| Parkinson’s disease(PD)is a neurodegenerative disease and characterized by motor symptoms.More recently,non-motor symptoms of PD,i.e.pain,depression and anxiety,and learning and memory dysfunction,have gradually attracted the attention of scientific researchers and clinicians.As one of non-motor symptoms,pain has high prevalence and early onset of feature.Our previous research has shown that in rats with early-stage PD,no significant changes in both mechanical and heat pain threshold were found.While,increased endogenous descending facilitation and decreased endogenous descending inhibition on pain were observed.Inadequate activity of dopamine receptor in the thalamic mediodorsal(MD)nucleus and ventromedial(VM)nucleus play roles in increased endogenous descending facilitation and decreased endogenous descending inhibition,respectively.In the present study,spontaneous pain behavior evoked by intramuscular injection with formalin,noxious mechanical and heat evoked paw withdrawal reflexes were observed to investigate the potential changes in endogenous modulation of pain in early-stage PD rats.Learning and memory abilities were evaluated in PD rats by water maze experiment;emotional changes in PD rats were evaluated by elevated cross arm test.Effects of thalamic dopamine D3 receptor activity on endogenous descending modulation of pain,emotion,learning and memory were explored in PD rats.Objective:1.To explore the changes of endogenous descending modulation of pain in early-stage PD model rats induced by unilateral intrastriatal injection of 6-OHDA.2.To explore the cognitive and emotional changes in early-stage PD model rats.3.To explore the effects of dopamine D3 receptors in the thalamic MD/VM nucleus on descending modulation of pain in PD rats.4.To explore the roles of dopamine D3 receptors in the thalamic VM and MD nuclei in emotion,learning and memory in a rat model of PD.Methods:1.The rat model of early PD was induced by unilateral microinjection of 3μl 6-OHDA(a dose of 6μg of 6-OHDA diluted in 3μl of 0.9%saline with 0.2 %ascorbic acid)into striatum.2.Dopamine D3 receptor agonists of 0.5-4.5nmol/0.5μl of SK609 or 0.5μl normal saline were injected into the thalamic MD/VM nucleus,respectively.Mechanical and heat evoked paw withdrawal reflexes were observed bilaterally 30 min,1-4h and 1day after intracerebral injection.3.Learning and memory abilities were evaluated in PD rats by water maze search latency;emotional changes in PD rats were evaluated by changes in percentage of open arm residence time.4.25μl 2.5% formalin was injected into gastrocnemius muscle to induce persistence muscle pain.Numbers of spontaneous flinches were observed,mechanical and heat evoked paw withdrawal reflexes were observed bilaterally 30 min,1-4h and 1day after intramuscular injection.5.Twenty minutes prior to intramuscular injection of formalin,4.5nmol of SK609 or0.5μl normal saline was injected into the thalamic MD/VM nucleus.Numbers of spontaneous flinches were observed,mechanical and heat evoked paw withdrawal reflexes were evaluated bilaterally 30 min,1-4h and 1day after intramuscular injection.6.Twenty minutes prior to elevated cross arm test,4.5nmol of SK609 or 0.5μl normal saline was injected into the thalamic MD/VM nucleus.Changes in percentage of staying time at open arm were observed.Results:1.Unilateral striatal microinjection of 6-OHDA in rats was used to establish an early PD model.No significant changes in bilateral mechanical and heat evoked paw withdrawal reflexes were observed(P > 0.05).2.No significant changes in bilateral mechanical and heat evoked paw withdrawal reflexes were observed following microinjection of different doses of dopamine D3 receptor agonist SK609 into the thalamic MD and VM nucleus in PD rats.3.No significant differences were found in the water maze search latency in PD rats compared to naive rats and sham lesioned rats(P > 0.05).No significant differences in the times of crossing the original platform and time in searching platform were found among the three groups(P > 0.05).4.In elevated cross maze experiment,the percentage of open arm residence time in PD rats decreased significantly(P < 0.05).Microinjection of D3 receptor agonist SK609 into the thalamic MD nucleus significantly increased the percentage of open arm retention time in PD rats(P < 0.05).5.Intramuscular injection of 25μl 2.5% formalin into gastrocnemius muscle muscle can induce spontaneous pain behavior in rats,which is manifested as a biphasic paw flinching behavior on the injection side: first phase(0-10 minutes)and the second phase(10-60 minutes)in both naive rats and sham lesioned rats,with a rest period of about 5-10 minutes between the two phases,during which no significant limb flinching behavior was observed.In PD rats,a significant increase in the number of limb flinches was observed in phase 1 and phase 2(P < 0.05).A inter-phase(5-10minutes)spontaneous pain behavior between the first and second phases was observed,significant prolonged spontaneous pain duration was found in PD rats(70-75 minutes).6.After intramuscular injection of formalin,mechanical hyperalgesia and heat hypoalgesia were observed in PD rats as well as na(?)ve rats and sham lesioned rats,no significant differences were found among the groups(P > 0.05).7.Microinjection of dopamine D3 receptor agonist SK609 into the MD nucleus of PD rats20 minutes before intramuscular injection of formalin significantly depressed the intramuscular injection of formalin induced spontaneous pain behavior in first phase,inter-phase and second phase(P < 0.05),and significantly shorten the duration of spontaneous pain behavior.Activation of dopamine D3 receptors in the MD nucleus significantly depressed bilateral mechanical hyperalgesia 1-4 hours following intramuscular injection of formalin(P < 0.05).8.Microinjection of SK609 into the VM nucleus in PD rats significantly reduced the intramuscular injection of formalin induced spontaneous pain behavior in the late-stage of second phase(P < 0.05),and significantly increased the bilateral paw withdrawal thermal latency 1-4 hours after intramuscular injection of formalin(P <0.05).Conclusion:1.Early-stage PD model elicited by microinjection of a dose of 6μg of 6-OHDA diluted in3μl of 0.9%saline with 0.2 %ascorbic acid into the unilateral striatum in rats was established.No significant changes in mechanical and thermal pain thresholds and no memory impairment were found in early-stage PD model rats,anxiety in early-stage PD model rats was observed.2.In early-stage PD model rats,enhanced descending facilitation and weakened descending inhibition of nociception manifested were found.3.The activation of dopamine D3 receptors in the thalamic MD and VM nucleus exhibited different effects on descending modulation of nociception;weaken descending facilitation and enhanced descending inhibition,respectively.4.Dopamine D3 receptors in the thalamic MD nucleus play important roles in the generation of anxious emotion in PD rats. |
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