| Objective:Pain responses can be altered in dementia from clinical investigations. According to these results from clinical studies indicate that patients with Alzheimer's disease have been shown to receive fewer analgesics and report less clinical pain than cognitively intact peers with similar situations of pain, it could aggravated patients'depression and sleep disturbance. This under-treatment could lead to heavier care demands and increased unpleasant patients. In this preclinical study, we examined the relationship between cognitive impairment and nociceptive behaviors. Our results also suggest that a preclinical model of combined memory impairment and persistent nociception may be useful to provide the method of clinical treatment.Methods:1. A solution with mixed Aβ1-40/1-42 (10μg/5μl) was injected into the CA1 area of rat's hippocampus bilaterally to induced cognitive impairment similar to that seen in rat models of Alzheimer's disease (AD).2. The evaluation of motor function.3. Morris Water maze task.4. Inflammatory nociception was produced in these rats by injecting 50μl of complete Freund's adjuvant (CFA) into the right tibio-tarsal joint. The withdrawn threshold to thermal and mechanical stimulation was examined.5. To further explore the relationship between cognitive impairment and nociceptive behavior, inflammatory nociception was produced in these rats by injecting 50μl of complete Freund's adjuvant (CFA) into the right tibio-tarsal joint. 6. cycloheximide (a protein synthesis inhibitor) was injected into the hippocampus to disrupt the memory of prior nociception induced by the CFA injection into the right tibio-tarsal joint.7. The latency was tested by Morris Water maze task. The withdrawn threshold to thermal and mechanical stimulation was examined.8. Expression of Aβ, ChaT, NMDAR1 and PKCγat CA1 area of the hippocampus and spinal cord were examined by immunohistochemistry.9. Expression of Aβ,ChaT,NMDAR1 and PKCγat CA1 area of the hippocampus,thalamus, basal ganglia, amygdale, and spinal cord were examined by immunohistochemistry.Results:1. All rats undergo ACSF or Aβinjection exhibited normal gait (score 0) during the whole experiment.2. Rats of AD group needed a significantly longer time to find the platform than rats of ACSF group and and Na?ve group did during the Morris water maze.3. Rats with CFA injection showed decreased paw withdrawal latency on the ipsilateral hindpaw to thermal stimuli and mechanical stimulation. The ANOVA test showed significant difference between AD/CFA group and AD/vehicle group and ACSF/CFA group and AD/CFA group.4. Rats of cycloheximide group spent longer time to find the platform than that of saline group.5. Compared with saline group, the thermal and mechanical threshold was increased on ipsilateral hindpaw in cycloheximide group.6. Results of immunohistochemistry: The increased Aβimmunoreactivity was detected in the hippocampus of AD rats, whereas it was barely detectable in the na?ve rats and ACSF rats'hippocampus. ChaT immunoreactivity was decreased on the contralateral hippocampus in the AD groups as compared with the other groups. Upregulation of NMDAR1 expression on the contralateral hippocampus of CFA-injected group was observed, but AD/CFA group has attenuated NMDAR1 expression as compared with ACSF/CFA group. The expression of PKCγwas distinct increased within CFA-injected group, whereas AD group had lesser increase than ACSF group.7. Results of Western Blot: The expression of Aβwas consistent with the immunoreactivity results. The results from Wetsern blot showed the substantial downregulation of ChaT expression on the contralateral hippocampus, thalamus, basal ganglia and amygdale in all AD groups as compared with na?ve and all ACSF groups. Upregulation of NMDAR1 expression was observed on the contralateral hippocampus, thalamus, basal ganglia and amygdale in both ACSF/CFA and AD/CFA group as compared with their own corresponding vehicle group, but AD/CFA group has attenuated NMDAR1 expression as compared with ACSF/CFA group. The expression of PKCγwas distinct increased within the contralateral hippocampus, thalamus, basal ganglia and amygdale in both ACSF/CFA and AD/CFA group as compared with corresponding vehicle group, whereas AD group had lesser increase than ACSF group.Conclusions:1. Cognitive impairment plays a significant role in nociceptive behavior. Rats with cognitive impairment were less sensitive to nociceptive thermal and mechanical stimulation than normal rats.2. Cycloheximide is a protein synthesis inhibitor, can block or disrupt memory consolidation. The cycloheximide injection significantly diminished nociceptive behaviors as compared with control rats.3. These data indicate that rats with cognitive impairment under pain stuation, the Aβand CFA injection induced the upregulation of Aβ, N-methyl-D-aspartate receptor (NR1) and protein kinase Cγ(PKCγ), but downregulation of choline acetyl transferase (ChaT), within the contralateral hippocampus, thalamus, basal ganglia, and amygdale, and ipsilateral spinal cord. We provide reasonable and precise information of combined memory impairment and persistent nociception to clinical treatment. |
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