Downregulation of miR-219 enhances brain-derived neurotrophic factor production in mouse dorsal root ganglia to mediate morphine analgesic tolerance by upregulating CaMKIIγ.
Increasing evidence suggests that microRNAs are functionally involved in the initiation and maintenance of pain hypersensitivity, including chronic morphine analgesic tolerance, through the posttranscriptional regulation of pain-related genes. We have previously demonstrated that miR-219 regulates inflammatory pain in the spinal cord by targeting calcium/calmodulin-dependent protein kinase II gamma (CaMKIIγ). However, whether miR-219 regulates CaMKIIγ expression in the dorsal root ganglia to mediate morphine tolerance remains unclear.



MiR-219 expression was downregulated and CaMKIIγ expression was upregulated in mouse dorsal root ganglia following chronic morphine treatment. The changes in miR-219 and CaMKIIγ expression closely correlated with the development of morphine tolerance, which was measured using the reduction of percentage of maximum potential efficiency to thermal stimuli. Morphine tolerance was markedly delayed by upregulating miR-219 expression using miR-219 mimics or downregulating CaMKIIγ expression using CaMKIIγ small interfering RNA. The protein and mRNA expression of brain-derived neurotrophic factor were also induced in dorsal root ganglia by prolonged morphine exposure in a time-dependent manner, which were transcriptionally regulated by miR-219 and CaMKIIγ. Scavenging brain-derived neurotrophic factor via tyrosine receptor kinase B-Fc partially attenuated morphine tolerance. Moreover, functional inhibition of miR-219 via miR-219-sponge in naive mice elicited thermal hyperalgesia and spinal neuronal sensitization, which were both suppressed by CaMKIIγ small interfering RNA or tyrosine receptor kinase B-Fc.



These results demonstrate that miR-219 contributes to the development of chronic tolerance to morphine analgesia in mouse dorsal root ganglia by targeting CaMKIIγ and enhancing CaMKIIγ-dependent brain-derived neurotrophic factor expression.
Department of Pain Medicine, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China Jiangsu Province Key Laboratory of Anesthesiology and Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Shanghai Medical College, Shanghai, China Institutes of Brain Science, Brain Science Collaborative Innovation Center, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China.
Xue-Ming
XM
Hu
Jiangsu Province Key Laboratory of Anesthesiology and Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China Department of Anesthesiology, Qilu Children's Hospital of Shandong University, Ji'nan, China.
Shou-Bin
SB
Cao
Jiangsu Province Key Laboratory of Anesthesiology and Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China.
Hai-Long
HL
Zhang
Department of Pharmacology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
Dong-Mei
DM
Lyu
Department of Pain Medicine, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China Jiangsu Province Key Laboratory of Anesthesiology and Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China.
Li-Ping
LP
Chen
Department of Pain Medicine, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China Jiangsu Province Key Laboratory of Anesthesiology and Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China.
Heng
H
Xu
Jiangsu Province Key Laboratory of Anesthesiology and Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China.
Zhi-Qiang
ZQ
Pan
Department of Pain Medicine, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China Jiangsu Province Key Laboratory of Anesthesiology and Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China shenwen19962@163.com zhiqiangp2002@aliyun.com.
Wen
W
Shen
D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D050882:CREB-Binding Protein / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004361:Drug Tolerance / Q000502:physiology*; D005620:Freund's Adjuvant / Q000633:toxicity; D005727:Ganglia, Spinal / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009020:Morphine / Q000494:pharmacology*; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
D000701:Analgesics, Opioid; D019208:Brain-Derived Neurotrophic Factor; C000609357:MIRN219 microRNA, mouse; D035683:MicroRNAs; D016760:Proto-Oncogene Proteins c-fos; D034741:RNA, Small Interfering; D009020:Morphine; D005620:Freund's Adjuvant; D050882:CREB-Binding Protein; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
CaMKIIγ; Morphine tolerance; brain-derived neurotrophic factor; dorsal root ganglia; hyperalgesia; miR-219