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Rab7 Silencing Prevents μ-Opioid Receptor Lysosomal Targeting and Rescues Opioid Responsiveness to Strengthen Diabetic Neuropathic Pain Therapy

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 respon...

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Autores principales: Mousa, Shaaban A., Shaqura, Mohammed, Khalefa, Baled I., Zöllner, Christian, Schaad, Laura, Schneider, Jonas, Shippenberg, Toni S., Richter, Jan F., Hellweg, Rainer, Shakibaei, Mehdi, Schäfer, Michael
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3609597/
https://www.ncbi.nlm.nih.gov/pubmed/23230081
http://dx.doi.org/10.2337/db12-0590
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author Mousa, Shaaban A.
Shaqura, Mohammed
Khalefa, Baled I.
Zöllner, Christian
Schaad, Laura
Schneider, Jonas
Shippenberg, Toni S.
Richter, Jan F.
Hellweg, Rainer
Shakibaei, Mehdi
Schäfer, Michael
author_facet Mousa, Shaaban A.
Shaqura, Mohammed
Khalefa, Baled I.
Zöllner, Christian
Schaad, Laura
Schneider, Jonas
Shippenberg, Toni S.
Richter, Jan F.
Hellweg, Rainer
Shakibaei, Mehdi
Schäfer, Michael
author_sort Mousa, Shaaban A.
collection PubMed
description 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.
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spelling pubmed-36095972014-04-01 Rab7 Silencing Prevents μ-Opioid Receptor Lysosomal Targeting and Rescues Opioid Responsiveness to Strengthen Diabetic Neuropathic Pain Therapy Mousa, Shaaban A. Shaqura, Mohammed Khalefa, Baled I. Zöllner, Christian Schaad, Laura Schneider, Jonas Shippenberg, Toni S. Richter, Jan F. Hellweg, Rainer Shakibaei, Mehdi Schäfer, Michael Diabetes Original Research 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. American Diabetes Association 2013-04 2013-03-14 /pmc/articles/PMC3609597/ /pubmed/23230081 http://dx.doi.org/10.2337/db12-0590 Text en © 2013 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
spellingShingle Original Research
Mousa, Shaaban A.
Shaqura, Mohammed
Khalefa, Baled I.
Zöllner, Christian
Schaad, Laura
Schneider, Jonas
Shippenberg, Toni S.
Richter, Jan F.
Hellweg, Rainer
Shakibaei, Mehdi
Schäfer, Michael
Rab7 Silencing Prevents μ-Opioid Receptor Lysosomal Targeting and Rescues Opioid Responsiveness to Strengthen Diabetic Neuropathic Pain Therapy
title Rab7 Silencing Prevents μ-Opioid Receptor Lysosomal Targeting and Rescues Opioid Responsiveness to Strengthen Diabetic Neuropathic Pain Therapy
title_full Rab7 Silencing Prevents μ-Opioid Receptor Lysosomal Targeting and Rescues Opioid Responsiveness to Strengthen Diabetic Neuropathic Pain Therapy
title_fullStr Rab7 Silencing Prevents μ-Opioid Receptor Lysosomal Targeting and Rescues Opioid Responsiveness to Strengthen Diabetic Neuropathic Pain Therapy
title_full_unstemmed Rab7 Silencing Prevents μ-Opioid Receptor Lysosomal Targeting and Rescues Opioid Responsiveness to Strengthen Diabetic Neuropathic Pain Therapy
title_short Rab7 Silencing Prevents μ-Opioid Receptor Lysosomal Targeting and Rescues Opioid Responsiveness to Strengthen Diabetic Neuropathic Pain Therapy
title_sort rab7 silencing prevents μ-opioid receptor lysosomal targeting and rescues opioid responsiveness to strengthen diabetic neuropathic pain therapy
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3609597/
https://www.ncbi.nlm.nih.gov/pubmed/23230081
http://dx.doi.org/10.2337/db12-0590
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