Analgesic And Anti-depressive Effects Of Vortioxetine On Spared Nerve Injury Model And The Mechanisms

BackgroundNeuropathic pain is a common chronic pain syndrome caused by damage or dysfunction of the nervous system with a high incidence and involves a variety of pathophysiological mechanisms.It is very common in clinic but commonly used pain relievers often don't work as well.Patients with chronic pathological neuralgia are often accompanied by mood disorders,even depressive symptoms.In recent years,more and more antidepressants have been studied and used in the treatment of chronic pain syndrome.Basic and clinical studies have shown that some antidepressants could reduce pain symptoms in patients while preventing and alleviating mood disorders caused by long-term pain.Among the antidepressants,Duloxetine,a representative of the 5-HT/NE dual reuptake inhibitor class,has been approved by the FDA for the treatment of some chronic pain syndromes.However,the analgesic effect of 5-HT reuptake inhibitors was not significant.Basic studies have shown that,because there were several types of 5-HT receptors and different types of 5-HT receptors might facilitate or inhibit pain signal in the process of pain transmission.Several studies have shown that the antagonists of 5-HT3 receptor presented analgesic effects.Vortioxetine is a new drug for the treatment of depression.It can inhibit the reabsorption of 5-HT,stimulate 5-HT1 A and 5-HT1 B receptors,and antagonize 5-HT1 D,5-HT3 and 5-HT7 receptors.Its binding rate to5-HT3 receptor ranks only second to the inhibition of serotonin transporter,but presents a lower binding rate with other receptors.It appears to have almost the same effect as the typical 5 HT3 receptor antagonist Ondansetron.Compared withDuloxetine,Vortioxetine has a certain therapeutic effect on cognitive disorder and sleep disorder caused by chronic pain,and is safe and well tolerated without significant weight gain,sexual dysfunction,or adverse cardiovascular events.In this study,we used a mouse model of chronic neuropathic pain to study the potential analgesic effect of Vortioxetine and its depression preventive effect on long-term pain-induced depressive behavior and the related molecular mechanisms.Because most studies have reported that the activation of neuroglia,increase of proinflammatory cytokines,and elevation of Brain-derived neurotrophic factor level were involved in the development and maintenance of neuropathic pain,and the occurrence of depressive behavior,we studied the mechanisms through these three aspects,and further explored the role of 5-HT3 receptor in the analgesic and antidepressant effects of Vortioxetine.This paper is divided into four parts with the main content located in the second part and the third part.ObjectiveThe first part of the experiment was aimed to study the analgesic effect and depression preventive effect of Vortioxetine on chronic neuropathic pain induced by spared nerve injury(SNI),to explore the possible mechanisms from the changes of the activation of microglia and astroglia,the secretory levels of proinflammatory cytokines TNF-a,IL-1? and IL-6,and the protein levels of ERK-CREB-BDNF signaling pathway in the lumber spinal cord,the prefrontal cortex,and the hippocampus.The second part of the experiment was based on the fact that,Vortioxetine can antagonize 5-HT3 receptors except for binding to 5-HT transporters to inhibit 5-HT reabsorption,and it has a high binding rate to 5-HT3 receptors,the role of 5-HT3 receptor in the analgesic and antidepressant effects of Vortioxetine was further investigated by using a 5-HT3 receptor agonist SR 57227.MethodsIn the first part of the experiment,we used the animal model of spared nerve injury(SNI)to evaluate the chronic analgesic and depression preventive effects of Vortioxetine.Duloxetine was used as a positive drug control group(15mg / kg,i.g).Vortioxetine was administered in three increasing dosage groups(5 mg / kg,10 mg /kg,15 mg / kg,i.g).After a week of the surgery,the intragastrical administration of the drugs or vehicle began and last for two weeks.The pain threshold was measured with von Frey monofilament before the surgery,a week after the surgery and every two days during administration.After two weeks of administration,the animals were subjected to behavioral tests for voluntary activity and depression.Then the animals were killed and the lumber spinal cord,the prefrontal cortex and the hippocampus were harvested for molecular test.Western blot was used to examine the expression of astroglia marker GFAP and