&nbsp;N-methyl-D-aspartic acid receptor/MAPK/cAMP-response element binding protein pathway mediating pain-related aversion in anterior cingulate cortex

ZHANG Ya-Qing; JI Wei-Zhong; WANG Ling

doi:10.16098/j.issn.0529-1356.2023.05.003

PDF(10656 KB)

Acta Anatomica Sinica ›› 2023, Vol. 54 ›› Issue (5) : 512-520. DOI: 10.16098/j.issn.0529-1356.2023.05.003

N-methyl-D-aspartic acid receptor/MAPK/cAMP-response element binding protein pathway mediating pain-related aversion in anterior cingulate cortex

ZHANG Ya-qing¹JI Wei-zhong^2* WANG Ling³

Author information +

History +

Abstract

Objective To explore the mechanism of N-methyl-D-aspartic acid (NMDA）receptor/MAPK/cAMP-response element binding protein (CREB) pathway involved in pain-related aversion mediated by anterior cingulate cortex. Methods A total of 42 healthy SD rats were randomly divided into control group (Ctrl), normal saline(NS) injection group (NS), complete freund adjuvant (CFA) model group(CFA), injected CFA into the soles of the foot and injected NS into rostral part of anterior cingulate cortex (rACC)group (CFA+NS), injected NS into the soles of the foot and injected NS into rACC group (NS+NS), injected CFA into the soles of the foot and injected NMDA receptor antagonist (APⅤ) into rACC group (CFA+APⅤ), injected NS into the soles of the foot and injected APⅤ into rACC group (NS+APⅤ) with 6 rats in each group. Rats avoidance score was analysised and rat thermal foot contraction latency (PWL) ws alserved, the expression of NMDA receptor in rACC region was detected by immunohistochemical staining, the expression of NMDA receptor, phosphorylated ERK(p-ERK) and phosphorylated CREB(p-CREB) in rACC region was detected by immunofluorescent staining, the number of Nissl bodies in rACC region was observed by Nissl staining, and the expression of NMDA receptor, MAPK, CREB, ERK, p-ERK, p-CREB, synaptosomal-associated protein 25 interaction protein 30 (SIP30) protein in rACC region was detected by Western blotting, and Real-time PCR was used to detect the mRNA expression of NMDA receptor, MAPK, CREB and ERK in the rACC region. Results Compared with the Ctrl group, the avoidance score and PWL decreased significantly and the expression of NMDA receptor, MAPK and CREB increased significantly in the CFA group (P<0.05). Compared with the CFA+NS group, the number of Nissl bodies in CFA+APⅤ and NS+APⅤ groups increased significantly, while the expression of NMDA receptor, MAPK, CREB, p-ERK and p-CREB decreased significantly in NS+NS and NS+APⅤ groups (P<0.05). Conclusion NMDA receptor-MAPK-CREB signal pathway in rACC is involved in pain-related aversion, and inhibition of NMDA can reduce pain-related negative aversion.

Key words

Rostral anterior cingulate cortex

/ Conditional position avoidance / N-methy1-D-aspartic acid receptor / Pain-related aversion / Western blotting / Rat

Cite this article

EndNote

Ris (Procite)

Bibtex

Download Citations

ZHANG Ya-qing JI Wei-zhong WANG Ling.

N-methyl-D-aspartic acid receptor/MAPK/cAMP-response element binding protein pathway mediating pain-related aversion in anterior cingulate cortex

[J]. Acta Anatomica Sinica. 2023, 54(5): 512-520 https://doi.org/10.16098/j.issn.0529-1356.2023.05.003

References

［1］Fang F, Shao XM, Shen Z, et al. Comparisons of expression of phosphorylated extracellular signal-regulated kinase in different levels of anterior cingulate cortex in the rat with neuropathic pain ［J］. Acta Anatomica Sinica, 2014, 45(5): 610-615. (in Chinese)

方芳, 邵晓梅, 沈醉, 等. 神经病理痛模型大鼠前扣带皮层不同水平磷酸化细胞外信号调节激酶表达差异比较［J］. 解剖学报, 2014, 45(5): 610-615.

［2］Meda KS, Patel T, Braz JM, et al. Microcircuit mechanisms through which mediodorsal thalamic input to anterior cingulate cortex exacerbates pain related aversion ［J］. Neuron, 2019, 102(5):944-959.

［3］Cimpean A, David D. The mechanisms of pain tolerance and pain-related anxiety in acute pain ［J］. Health Psychol Open, 2019, 6(2):2055102919865161.

［4］Jarrin S, Pandit A, Roche M, et al. Differential role of anterior cingulate cortical glutamatergic neurons in pain-related aversion learning and nociceptive behaviors in male and female rats ［J］. Front Behav Neurosci, 2020, 14:139.

［5］Shi Y, Yao S, Shen Z, et al. Effect of electroacupuncture on pain perception and pain-related affection: dissociation or interaction based on the anterior cingulate cortex and S1 ［J］. Neural Plast, 2020, 2020:8865096.

［6］Xiao X, Yang Y, Zhang Y, et al. Estrogen in the anterior cingulate cortex contributes to pain-related aversion ［J］. Cereb Cortex, 2013, 23(9): 2190-2203.

