Study On The Expression Of CNS Vomiting Related Receptors In SD Rats Induced By Chronic Stress

ObjectiveChemotherapy is an important means of treating cancer.Nausea and vomiting are extremely painful side effects that occur frequently in cancer patients during chemotherapy.Our previous clinical studies have found that cancer patients have a high incidence of depression and a positive correlation between the degree of depression and the severity of chemotherapy-induced nausea and vomiting(CINV).Depression can aggravate the incidence of chemotherapy-induced nausea and vomiting in patients with malignant tumors,reduce the quality of life of patients and affect the efficacy of chemotherapy,leading to difficulties in subsequent chemotherapy and failure of tumor treatment.Chemotherapy drugs stimulate the secretion of serotonin,dopamine,substance P,etc.from the gastrointestinal pheochromic cells to bind to the corresponding receptors,and the nerve impulses are transmitted to the medulla and fourth ventricle base to induce vomiting chemistry through the abdominal vagus nerve afferent fibers.The sensory zone(CTZ)and further conduction to the vomiting center leads to vomiting,or directly stimulate the receptor excitation zone by chemical drugs,which is caused by nerve conduction to the vomiting center.However,the levels of serotonin and dopamine in the plasma of depressed patients are all decreased.The levels of 5-HT/DA seem to be contradictory in terms of vomiting induced by depression/release of chromophilic cells stimulated by chemotherapy drugs.We speculate depression in patients with cancer might enhance chemotherapy induced nausea and vomiting,which is involved by altering e expression of serotonin 3 receptor(5-HT3R),dopamine receptor(DA2R),endocannabinoid receptor(CB1R),and substance P receptor(NK1R)in the posterior polar region of the fourth ventricle and the CTZ in the medulla.To validate the above hypothesis,we constructed a chronic unpredictable mild stress-induced SD rat depression model.MethodsRat model of chronic unpredictable mild stress-induced depression was established at first.A behavioral assessment model was employed.Blood levels of serotonin,dopamine,substance P,and endogenous cannabinoids(AEA)were measured by ELISA.Quantitative PCR was used to detect m RNA gene expression change of serotonin receptor(5-HT3R),dopamine receptor(DA2R),substance P receptor(NK1R),and endogenous cannabinoid receptor(CB1R)in the posterior region of the fourth ventricle and in the medulla.Western blot was used to detect the protein expression of serotonin receptor(5-HT3R),dopamine receptor(DA2R),substance P receptor(NK1R),and endogenous cannabinoid receptor(CB1R).The expression of 5-HT3 R,DA2R,NK1 R and CB1 positive products in the medulla oblongata of SD rats was detected by immunohistochemistry.ResultThere were significant differences in behavioral evaluation scores between the depression model group and the control group,indicating that the CUMS rat depression model was successfully built up.Compared with the normal control group,the level of endogenous substances 5-HT,DA,and substance P in the SD rats in the depression group was significantly decreased while AEA was significantly increased.However,the m RNA and protein expression levels of 5-HT3 R,DA2R,NK1 R in CNS in depression model group rats were increased,meanwhile the expression level of CB1 R protein was decreased.Immunohistochemical assay showed that the four receptors were expressed in the medulla of the two groups of SD rats.The number of 5-HT3 R,DA2R and NK1 R positive granules were increased and the more deeper than that in control group.The CB1 R positive granules were similar in two groups.ConclusionChronic unpredictable mild stress-induced depression alters the expression of vomiting-related receptors in the fourth ventricle and medulla oblongata of rats,leading to sensitization to neurotransmitters and enhancement of chemotherapyinduced nausea and vomiting.