the microglia marker Iba-1,the secretory levels of proinflammatory cytokines TNF-a,IL-1?,IL-6,and the protein levels of the ERK-CREB-BDNF signaling pathway.Immunofluorescence was used to detect the distribution and morphological changes of microglia and astrocyte.In the second part of the experiment,the same model was used to explore the role of 5-HT3 receptor in the analgesic and anti-depressive effects of Vortioxetine.The experimental group was given intraperitoneal injection of 5-HT3 receptor agonist SR57227(10mg / kg,i.p)10 minutes before the intragastrical administration of Vortioxetine(15mg / kg,i.g).In addition,another four groups were included:SNI+Vortioxetine(15mg / kg,i.g)group,SNI+5-HT3 receptor agonist SR 57227(10mg / kg,i.p)group,SNI + vehicle group and sham operation group.The pain threshold,depression behavior and related molecular tests were measured in the same way as the first part of the experiment.ResultsResults of the first part of the experiment showed that,compared with the sham-operation group,the mechanical pain threshold of the SNI model group was significantly lower after surgery.Both Duloxetine and Vortioxetine could gradually increase the mechanical pain threshold during the two weeks.After two weeks of medicine administration,behavioral tests showed that both Duloxetine and Vortioxetine could improve the depressive behavior induced by SNI,and Vortioxetine reduced pain and depressive behaviors in a dose-dependent fashion.Compared with the sham-operation group,the SNI model group showed significant increased expression of the astroglia marker GFAP and the microglia marker Iba-1,and the immunofluorescence also showed an increasing density,cell size,and synaptic branches of the neuroglia.The levels of proinflammatory cytokines TNF-?,IL-1?,and IL-6 also elevated in SNI models.The changes of the proteins in ERK-CREB-BDNF signaling pathway were different in lumber spinal cord,prefrontal cortex,and hippocampus.In lumber spinal cord,the levels of p-ERK,p-CREB and BDNF were increased.The level of p-ERK was also increased in prefrontal cortex and hippocampus,but p-CREB and BDNF were decreased.Vortioxetine could significantly reverse these changes in SNI models does-dependently.Results of the second part of the experiment showed that,be administered 10 minutes before the administration of Vortioxetine,the 5-HT3 receptor agonist SR 57227 could hinder the analgesic and depression preventive effects of Vortioxetine on neuropathic pain model.The 5-HT3 receptor agonist SR57227 alone had no analgesic and antidepressant effects.At the molecular and cellular level,the 5-HT3 receptor agonist SR 57227 inhibited the alteration of astroglia and microglia activation,the secretory levels of proinflammatory cytokines TNF-?,IL-1?,IL-6 and of protein levels in ERK-CREB-BDNF signaling pathway induced by Vortioxetine in lumber spinal cord,the prefrontal cortex and the hippocampus.The 5-HT3 receptor agonist SR 57227 alone had no significant effect on these changes.ConclusionVortioxetine has a dose-dependent analgesic effect on chronic neuropathic pain induced by selective injury of the sciatic nerve branches in mice,and can prevent depression induced by chronic neuralgia.The expressions of GFAP,Iba-1,TNF-?,IL-1?,IL-6,p-ERK,p-CREB and BDNF were increased in lumbar spinal cord after nerve injury,which promoted the neuropathic pain.These changes in the spinal cord were reversed in a dose-dependent manner after the administration of Vortioxetine.It is possible that Vortioxetine attenuates the neuralgia by modulating inflammatoryresponse of the spinal cord and BDNF level.The decreases of p-CREB / CREB and BDNF in the prefrontal cortex and hippocampus may be the mechanisms of depression after neuropathic pain.Vortioxetine can prevent the depression behaviors by increasing the levels of p-CREB / CREB and BDNF in prefrontal cortex and hippocampus.BDNF is involved in the pathogenesis of neuropathic pain and depression,but the mechanism is different.When administered 10 minutes before the administration of Vortioxetine,the 5-HT3 receptor agonist SR 57227 can inhibit the antinociceptive and anti-depressive effects of Vortioxetine,and antagonize the regulation on neuroinflammation and BDNF expression of Vortioxetine in spinal cord,prefrontal cortex and hippocampus.The analgesic and anti-depressive effects of Vortioxetine on the SNI model are at least partially mediated by its antagonism to the 5-HT3 receptor.Vortioxetine may be a new option for the treatment of chronic neuropathic pain,especially those with depression.