Blockade D1-like And D2-like Dopamine Receptors Within Nucleus Accumbens Attenuate Hyperalgesia Responses In A 6-OHDA Induced Parkinson’s Disease Rat Model

Background: Pain is a high incidence of non-motor symptoms of Parkinson’s disease(PD),with a prevalence of 40% to 85%.However,the current studies of PD-related pain mechanisms demonstrate that the mechanism of pain is complex and not yet clear.To further investigate PD-related pain mechanisms,we investigated the role of the dopamine(DA)D1-like and D2-like receptors in the nucleus accumbens in the regulation of pain in a rat model of Parkinson’s disease induced by 6-OHDA.Materials and Methods: 120 male SD rats,weighing 180±10g.Randomly divided into Sham group and 6-OHDA model group,the bilateral substantia nigra(AP: 5.3 ML: ± 1.8 DV: 7.8)destroyed brain stereotaxic modeling.After three weeks of modeling,Rotarod test and open field test were used to evaluate motor function.The von Frey test and radiant heat test were conducted to evaluate mechanical and thermal pain thresholds,respectively.Immunohistochemistry was used to examine DA neurons in the substantia nigra pars compacta(SNc)and ventral tegmental area(VTA).HPLC was used to determine DA and DOPAC levels in NAc.Western Blot method to detect expression of DA receptor in nucleus accumbens,and further confirmed by immunofluorescence.The pain threshold was tested by cannula infusion(SCH-23390,Raclopride,GBR-12090,SKF-38393,Quinpirole,Pramipexole)Results: The experimental results of the rotarod showed that the time on the rod of model rats were decreased significantly,compared with the Sham group,which indicate the ability of balance of the model rats were impaired.The results of the open-field test showed that the total distance has no significant change between the model rats with Sham group,indicating that the ability of autonomous exercise of model rats was not significantly affected.The results of the pain threshold assay showed that the thresholds of mechanical and thermal pain were significantly decreased in the model rats,compared with the Sham group,indicating that the model rats had hyperalgesia.DAB results also showed that DA neurons in SNc lost and DA neurons in VTA had no changes.The results of HPLC showed that the DA and DOPAC transmitters in the nucleus accumbens also decreased significantly,but the metabolic rate of DA showed only an upward trend.The results of Western Blot showed that D1 and D2 receptors were up-regulated in nucleus accumbens,but there was no significant change in D3 receptor expression.Immunofluorescence showed that D1 and D2 receptors were expressed on neurons and were increase in NAc shell.Antagonists(SCH-23390 4?g and raclopride 4?g)could effectively alleviate the hyperalgesia in 6-OHDA-induced rats after administration of nucleus accumbens.There was no significant effect of agonists(SKF-38393 4?g,Quinpirole 4?g and Pramipexole 4?g)on hyperalgesia in 6-OHDA-induced rats.The effect of DA reuptake inhibitors(GBR-12090 0.26?g)on the hyperalgesia in 6-OHDA-induced rats was not obvious.Conclusion: Our data suggested that the decreased DA contents、D1-like receptors and D2-like receptors in the NAc may be involved in hyperalgesia in the 6-OHDA-induced rats,whereas the use of D1-like and D2-like receptor antagonists was effective in relieving pain.