in China are affected. Pain has influenced the life quality of patient severely, and brought huge psychological burden to patients, the problem of pain has caused a highly attention in the international society. However, the pathogenesis of neuropathic pain is too complex and lack of effective treatments. Therefore, it is urgent to understand the mechanism underlying generation and modulation of pain and find therapeutic targets to relieve pain.Marijuana has been used for relieving pain for more than four centuries, but its analgesic mechanism was only understood during the past two decades. Studies suggest that the analgesic effect of cannabinoid was related to CB1 and CB2 receptor.There is a negative feedback loop of pain modulation in central nervous system, it is composed of spinal cord-thalamic nucleus submedius (Sm)-ventrolateral orbital cortex (VLO)-periaqueductal gray (PAG)-spinal cord. Opioid peptides, serotonin, glutamate, dopamine, ?-aminobutyric acid neurotransmitter and their related receptors are involved in spinal cord-Sm-VLO-PAG-spinal cord mediated antinociception. Receiving projections from Sm and containing neurons that project to the PAG, VLO plays an important role in pain modulation. Studies has reported that opioid receptors and GABA receptors in VLO play an important role in antinociception. Despite the fact that lots of CB1 receptor expressed in VLO, whether CB1 receptor in VLO is involved in the analgesic effect of cannabinoid remains unknown.In this study, we used common peroneal nerve (CPN) ligation neuropathic pain model of mice combined with microinjection of drugs in brain, and measured 50% paw withdrawal threshold induced by mechanical stimulus, to test whether activation of CB1 receptor in VLO reduce pain behavior in the mice CPN ligation model of neuropathic pain. Results are as following:1. CPN model is developed and paw withdrawal latency (PWL) induced by radiant heat and paw withdrawal threshold (PWT) induced by mechanical stimulus were measured to test the validity of the model. After CPN ligation, PWL and PWT are significantly decreased in more than 21 days. PWL and PWT in the CPN ligation group is significantly lower than Sham operated group.2. Microinjection of HU210 (100,200,400 ng), a CB1 receptor agonist, into the VLO increased 50% PWT. There is a positive correlation between 50% PWT and concentration of HU210 (r=0.57, P=0.000). This effect was blocked by pre-microinjection of the CB1 receptor antagonist AM281(50 ng). These results suggests that activation of CB1 receptor in VLO produces antinociception.3. Microinjection of bicuculline (2.5,5.0,7.5 ng), a GABAA receptor antagonist, into the VLO increased 50% PWT. There is a positive correlation between 50% PWT and concentration of bicuculline (r=0.73, P=0.000). This result suggests that blockage of GABAA receptor in VLO results in antinociception.4. Microinjection of muscimol (50 ng), a GABAA receptor agonist, into the VLO can completely blocked HU210(100 ng)-induced increase in 50% PWT. This result suggests that the mechanism underlying nociceptive effect of HU210 may be decreased GABA release from the GABAergic neurons through activation of CB1 receptor. |
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