title: New insights into mechanisms of opioid inhibitory effects on capsaicin-induced TRPV1 activity during painful diabetic neuropathy.
abstract: Painful diabetic neuropathy is a disease of the peripheral sensory neuron with impaired opioid responsiveness. Since μ-opioid receptor (MOR) activation can inhibit the transient receptor potential vanilloid 1 (TRPV1) activity in peripherally sensory neurons, this study investigated the mechanisms of impaired opioid inhibitory effects on capsaicin-induced TRPV1 activity in painful diabetic neuropathy. Intravenous injection of streptozotocin (STZ, 45 mg/kg) in Wistar rats led to a degeneration of insulin producing pancreatic β-cells, elevated blood glucose, and mechanical hypersensitivity (allodynia). In these animals, local morphine's inhibitory effects on capsaicin-induced nocifensive behavior as well as on capsaicin-induced TRPV1 current in dorsal root ganglion cells were significantly impaired. These changes were associated with a loss in MOR but not TRPV1 in peripheral sensory neurons. Intrathecal delivery of nerve growth factor in diabetic animals normalized sensory neuron MOR and subsequently rescued morphine's inhibitory effects on capsaicin-induced TRPV1 activity in vivo and in vitro. These findings identify a loss in functional MOR on sensory neurons as a contributing factor for the impaired opioid inhibitory effects on capsaicin-induced TRPV1 activity during advanced STZ-induced diabetes. Moreover, they support growing evidence of a distinct regulation of opioid responsiveness during various painful states of disease (e.g. arthritis, cancer, neuropathy) and may give novel therapeutic incentives.
authors.affiliation: Department of Anaesthesiology and Intensive Care Medicine, Charité University Berlin, Campus Virchow Klinikum and Campus Charite Mitte, Augustenburgerplatz 1, 13353 Berlin, Germany.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Shaqura
authors.affiliation: Department of Anaesthesiology and Intensive Care Medicine, Charité University Berlin, Campus Virchow Klinikum and Campus Charite Mitte, Augustenburgerplatz 1, 13353 Berlin, Germany.
authors.forename: Baled I
authors.initials: BI
authors.lastname: Khalefa
authors.affiliation: Department of Anatomy, Ludwig-Maximilian-University Munich, Germany.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Shakibaei
authors.affiliation: Department of Anaesthesiology, Universitätsklinikum Hamburg Eppendorf, Hamburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Zöllner
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Al-Khrasani
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.
authors.forename: Susanna
authors.initials: S
authors.lastname: Fürst
authors.affiliation: Department of Anaesthesiology and Intensive Care Medicine, Charité University Berlin, Campus Virchow Klinikum and Campus Charite Mitte, Augustenburgerplatz 1, 13353 Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schäfer
authors.affiliation: Department of Anaesthesiology and Intensive Care Medicine, Charité University Berlin, Campus Virchow Klinikum and Campus Charite Mitte, Augustenburgerplatz 1, 13353 Berlin, Germany. Electronic address: shaaban.mousa@charite.de.
authors.forename: Shaaban A
authors.initials: SA
authors.lastname: Mousa
mesh_terms: D000818:Animals; D001786:Blood Glucose; D002211:Capsaicin / Q000633:toxicity*; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology; D003929:Diabetic Neuropathies / Q000503:physiopathology*; D005727:Ganglia, Spinal / Q000503:physiopathology; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D020932:Nerve Growth Factor / Q000378:metabolism*; D009437:Neuralgia / Q000503:physiopathology*; D017208:Rats, Wistar; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000502:physiology; D013116:Spinal Cord / Q000503:physiopathology; D050916:TRPV Cation Channels / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D017450:Receptors, Opioid, mu; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D020932:Nerve Growth Factor; D002211:Capsaicin
keywords: Diabetes; Nerve growth factor; Neuropathic pain; Opioids; Sensory neuron; TRPV1