title: Rab7 silencing prevents μ-opioid receptor lysosomal targeting and rescues opioid responsiveness to strengthen diabetic neuropathic pain therapy.
abstract: Painful diabetic neuropathy is poorly controlled by analgesics and requires high doses of opioids, triggering side effects and reducing patient quality of life. This study investigated whether enhanced Rab7-mediated lysosomal targeting of peripheral sensory neuron μ-opioid receptors (MORs) is responsible for diminished opioid responsiveness in rats with streptozotocin-induced diabetes. In diabetic animals, significantly impaired peripheral opioid analgesia was associated with a loss in sensory neuron MOR and a reduction in functional MOR G-protein-coupling. In control animals, MORs were retained mainly on the neuronal cell membrane. In contrast, in diabetic rats, they were colocalized with upregulated Rab7 in LampI-positive perinuclear lysosome compartments. Silencing endogenous Rab7 with intrathecal Rab7-siRNA or, indirectly, by reversing nerve growth factor deprivation in peripheral sensory neurons not only prevented MOR targeting to lysosomes, restoring their plasma membrane density, but also rescued opioid responsiveness toward better pain relief. These findings elucidate in vivo the mechanisms by which enhanced Rab7 lysosomal targeting of MORs leads to a loss in opioid antinociception in diabetic neuropathic pain. This is in contrast to peripheral sensory neuron MOR upregulation and antinociception in inflammatory pain, and provides intriguing evidence that regulation of opioid responsiveness varies as a function of pain pathogenesis.
authors.affiliation: Department of Anaesthesiology and Intensive Care Medicine, Charité University Berlin, Campus Virchow Klinikum and Campus Charite Mitte, Berlin, Germany. micha.schaefer@charite.de
authors.forename: Shaaban A
authors.initials: SA
authors.lastname: Mousa
authors.forename: Mohammed
authors.initials: M
authors.lastname: Shaqura
authors.forename: Baled I
authors.initials: BI
authors.lastname: Khalefa
authors.forename: Christian
authors.initials: C
authors.lastname: Zöllner
authors.forename: Laura
authors.initials: L
authors.lastname: Schaad
authors.forename: Jonas
authors.initials: J
authors.lastname: Schneider
authors.forename: Toni S
authors.initials: TS
authors.lastname: Shippenberg
authors.forename: Jan F
authors.initials: JF
authors.lastname: Richter
authors.forename: Rainer
authors.initials: R
authors.lastname: Hellweg
authors.forename: Mehdi
authors.initials: M
authors.lastname: Shakibaei
authors.forename: Michael
authors.initials: M
authors.lastname: Schäfer
mesh_terms: D000701:Analgesics, Opioid / Q000627:therapeutic use; D000818:Animals; D001786:Blood Glucose; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D003929:Diabetic Neuropathies / Q000188:drug therapy*; D005283:Fentanyl / Q000627:therapeutic use; D020868:Gene Silencing; D006930:Hyperalgesia; D008247:Lysosomes / Q000378:metabolism*; D008297:Male; D010147:Pain Measurement; D021381:Protein Transport; D034741:RNA, Small Interfering; D051381:Rats; D017208:Rats, Wistar; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D015430:Weight Gain; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000090802:rab7 GTP-Binding Proteins
chemical_list: D000701:Analgesics, Opioid; D001786:Blood Glucose; D034741:RNA, Small Interfering; D017450:Receptors, Opioid, mu; D000090802:rab7 GTP-Binding Proteins; C000716466:rab7 GTP-binding proteins, rat; D020691:rab GTP-Binding Proteins; D005283:Fentanyl