title: Src family kinases involved in CXCL12-induced loss of acute morphine analgesia.
abstract: 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 (1μg) significantly attenuated the subcutaneous morphine (4mg/kg) analgesia. Conversely, pretreatment with a potent CXCR4 antagonist (5μg) significantly enhanced morphine analgesia. Similar effects were obtained after an intrathecal injection of a specific SFK inhibitor, PP2 (10μg). 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.
authors.affiliation: Institut des Neurosciences, INSERM U1051, 34091 Montpellier, France.
authors.forename: Cyril
authors.initials: C
authors.lastname: Rivat
authors.affiliation: Pain Group, CRICM, Université Pierre et Marie Curie, UMRS 975, Paris, France.
authors.forename: Soumia
authors.initials: S
authors.lastname: Sebaihi
authors.affiliation: Pathophysiology and Neuroprotection in Brain Damage, INSERM UMR 676, Université Paris 7, Hôpital Robert Debré, Paris, France.
authors.forename: Juliette
authors.initials: J
authors.lastname: Van Steenwinckel
authors.affiliation: Centre de Recherche Institut de la Vision, Université Pierre et Marie Curie, INSERM, UMR_S968, CNRS, UMR_7210, Paris, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Fouquet
authors.affiliation: Pain Group, CRICM, Université Pierre et Marie Curie, UMRS 975, Paris, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Kitabgi
authors.affiliation: Centre de Psychiatrie et Neurosciences, INSERM UMR894, Equipe: Douleurs, Neuroinflammation et Stress, 75014 Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Pohl
authors.affiliation: Centre de Recherche Institut de la Vision, Université Pierre et Marie Curie, INSERM, UMR_S968, CNRS, UMR_7210, Paris, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Melik Parsadaniantz
authors.affiliation: Centre de Recherche Institut de la Vision, Université Pierre et Marie Curie, INSERM, UMR_S968, CNRS, UMR_7210, Paris, France. Electronic address: annabelle.reaux@inserm.fr.
authors.forename: Annabelle
authors.initials: A
authors.lastname: Reaux-Le Goazigo
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D054377:Chemokine CXCL12 / Q000494:pharmacology*; D004361:Drug Tolerance; D005727:Ganglia, Spinal / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000378:metabolism; D009020:Morphine / Q000494:pharmacology*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D019718:Receptors, CXCR4 / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D000701:Analgesics, Opioid; C575935:CXCL12 protein, rat; D054377:Chemokine CXCL12; C486264:Cxcr4 protein, rat; D019718:Receptors, CXCR4; D009020:Morphine; D019061:src-Family Kinases
keywords: Analgesia; CXCR4; Chemokine; Microglia; Opioid receptors; Spinal cord; Src kinases