Rab7 silencing prevents μ-opioid receptor lysosomal targeting and rescues opioid responsiveness to strengthen diabetic neuropathic pain therapy

TY - JOUR

T1 - Rab7 silencing prevents μ-opioid receptor lysosomal targeting and rescues opioid responsiveness to strengthen diabetic neuropathic pain therapy

AU - Mousa, Shaaban A

AU - Shaqura, Mohammed

AU - Khalefa, Baled I

AU - Zöllner, Christian

AU - Schaad, Laura

AU - Schneider, Jonas

AU - Shippenberg, Toni S

AU - Richter, Jan F

AU - Hellweg, Rainer

AU - Shakibaei, Mehdi

AU - Schäfer, Michael

PY - 2013/4/1

Y1 - 2013/4/1

N2 - 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.

AB - 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.

KW - Analgesics, Opioid

KW - Animals

KW - Blood Glucose

KW - Diabetes Mellitus, Experimental

KW - Diabetic Neuropathies

KW - Fentanyl

KW - Gene Silencing

KW - Hyperalgesia

KW - Lysosomes

KW - Male

KW - Pain Measurement

KW - Protein Transport

KW - RNA, Small Interfering

KW - Rats

KW - Rats, Wistar

KW - Receptors, Opioid, mu

KW - Weight Gain

KW - rab GTP-Binding Proteins

U2 - 10.2337/db12-0590

DO - 10.2337/db12-0590

M3 - SCORING: Journal article

C2 - 23230081

VL - 62

SP - 1308

EP - 1319

JO - DIABETES

JF - DIABETES

SN - 0012-1797

IS - 4

ER -