Src family kinases involved in CXCL12-induced loss of acute morphine analgesia

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• 作者：Cyril Rivat^a ; Soumia Sebaihi^b ; Juliette Van Steenwinckel^c ; Sté ; phane Fouquet^e ; Patrick Kitabgi^b ; Michel Pohl^d ; Sté ; phane Melik Parsadaniantz^e ; Annabelle Reaux-Le Goazigo^e ; ^{annabelle.reaux@inserm.fr" class="auth_mail}
• 关键词：DOR ; delta-opioid receptor ; DRG ; dorsal root ganglia ; GPCR ; G protein-coupled receptor ; IR ; immunoreactivity ; i.t. ; intrathecal ; MOR ; mu-opioid receptor ; PAG ; periaqueductal gray matter ; PBS ; phosphate-buffered saline ; s.c. ; subcutaneously ; SFK ; Src family kinases
• 刊名：Brain, Behavior, and Immunity
• 出版年：May, 2014
• 年：2014
• 卷：38
• 期：Complete
• 页码：38-52
• 全文大小：7126 K

文摘

Functional interactions between the chemokine receptor CXCR4 and opioid receptors have been reported in the brain, leading to a decreased morphine analgesic activity. However the cellular mechanisms responsible for this loss of opioid analgesia are largely unknown. Here we examined whether Src family-kinases (SFK)-linked mechanisms induced by CXCR4 contributed to the loss of acute morphine analgesia and could represent a new physiological anti-opioid signaling pathway. In this way, we showed by immunohistochemistry and western blot that CXCL12 rapidly activated SFK phosphorylation in vitro in primary cultured lumbar rat dorsal root ganglia (DRG) but also in vivo in the DRG and the spinal cord. We showed that SFK activation occurred in a sub population of sensory neurons, in spinal microglia but also in spinal nerve terminals expressing mu-(MOR) and delta-opioid (DOR) receptor. In addition we described that CXCR4 is detected in MOR- and DOR-immunoreactive neurons in the DRG and spinal cord. In vivo, we demonstrated that an intrathecal administration of CXCL12 (1 渭g) significantly attenuated the subcutaneous morphine (4 mg/kg) analgesia. Conversely, pretreatment with a potent CXCR4 antagonist (5 渭g) significantly enhanced morphine analgesia. Similar effects were obtained after an intrathecal injection of a specific SFK inhibitor, PP2 (10 渭g). Furthermore, PP2 abrogated CXCL12-induced decrease in morphine analgesia by suppressing SFK activation in the spinal cord. In conclusion, our data highlight that CXCL12-induced loss of acute morphine analgesia is linked to Src family kinases activation.