［7］Guan XY. Studies on the mechanism of NMDA receptor mediating the affective pain in the anterior cingulate cortex ［D］. Taiyuan: Shanxi Medical University, 2019. (in Chinese)

关晓雅. NMDA受体在前扣带皮层介导痛相关情绪的机制研究［D］.太原：山西医科大学, 2019.

［8］Li TT, Ren WH, Xiao X, et al. NMDA NR2A and NR2B receptors in the rostral anterior cingulate cortex contribute to pain-related aversion in male rats ［J］. Pain, 2009, 146(1-2):183-193.

［9］Tang YL, Zhang YQ. Molecular mechanisms of NMDA receptor-MAPK-CREB pathway underlying the involvement of the anterior cingulate cortex in pain-related aversion ［J］. Acta Physiologica Sinica, 2017, 69(5):637-646. (in Chinese)

唐雨龙, 张玉秋. 前扣带皮层NMDA受体-MAPK-CREB通路参与痛厌恶情绪的分子机制［J］. 生理学报, 2017, 69(5):637-646.

［10］Wang X, Zhang L, Zhan Y, et al. Contribution of BDNF/TrkB signalling in the rACC to the development of pain-related aversion via activation of ERK in rats with spared nerve injury ［J］. Brain Res, 2017, 1671:111-120.

［11］Fenu S, Spina L, Rivas E, et al. Morphine-conditioned single-trial place preference: role of nucleus accumbens shell dopamine receptors in acquisition, but not expression ［J］. Psychopharmacology (Berl), 2006, 187(2):143-153.

［12］Hargreaves K, Dubner R, Brown F, et al. A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia ［J］. Pain, 1988, 32(1):77-88.

［13］Wang Y. Observation on the role of NMDA receptors in the formation of painful emotions in anterior cingulate cortex neurons ［D］. Taiyuan : Shanxi Medical University, 2016. (in Chinese)

王媛.前扣带皮层神经元NMDA受体在痛情绪形成中的作用观察［D］.太原：山西医科大学, 2016.

［14］Chaplan SR, Bach FW, Pogrel JW, et al. Quantitative assessment of tactile allodynia in the rat paw ［J］. J Neurosci Methods，1994, 53(1):55-63.

［15］Cui Y, Shi H, Ma ZhL, et al. Effects of special CaMKⅡ inhibitor m-AIP on sensory-discriminative and affective-motivational pain responses in chronic constriction injury of sciatic nerve rats ［J］. Chinese Journal of Behavioral Medicine and Brain Science, 2013,(7): 581-583. (in Chinese)

崔银, 石寒, 马正良, 等. 鞘内注射m-AIP对坐骨神经结扎大鼠疼痛感觉分辨和情绪体验的影响［J］.中华行为医学与脑科学杂志, 2013，(7): 581-583.

［16］Zhang L. The role of BDNF expression in rACC neurons in neuropathic pain-related aversive emotions and related mechanisms ［D］. Ji’nan: Shandong University, 2017. (in Chinese)

张乐. rACC神经元中BDNF的表达在神经病理性痛相关厌恶情绪中的作用及相关机制研究［D］.济南：山东大学, 2017.

［17］Ding Y, Shi W, Xie G, et al. CX3CR1 mediates nicotine withdrawal-induced hyperalgesia via microglial p38 MAPK signaling ［J］. Neurochem Res,2015, 40(11): 2252-2261.

［18］Navratilova E, Nation K, Remeniuk B, et al. Selective modulation of tonic aversive qualities of neuropathic pain by morphine in the central nucleus of the amygdala requires endogenous opioid signaling in the anterior cingulate cortex ［J］. Pain, 2020, 161(3):609-618.

［19］Xu Z, Fang J, Xiang X, et al. Electroacupuncture alleviates pain-related emotion by upregulating the expression of NPS and its receptor NPSR in the anterior cingulate cortex and hypothalamus ［J］. Evid Based Complement Alternat Med, 2020, 2020:8630368.

［20］McIlwrath SL, Montera MA, Gott KM, et al. Manganese-enhanced MRI reveals changes within brain anxiety and aversion circuitry in rats with chronic neuropathic pain-and anxiety-like behaviors ［J］. Neuroimage, 2020, 223:117343.

［21］Feng H, Chen Z, Wang G, et al. Effect of the ifenprodil administered into rostral anterior cingulate cortex on pain-related aversion in rats with bone cancer pain ［J］. BMC Anesthesiol, 2016, 16(1):117.

［22］Han M, Xiao X, Yang Y, et al. SIP30 is required for neuropathic pain-evoked aversion in rats ［J］. J Neurosci, 2014, 34(2):346-355.

［23］Wang X, Liu Y, Zhang H, et al. Sinomenine alleviates dorsal root ganglia inflammation to inhibit neuropathic pain via the p38 MAPK/CREB signalling pathway ［J］. Eur J Pharmacol, 2021, 897:173945.

［24］Ruan JP, Chen L, Ma ZL. Activation of spinal extacellular signal-regulated kinases and c-jun n-terminal kinase signaling pathways contributes to morphine- induced acute and chronic hyperalgesia in mice ［J］. J Cell Biochem, 2019, 120(9):15045-15056.