Modulation Of Opioid ? Receptors In Chronic Stress-induced Hyperalgesia And Mood Disorders

Stress stimulation has a regulatory effect on the pain response.According to the duration and intensity of the stressors,stress can be divided into acute stress(AS)and chronic stress(CS).In general,acute stress can cause analgesia in the body,while chronic stress can cause hyperalgesia phenomenon.In addition,there are studies that find that there is a very complex relationship between stress and pain and emotional disorders.Stress will increase the risk of mental illness in the body and increase the severity of mental illness.The study found that chronic stress can induce CA3 dendritic retraction in the hippocampus,and apoptosis of CA3 or dentate gyrus cells,which impairs the activity of the hypothalamic-pituitary-adrenal(HPA)axis and eventually causes abnormal emotions in the body.Pain can cause mental illness such as anxiety and depression in individuals.Mental illness also accompanied by excessive activity of the HPA axis and dysfunction of the serotonergic and noradrenergic systems,further aggravating the symptoms of painful diseases in individuals.In summary,due to the complex relationship among pain,stress and mental illness,the treatment of clinical pain disorders is facing greater challenges.Study finds opioid peptides play powerful analgesic effect through endogenous pain control system.Opioid peptides are a class of proteins related to neuromodulation.Endogenous opioid peptides mainly include ?-endorphin,enkephalin and dynorphin,which can activate mu receptor,? receptor and ? receptor in the opioid system.When the body is in a dangerous or aversive environment,its stress response is mediated,regulated and terminated by the release of endogenous opioids.Theresearchs on central and peripheral neuropathic pain has reported the analgesic effect of opioid receptor agonists,especially mu opioid receptor(MOR)agonist morphine,and patients with clinical pain are usually treated with opioid agonists.Although the opioid agonist drugs have been widely used in the treatment of pain diseases so far,their side effects on the treatment of pain diseases have caused greater concern.For example,it has been clinically found that if pain patients take opioid analgesia for a long time,there will be problems of immunology,physical dependence and even mental dependence,which greatly limit the scope of use of opioid analgesics.At the same time,studies have found that in most stressful environments,endogenous opioid receptors can produce analgesic effects.However,when the body is repeatedly exposed to stressors,the frequency of endogenous opioid release in the body increases,which will cause the opioid receptor to be over-activated,desensitized and eventually cause tolerance to the analgesic effects.So far,most studies suggest that SIA is mediated by the brainstem pain regulatory system,but the research on the specific regulatory mechanism of SIH is still not very clear.In summary,this subjectconstruct chronic stress-induced hyperalgesia animal model by useing forced swimming stress and utilize the heat radiation to test the pain threshold.At the same time,we use the gene knockout mice to explore systemic mu receptors and role of mu-receptors on astrocytes,gamma-aminobutyric energy neurons and glutamatergic neurons in chronic stress-induced hyperalgesia and emotional disorders formation.Results are as following:1.The genotypes of various genetic mice were identified by polymerase chain reaction and the results showed that the knockout mice model was constructedsuccessfully.2.In the process of repeated forced swimming,the immobility time of the mice in the swimming test increases with the numbers of swimming days and the immobility time of the forced swimming on the 6th day is significantly higher than the 1st day.The results show that depression-like emotions appeared in mice after 6 days of swimming stress.3.Compared with the stress before forced swimming,the tail flick latency of wild-type mice is significantly reduced after stress,which indicates that repeated forced swimming stress does reduce the pain threshold and the mice appears hyperalgesia.The results show that the animal model of hyperalgesia induced by repeated forced swimming stress was successfully constructed.4.The mice in the intraperitoneal injection of saline group had hyperalgesia after stress,which showed that the latency of tail flick after stress was significantly reduced,while the mice in the intraperitoneal injection of ? receptor antagonist?-Funaltrexamine hydrochloride(?-FNA)group did not have hyperalgesia after stress,manifested as no change in tail flick latency before and after stress;The wild-type mice had hyperalgesia after stress,which showed that the latency of tail flick after stress was significantly reduced,while the systemic Oprml knockout mice(CMV-Oprm-/-)did not have hyperalgesia after stress,manifested as no change in tail flick latency before and after stress.These results indicate that mu receptors are involved in regulating the formation of stress-induced hyperalgesia.5.The wild-type mice had hyperalgesia after stress,which showed that the latency of tail flick after stress was significantly reduced.The astrocyte-specific Oprm1 knockout mice(GFAP-Oprm-/-)and glutamate-specific neuron Oprml knockout mice(vGlutl-Oprm-/-)also had hyperalgesia after stress.While the GABAergic neuron-specific Oprm1 knockout mice(Gad2-Oprm-/-)did not have hyperalgesia after stress.These results indicate that GABAergic neurons are the major targets of mu receptors involved in regulating stress-induced hyperalgesia.6.Compared with the mice without forced swimming stress,the time of forced swimming mice in staying in the center of the open field and open arms in the elevated plus maze was significantly reduced;Compared to wild-type littermates undergoing forced swimming stress,the residence time of CMV-Oprm-/-,GFAP-Oprm-/-,Gad2-Oprm-/-and vGlutl-Oprm-/-mice in the central area of the open field and the open arms in the elevated plus maze was also significantly reduced,however,there was no significant change in immobility time in the tail suspension test.The above results show that repeated forced swimming can induce anxiety/depression-like emotions in mice,but the role of mu receptors is not obvious.In summary,mice will have hyperalgesia after repeated forced swimming stress.This behavioral change is related to the regulation of mu receptors and the GABAergic neurons are the major targets of mu receptors involved in regulating stress-induced hyperalgesia.In addition,forced swimming stress can induce anxiety/depression-like emotions in mice,but the role of mu receptors is not obvious and needs further research.