Cellular and Molecular Mechanisms of Calcium/Calmodulin-Dependent Protein Kinase II in Chronic Pain

Zhou, Ya‐Qun; Liu, Dai-Qiang; Chen, Shuping; Sun, Jia; Zhou, Xiong; Luo, Fang; Tian, Yuan; Ye, Dawei

doi:10.1124/jpet.117.243048

Cited by 42 publications

(26 citation statements)

References 99 publications

(93 reference statements)

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“…Currently, the World Health Organization (WHO) analgesic ladder remains the golden standard for the management of CIBP in clinic [3] , [4] . However, current therapeutic strategies often provided inadequate pain relief and are associated with numerous unavoidable side effects which limit their prolonged application [5] , [6] . Despite marked advance has been made regarding the mechanisms of CIBP, few effective drugs has been developed for the management of CIBP in the past decades.…”

Section: Introductionmentioning

confidence: 99%

Reactive oxygen species scavengers ameliorate mechanical allodynia in a rat model of cancer-induced bone pain

et al. 2018

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Cancer-induced bone pain (CIBP) is a frequent complication in patients suffering from bone metastases. Previous studies have demonstrated a pivotal role of reactive oxygen species (ROS) in inflammatory and neuropathic pain, and ROS scavengers exhibited potent antinociceptive effect. However, the role of spinal ROS remains unclear. In this study, we investigated the analgesic effect of two ROS scavengers in a well-established CIBP model. Our results found that intraperitoneal injection of N-tert-Butyl-α-phenylnitrone (PBN, 50 and 100 mg/kg) and 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (Tempol, 100 and 200 mg/kg) significantly suppressed the established mechanical allodynia in CIBP rats. Moreover, repeated injection of PBN and Tempol showed cumulative analgesic effect without tolerance. However, early treatment with PBN and Tempol failed to prevent the development of CIBP. Naive rats received repetitive injection of PBN and Tempol showed no significant change regarding the nociceptive responses. Finally, PBN and Tempol treatment notably suppressed the activation of spinal microglia in CIBP rats. In conclusion, ROS scavengers attenuated established CIBP by suppressing the activation of microglia in the spinal cord.

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Section: Introductionmentioning

confidence: 99%

Reactive oxygen species scavengers ameliorate mechanical allodynia in a rat model of cancer-induced bone pain

et al. 2018

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“…35–37 The activation of CAMKII was proven to participate in cyclic adenosine monophosphate response element-binding protein (CREB) phosphorylation. 38,39 The activated CaMKII/CREB pathway has been extensively confirmed in different pain models. 28,40,41 In an inflammatory pain model, sinomenine was reported to attenuate mechanical allodynia and thermal hyperalgesia by down-regulating the CAMKII/CREB pathway.…”

Section: Introductionmentioning

confidence: 99%

Sinomenine attenuates cancer-induced bone pain via suppressing microglial JAK2/STAT3 and neuronal CAMKII/CREB cascades in rat models

et al. 2018

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Cancer-induced bone pain is one of the most severe types of pathological pain, which often occurs in patients with advanced prostate, breast, and lung cancer. It is of great significance to improve the therapies of cancer-induced bone pain due to the opioids’ side effects including addiction, sedation, pruritus, and vomiting. Sinomenine, a traditional Chinese medicine, showed obvious analgesic effects on a rat model of chronic inflammatory pain, but has never been proven to treat cancer-induced bone pain. In the present study, we investigated the analgesic effect of sinomenine after tumor cell implantation and specific cellular mechanisms in cancer-induced bone pain. Our results indicated that single administration of sinomenine significantly and dose-dependently alleviated mechanical allodynia in rats with cancer-induced bone pain and the effect lasted for 4 h. After tumor cell implantation, the protein levels of phosphorylated-Janus family tyrosine kinase 2 (p-JAK2), phosphorylated-signal transducers and activators of transcription 3 (p-STAT3), phosphorylated-Ca2+/calmodulin-dependent protein kinase II (p-CAMKII), and phosphorylated-cyclic adenosine monophosphate response element-binding protein (p-CREB) were persistently up-regulated in the spinal cord horn. Chronic intraperitoneal treatment with sinomenine markedly suppressed the activation of microglia and effectively inhibited the expression of JAK2/STAT3 and CAMKII/CREB signaling pathways. We are the first to reveal that up-regulation of microglial JAK2/STAT3 pathway are involved in the development and maintenance of cancer-induced bone pain. Moreover, our investigation provides the first evidence that sinomenine alleviates cancer-induced bone pain by inhibiting microglial JAK2/STAT3 and neuronal CAMKII/CREB cascades.

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“…It has been reported that increased intracellular calcium concentration ([Ca 2+ ] i ) is a key contributing to neuropathic pain . Thus, we investigated whether ERK gene silence alters [Ca 2+ ] i in DRG neurons by performing calcium imaging.…”

Section: Resultsmentioning

confidence: 99%

Gene therapy by lentivirus‐mediated RNA interference targeting extracellular‐regulated kinase alleviates neuropathic pain in vivo

Jia

Yang

et al. 2018

J of Cellular Biochemistry

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Backgrounds Neuropathic pain is an abnormal pain, which is related to the activation of extracellular‐regulated kinase (ERK) signaling. This study was to investigate the effects of ERK knockdown via lentivirus‐mediated RNA interference on allodynia in rats with chronic compression of the dorsal root ganglia (DRG) and to uncover the potential mechanisms. Methods The model of chronic compression of the dorsal root ganglia (CCD) was established in rats by surgery. Gene silence was induced by injecting rats with lentivirus expressing ERK short hairpin RNA (shRNA). Behavioral test was performed by calculating paw withdrawal mechanical threshold (PWMT) and thermal paw withdrawal latency (TPWL). Results We firstly generated lentivirus expressing ERK shRNA to downregulate ERK gene expression both in vitro and in vivo by using Western blot analysis and quantitative reverse transcription polymerase chain reaction. In CCD, ERK mRNA, and protein levels in DRG neurons were dramatically increased, accompanied with decreased PWMT and TPWL. Lentivirus‐mediated RNA interference decreased ERK gene expression in DRG neurons and normalized the PWMT and TPWL in CCD rats, but not in rats infected with lentivirus expressing negative control shRNA. Further, calcium responses of DRG neurons to the hypotonic solution and 4α‐phorbol 12,13‐didecanoate were enhanced in CCD rats, which were suppressed by lentivirus‐mediated ERK gene silence. Finally, the levels of transient receptor potential vanilloid 4 gene expressions in DRG neurons and L4 to L5 spinal cord isolated from CCD rats were dramatically upregulated, which were reversed by lentivirus‐mediated ERK gene knockdown. Conclusion Lentivirus‐mediated RNA interference (RNAi) silencing targeting ERK might reverse CCD‐induced neuropathic pain in rats through transient receptor potential vanilloid 4.

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Cellular and Molecular Mechanisms of Calcium/Calmodulin-Dependent Protein Kinase II in Chronic Pain

Cited by 42 publications

References 99 publications

Reactive oxygen species scavengers ameliorate mechanical allodynia in a rat model of cancer-induced bone pain

Reactive oxygen species scavengers ameliorate mechanical allodynia in a rat model of cancer-induced bone pain

Sinomenine attenuates cancer-induced bone pain via suppressing microglial JAK2/STAT3 and neuronal CAMKII/CREB cascades in rat models

Gene therapy by lentivirus‐mediated RNA interference targeting extracellular‐regulated kinase alleviates neuropathic pain in vivo

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