Anterior Cingulate Cortex Modulating The Nociception Of Spinal In CCI Rats

Chronic pain has an severe effect on patient’s normal life physically and psychologically.It is not only accompanied by unpleasant sensory,but also accompanied by anxiety,fear,depression and other negative emotional experience.Clinically more than 30% of patients with chronic pain are often associated with severe emotional distress.The strong emotional response is also a significant difference between the pain and the other stimuli to body.The clinical study showed that adverse emotional experience is one of the important fact associated with persistent pain or even increased the feeling of pain.Therefore,revealing the underlying mechanism of the influence of the negative emotions of pain and to find a solution to relief pain seems very important today.As well known,the primary regulatory center of pain is in the spinal cord,where the nociceptive receptors project harmful signals into the dorsal horn of the spinal cord,which is then transmitted to the somatosensory cortex of the brain through the thalamus.The nociceptive information of the spinal cord is regulated by supra-spinal center.The supraspinal center modulate spinal nociceptive transmission through two different system: endogenous descending inhibition and facilitation system.Recent studies show that the stimulation of chronic pain can lead to enhanced activity of the the descending facilitation,which may be the mechanism of the maintenance and development of chronic pain.It indicate that descending facilitatory modulation is probably a importan mechanism to the occurrence and maintenance of neuropathic pain.Anterior cingulate cortex(ACC)is an important part of the limbic system and the highlevel center of brain.Previous studies have found that ACC plays an important role in human cognitive function,memory and attention control.Recently,it also has been proved that ACC is the high-level center of pain regulation,which is mainly involved in the mechanism of the emotional component part of pain.ACC has extensive fiber projection to the nucleus of the cerebral cortex,thalamus,locus ceruleus and etc,which receives all kinds of information from sub-cortex and always activated by peripheral noxious stimuli.Though the adequate data has been collected that ACC modulate sensatory and emotional component of pain.The research on how the ACC transmits nociceptive information and then how it regulates spinal nociception has little known.So here comes the question : how the ACC modulate nociceptive information in the spinal cord.We investigated the possible mechanism of ACC modulate nociceptive information in spinal cord with chronic constrictive injury(CCI)rats.1.Establishment of a rat pain-depression / anxiety comorbidity modelThe CCI model is the most commonly used models of neuropathic pain,which is the classical model of chronic pain.In the pre-experiment,two weeks after CCI the paw withdrawal mechanical threshold(PWMT)and paw withdrawal thermal latency(PWTL)of rats were significantly decreased,rats spent less time in the light compartment and number of transition were decreased.The immobility time in forced swimming test(FST)were also significantly prolonged,reflect the rats showed anxiety emotion.There is no significant difference between four weeks and two weeks after CCI in the test of PWMT,PWTL and anxiety emotion.So two weeks after CCI rats be used as the model of pain-anxiety comorbidity rat model in the following experiment.2.Use of antidepressants can reduce the pain of CCI ratsThe PWMT and PWTL of CCI rats were significantly decreased,rats spent less time in the light compartment and number of transition were decreased.The immobility time in FST were also significantly prolonged,reflect the rats showed both hyperalgesia and anxietydepression emotion.The expression of cAMP-response element binding protein(pCREB)and extracellular regulated protein kinases(pERK)increased significantly in ACC in CCI group.The expression of pCREB,pERK in spinal cord was increased in CCI group.Two weeks after CCI before the behavioral test rats were given analgesics tramadol,showed less hyperalgesia.The expression of pCREB,pERK in spinal cord was decreased.Two weeks after CCI before the behavioral test rats were given antidepressant paroxetine,showed less hyperalgesia and anxiety-depression emotion.The expression of pCREB,pERK in spinal cord was decreased.The expression of pCREB,pERK in ACC was decreased.3.Anterior cingulated cortex modulating the nociception of spinalACC is an important center for the regulation of emotional component part of pain.Excitatory amino acids,especially glutamate,play a key role in the excitatory synaptic transmission of ACC.The N-methyl-D-aspartic acid receptor(NMDA)is a necessary mechanism for the generation of emotional component part of pain.On the 13 th day after CCI,we injected NMDA receptor antagonist AP-5 into the nucleus of ACC,which could inhibit the anxiety and depression behavior of rats after chronic pain caused by CCI,at the same time the mechanical hyperalgesia of CCI rats was also relieved.The expression of pCREB,pERK in spinal cord was decreased in CCI group.The expression of pCREB,pERK in ACC was decreased in CCI group.This may suggest that ACC is involved in the regulation of nociceptive information transmission in spinal cord.4.Endogenous descending facilitatory system contribute to ACC modulating spinal nociceptive transmssionDescending facilitatory system including ACC,hypothalamus,central amygdaloid nucleus,periaqueductal gray(PAG),rostral ventromedial nucleus(RVM),the nucleus of the solitary tract and the dorsal reticular nucleus structure.CCI rats showed both hyperalgesia and anxiety-depression emotion,the fos expression in ACC,PAG,RVM and dorsal horn of spinal cord increased in the corresponding time points.The fos expression in ACC,PAG,RVM and dorsal horn of spinal cord increased in the corresponding time points.Two weeks after CCI before the behavioral test rats were given antidepressant paroxetine,showed less hyperalgesia and anxiety-depression emotion.The fos expression in ACC,PAG,RVM and dorsal horn of spinal cord was decreased.On the 13 th day after CCI,NMDA receptor antagonist AP-5 were injected into the nucleus of ACC,rats showed less hyperalgesia and anxiety-depression emotion.The fos expression in ACC,PAG,RVM and dorsal horn of spinal cord was decreased.This may suggest that endogenous descending facilitatory system contribute to ACC modulating spinal nociceptive transmission.Taken together,in the CCI model,rats showed pain-anxiety / depression comorbidity.ACC is involved in the regulation of nociceptive information transmission in spinal cord.Endogenous descending facilitatory system take part in ACC modulating spinal nociceptive transmission.