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The Journal of Neuroscience, June 25, 2008, 28(26):6652-6658; doi:10.1523/JNEUROSCI.5530-07.2008

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Neurobiology of Disease
Continuous -Opioid Receptor Activation Reduces Neuronal Voltage-Gated Sodium Channel (Na_V1.7) Levels through Activation of Protein Kinase C in Painful Diabetic Neuropathy

Munmun Chattopadhyay,^1,2 Marina Mata,^1,2 and David J. Fink^1,2

¹Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109-0316, and ²VA Ann Arbor Healthcare System, Ann Arbor, Michigan 48105

Correspondence should be addressed to Dr. David J. Fink, 1914 Taubman Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0316. Email: djfink{at}umich.edu

The Na_V1.7 tetrodotoxin-sensitive voltage-gated sodium channel isoform plays a critical role in nociception. In rodent models of diabetic neuropathy, increased Na_V1.7 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_V1.7 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_V1.7 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_V1.7 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_V1.7 levels was prevented by naltrindole. The results of these studies suggest that activation of the presynaptic -opioid receptor by enkephalin prevents the increase in neuronal Na_V1.7 in DRG through inhibition of PKC and p38. These results establish a novel interaction between the -opioid receptor and voltage-gated sodium channels.

Key words: pain; diabetic neuropathy; sodium channel; gene therapy; herpes simplex; enkephalins

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Received July 4, 2007; revised May 11, 2008; accepted May 15, 2008.

Correspondence should be addressed to Dr. David J. Fink, 1914 Taubman Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0316. Email: djfink{at}umich.edu

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