Continuous delta-opioid receptor activation reduces neuronal voltage-gated sodium channel (NaV1.7) levels through activation of protein kinase C in painful diabetic neuropathy.
The Na(V)1.7 tetrodotoxin-sensitive voltage-gated sodium channel isoform plays a critical role in nociception. In rodent models of diabetic neuropathy, increased Na(V)1.7 in dorsal root ganglia (DRG) neurons correlates with the emergence of pain-related behaviors characteristic of painful diabetic neuropathy (PDN). We examined the effect of transgene-mediated expression of enkephalin on pain-related behaviors and their biochemical correlates in DRG neurons. Transfection of DRG neurons by subcutaneous inoculation of a herpes simplex virus-based vector expressing proenkephalin reversed nocisponsive behavioral responses to heat, cold, and mechanical pressure characteristic of PDN. Vector-mediated enkephalin production in vivo prevented the increase in DRG Na(V)1.7 observed in PDN, an effect that correlated with inhibition of phosphorylation of p38 MAPK (mitogen-activated protein kinase) and protein kinase C (PKC). Primary DRG neurons in vitro exposed to 45 mm glucose for 18 h also demonstrated an increase in Na(V)1.7 and increased phosphorylation of p38 and PKC; these changes were prevented by transfection in vitro with the enkephalin-expressing vector. The effect of hyperglycemia on Na(V)1.7 production in vitro was mimicked by exposure to PMA and blocked by the myristolated PKC inhibitor 20-28 or the p38 inhibitor SB202190 [4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole]; the effect of vector-mediated enkephalin on Na(V)1.7 levels was prevented by naltrindole. The results of these studies suggest that activation of the presynaptic delta-opioid receptor by enkephalin prevents the increase in neuronal Na(V)1.7 in DRG through inhibition of PKC and p38. These results establish a novel interaction between the delta-opioid receptor and voltage-gated sodium channels.
Chattopadhyay
Munmun
M
Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109-0316, USA.
Mata
Marina
M
Fink
David J
DJ
D000818:Animals; D002478:Cells, Cultured; D003929:Diabetic Neuropathies / Q000201:enzymology* / Q000235:genetics / Q000628:therapy; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004745:Enkephalins / Q000235:genetics*; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000187:drug effects / Q000201:enzymology; D005822:Genetic Vectors / Q000235:genetics; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D062556:NAV1.7 Voltage-Gated Sodium Channel; D009292:Narcotic Antagonists / Q000494:pharmacology; D009475:Neurons, Afferent / Q000187:drug effects / Q000201:enzymology*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D004745:Enkephalins; D004791:Enzyme Inhibitors; D062556:NAV1.7 Voltage-Gated Sodium Channel; D009292:Narcotic Antagonists; D017465:Receptors, Opioid, delta; C503480:Scn9a protein, rat; D015222:Sodium Channels; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate