title: Protein kinase C-mediated mu-opioid receptor phosphorylation and desensitization in rats, and its prevention during early diabetes.
abstract: Painful diabetic neuropathy is associated with impaired opioid analgesia; however, the precise mechanism in sensory neurons remains unclear. This study aimed to identify putative mechanisms involved in modified opioid responsiveness during early streptozotocin-induced diabetes in rats. In this study, we demonstrate that in diabetic animals, impaired peripheral opioid analgesia is associated with a reduction in functional mu-opioid receptor (MOR) G protein coupling. Mu-opioid receptor immunoreactive neurons colocalized with activated forms of protein kinase C (PKC) and with the receptor for advanced glycation end products (RAGE) during streptozotocin-induced diabetes. Moreover, MOR phosphorylation at Thr370 in sensory neurons of diabetic rats, and thus desensitization, was due to RAGE-dependent PKC activation. Importantly, blocking PKC activation using PKC selective inhibitor, silencing RAGE with intrathecal RAGE siRNA, or inhibiting advanced glycation end product (AGE) formation prevented sensory neuron MOR phosphorylation and, consequently, restored MOR G protein coupling and analgesic efficacy. Thus, our findings give the first in vivo evidence of a RAGE-dependent PKC-mediated heterologous MOR phosphorylation and desensitization in sensory neurons under pathological conditions such as diabetic neuropathy. This may unravel putative mechanisms and suggest possible prevention strategies of impaired opioid responsiveness.
authors.affiliation: Department of Anaesthesiology and Intensive Care Medicine, Charité University Berlin, Campus Virchow Klinikum and Campus Charité Mitte, Berlin, Germany Department of Anatomy, Ludwig Maximilian University Munich, Munich, Germany Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University, Jena, Germany Department of Internal Medicine, Paulinenkrankenhaus, Berlin, Germany.
authors.forename: Shaaban A
authors.initials: SA
authors.lastname: Mousa
authors.forename: Mohammed
authors.initials: M
authors.lastname: Shaqura
authors.forename: Jens
authors.initials: J
authors.lastname: Winkler
authors.forename: Baled I
authors.initials: BI
authors.lastname: Khalefa
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Al-Madol
authors.forename: Mehdi
authors.initials: M
authors.lastname: Shakibaei
authors.forename: Stefan
authors.initials: S
authors.lastname: Schulz
authors.forename: Michael
authors.initials: M
authors.lastname: Schäfer
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003929:Diabetic Neuropathies / Q000378:metabolism*; D008297:Male; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D017450:Receptors, Opioid, mu; D011493:Protein Kinase C