title: Reduced number, G protein coupling, and antinociceptive efficacy of spinal mu-opioid receptors in diabetic rats are reversed by nerve growth factor.
abstract: This study investigated putative mechanisms of impaired spinal opioid antinociception such as a downregulation of mu-opioid receptor (MOR) number, coupling, and efficacy in rats with advanced (12 weeks) streptozotocin (STZ)-induced diabetes. Intravenous injection of STZ (45 mg/kg) in Wistar rats led to selective degeneration of insulin-producing pancreatic ß-cells, elevated blood glucose, and mechanical hyperalgesia. In these animals, dose-dependent and naloxone-reversible intrathecal fentanyl antinociception was significantly impaired and associated with a loss in MOR immunoreactivity of calcitonin gene-related peptide-immunoreactive (CGRP-IR) sensory nerve terminals, membrane-bound MOR binding sites, and MOR-stimulated G protein coupling within the dorsal horn of the spinal cord. Intrathecal delivery of nerve growth factor (NGF) in diabetic animals normalized spinal MOR number and G protein coupling and rescued spinal fentanyl-induced antinociception. These findings identify for the first time a loss in functional MOR on central terminals of sensory neurons as a contributing factor for the impaired spinal opioid responsiveness during advanced STZ-induced diabetes that can be reversed by NGF. Moreover, they support growing evidence of a distinct regulation of opioid responsiveness during various painful states of disease (eg, arthritis, cancer, neuropathy) and may give novel therapeutic incentives.
  
  
  CONCLUSIONS
  In diabetic neuropathy a loss in sensory neuron mu-opioid receptor number and coupling contributes to impaired spinal opioid antinociception that can be reversed by NGF. These findings support growing evidence of a distinct regulation of opioid responsiveness during various painful diseases 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, Berlin, Germany.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Shaqura
authors.forename: Baled I
authors.initials: BI
authors.lastname: Khalefa
authors.forename: Mehdi
authors.initials: M
authors.lastname: Shakibaei
authors.forename: Jens
authors.initials: J
authors.lastname: Winkler
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Al-Khrasani
authors.forename: Susanna
authors.initials: S
authors.lastname: Fürst
authors.forename: Shaaban A
authors.initials: SA
authors.lastname: Mousa
authors.forename: Michael
authors.initials: M
authors.lastname: Schäfer
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003929:Diabetic Neuropathies / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D019204:GTP-Binding Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D020932:Nerve Growth Factor / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism*
chemical_list: D017450:Receptors, Opioid, mu; D020932:Nerve Growth Factor; D019204:GTP-Binding Proteins