Continuous  -Opioid Receptor Activation Reduces Neuronal Voltage-Gated Sodium Channel (NaV1.7) Levels through Activation of Protein Kinase C in Painful Diabetic Neuropathy

Abstract

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 ␦-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 ␦-opioid receptor and voltage-gated sodium channels.

Diabetic Painful and Insensate Neuropathy: Pathogenesis and Potential Treatments

“…27 Thermal hyperalgesia in STZ-diabetic rats was prevented or reversed by the AR inhibitor lidorestat, 19 the AGE formation inhibitor pyridoxamine, 25 the PKC LY333531, 26 several antioxidants (including ␣-lipoic acid, 20 the hydroxyl radical scavenger dimethylthiourea, 21 the xanthine oxidase inhibitor allopurinol, 28 and taurine 29 ), the PARP inhibitors 1,5-isoquinolinediol 12 and nicotinamide, 30 and the neurocytokine interleukin-6, 31 as well as by transgene-mediated expression of enkephalin in dorsal root ganglia neurons. 32 C-peptide and the glutamate carboxypeptidase II inhibitor treatments alleviated thermal hyperalgesia in type 1 diabetic BB/ Wor rats, 27,33 and taurine in type 2 Zucker diabetic fatty rats. 34 Whereas mechanisms underlying analgesic effect of these agents require further studies, a number of the treatments mentioned here have been reported to counteract glutamate excitotoxicity by reducing glutamate accumulation, 33,35,36 to restore impaired Ca 2ϩ homeostasis and signaling, 37 to inhibit mitogen-activated protein kinase (MAPK) activation, 38 and to counteract production of proinflammatory cytokines.…”

“…40 -43 Enkephalin has been shown to activate the presynaptic ␦-opioid receptor and, through inhibition of PKC and p38 MAPK, to prevent the increase in the neuronal Na V 1.7 tetrodotoxin-sensitive voltage-gated sodium channel isoform (which plays a critical role in nociception) in dorsal root ganglia. 32 Thermal hypoalgesia is present in a large proportion of patients with advanced PDN. This condition has been described in STZ-diabetic rats with longer-term (Ն12 weeks) diabetes, 19,44 and in a number of diabetic mouse models, including SVEV129ϫC57BL/6, 45 C57Bl/ 6J, 13,14,46,47 Swiss Webster, 48 -50 129S1/SvImJ, 44 and CD1 51 mice made diabetic with STZ, as well as nonobese diabetic (NOD) mice, 52 leptin-deficient (ob/ob) mice, 53,54 and diabetic Akita mice (V.R.…”

“…Rosuvastatin, 83 the PKC inhibitor LY333531, 26 and interleukin-6, 31 which corrected other manifestations of peripheral diabetic neuropathy, including thermal hyperalgesia, did not reduce an exaggerated sensitivity to mechanical noxious stimuli. Notably, two other PKC inhibitors, staurosporine and protein kinase C pseudosubstrate inhibitor peptide [PKC (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)], elevated mechanical nociceptive thresholds in STZdiabetic rats in a dose-dependent manner without altering nociceptive threshold in control rats. 84 Taurine also alleviated mechanical hyperalgesia in Zucker diabetic fatty rats.…”

Molecular Pharmacology ofδ-Opioid Receptors

“…In this setting, p38 had deleterious effects on neuronal survival after ischemic insults and DOPr activation during preconditioning reduced subsequent activation of MAPK during ischemia, restoring Bcl2/cytochrome c levels and increasing survival Hong et al, 2007). DOPr stimulation in cultured DRG neurons also inhibited p38 activation and the associated increase in Nav1.7 channel expression that was caused by increasing glucose concentrations in the incubation medium (Chattopadhyay et al, 2008). Similar observations were obtained in DRG neurons recovered from streptozotocin-diabetic mice that were injected with a viral vector codifying for proenkephalin.…”

Intrathecal Studies on Animal Pain Models

“…In addition to changes in protein expression, phosphorylation-induce change of conductance or gating property of Na + channels may also lead to enhanced neuronal excitability and NINP (Aurilio et al, 2008). The activation of presynaptic delta-opioid receptor by enkephalin has been reported to prevent the increase in neuronal Na V 1.7 in DRG through inhibition of PKC and p38 (Chattopadhyay et al, 2008). Tumor necrosis factor-(TNF-), a pro-inflammatory cytokine involved in NINP formation (Schafers et al, 2003), was found to enhance TTX-resistant Na + currents in isolated DRG neurons via a TNF receptor 1-and p38-dependent mechanism (Jin & Gereau, 2006).…”