Key points are not available for this paper at this time.
Diabetic neuropathy is a common form of peripheral neuropathy, yet the mechanisms responsible for pain in this disease are poorly understood. Alterations in the expression and function of voltage-gated tetrodotoxin-resistant (TTX-R) sodium channels have been implicated in animal models of neuropathic pain, including models of diabetic neuropathy. We investigated the expression and function of TTX-sensitive (TTX-S) and TTX-R sodium channels in dorsal root ganglion (DRG) neurons and the responses to thermal hyperalgesia and mechanical allodynia in streptozotocin-treated rats between 4–8 weeks after onset of diabetes. Diabetic rats demonstrated a significant reduction in the threshold for escape from innocuous mechanical pressure (allodynia) and a reduction in the latency to withdrawal from a noxious thermal stimulus (hyperalgesia). Both TTX-S and TTX-R sodium currents increased significantly in small DRG neurons isolated from diabetic rats. The voltage-dependent activation and steady-state inactivation curves for these currents were shifted negatively. TTX-S currents induced by fast or slow voltage ramps increased markedly in neurons from diabetic rats. Immunoblots and immunofluorescence staining demonstrated significant increases in the expression of Nav1.3 (TTX-S) and Nav 1.7 (TTX-S) and decreases in the expression of Nav 1.6 (TTX-S) and Nav1.8 (TTX-R) in diabetic rats. The level of serine/threonine phosphorylation of Nav 1.6 and In Nav1.8 increased in response to diabetes. addition, increased tyrosine phosphorylation of Nav1.6 and Nav1.7 was observed in DRGs from diabetic rats. These results suggest that both TTX-S and TTX-R sodium channels play important roles and that differential phosphorylation of sodium channels involving both serine/threonine and tyrosine sites contributes to painful diabetic neuropathy. Diabetic neuropathy is a common form of peripheral neuropathy, yet the mechanisms responsible for pain in this disease are poorly understood. Alterations in the expression and function of voltage-gated tetrodotoxin-resistant (TTX-R) sodium channels have been implicated in animal models of neuropathic pain, including models of diabetic neuropathy. We investigated the expression and function of TTX-sensitive (TTX-S) and TTX-R sodium channels in dorsal root ganglion (DRG) neurons and the responses to thermal hyperalgesia and mechanical allodynia in streptozotocin-treated rats between 4–8 weeks after onset of diabetes. Diabetic rats demonstrated a significant reduction in the threshold for escape from innocuous mechanical pressure (allodynia) and a reduction in the latency to withdrawal from a noxious thermal stimulus (hyperalgesia). Both TTX-S and TTX-R sodium currents increased significantly in small DRG neurons isolated from diabetic rats. The voltage-dependent activation and steady-state inactivation curves for these currents were shifted negatively. TTX-S currents induced by fast or slow voltage ramps increased markedly in neurons from diabetic rats. Immunoblots and immunofluorescence staining demonstrated significant increases in the expression of Nav1.3 (TTX-S) and Nav 1.7 (TTX-S) and decreases in the expression of Nav 1.6 (TTX-S) and Nav1.8 (TTX-R) in diabetic rats. The level of serine/threonine phosphorylation of Nav 1.6 and In Nav1.8 increased in response to diabetes. addition, increased tyrosine phosphorylation of Nav1.6 and Nav1.7 was observed in DRGs from diabetic rats. These results suggest that both TTX-S and TTX-R sodium channels play important roles and that differential phosphorylation of sodium channels involving both serine/threonine and tyrosine sites contributes to painful diabetic neuropathy. Diabetes mellitus is one of the most common chronic medical problems, affecting over 100 million people world-wide (1Spruce M.C. Potter J. Coppini D.V. Diabet. Med. 2003; 20: 88-98Crossref PubMed Scopus (107) Google Scholar). Diabetic patients frequently exhibit one or more types of stimulus-evoked pain, including increased responsiveness to noxious stimuli (hyperalgesia) as well as hyper-responsiveness to normally innocuous stimuli (allodynia). The underlying mechanisms of persistent pain in diabetic patients remain poorly understood. In animal models of diabetes, hyperalgesia to nonnoxious thermal stimulation as well as tactile allodynia have been observed (2Calcutt N.A. Jorge M.C. Yaksh T.L. Chaplan S.R. Pain. 1996; 68: 293-299Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar, 3Fox A. Eastwood C. Gentry C. Manning D. Urban L. Pain. 1999; 81: 307-316Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar, 4Malcangio M. Tomlinson D.R. Pain. 1998; 76: 151-157Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar). The streptozotocin (STZ) 1The abbreviations used are: STZ, streptozotocin; TTX-R, voltage-gated tetrodotoxin-resistant sodium channels; TTX-S, voltage-gated tetrodotoxin-sensitive sodium channels; DRG, dorsal root ganglion; F, farad.1The abbreviations used are: STZ, streptozotocin; TTX-R, voltage-gated tetrodotoxin-resistant sodium channels; TTX-S, voltage-gated tetrodotoxin-sensitive sodium channels; DRG, dorsal root ganglion; F, farad.-induced diabetic rat model demonstrates many of the abnormalities observed in humans (5Stevens M.J. Dananberg J. Feldman E.L. Lattimer S.A. Kamijo M. Thomas T.P. Shindo H. Sima A.A.F. Greene D.A. J. Clin. Investig. 1994; 94: 853-859Crossref PubMed Google Scholar). Treatment with insulin prevents development or reverses many of the abnormalities observed in early painful diabetic neuropathy (6Srinivasan S. Stevens M. Wiley J.W. Diabetes. 2000; 49: 1932-1938Crossref PubMed Scopus (225) Google Scholar, 7Barber A.J. Lieth E. Khin S.A. Antonetti D.A. Buchanan A.G. Gardner T.W. J. Clin. Investig. 1998; 102: 783-791Crossref PubMed Scopus (1038) Google Scholar). In diabetic rats with hyperalgesia, dorsal root ganglion (DRG) neurons display increased frequency of action potential generation in response to sustained suprathreshold mechanical stimulation (3Fox A. Eastwood C. Gentry C. Manning D. Urban L. Pain. 1999; 81: 307-316Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar, 4Malcangio M. Tomlinson D.R. Pain. 1998; 76: 151-157Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar, 8Ahlgren S.C. Wang J.F. Levine J.D. Neuroscience. 1997; 76: 285-290Crossref PubMed Scopus (64) Google Scholar, 9Ahlgren S.C. Levine J.D. Neuroscience. 1993; 52: 1049-1055Crossref PubMed Scopus (114) Google Scholar, 10Ahlgren S.C. Levine J.D. J. Neurophysiol. 1994; 72: 684-692Crossref PubMed Scopus (109) Google Scholar) and increased spontaneous activity (11Said G. J. Neurol. 1996; 243: 431-440Crossref PubMed Scopus (56) Google Scholar). Both effects are thought to contribute to the sensation of pain. Voltage-gated sodium channels generate and propagate action potentials in excitable cells. Based on differential sensitivity to tetrodotoxin (TTX), sodium currents in DRG neurons are classified into TTX-sensitive (TTX-S) and TTX-resistant (TTX-R) components (12Caffrey J.M. Eng D.L. Black J.A. Waxman S.G. Kocsis J.D. Brain Res. 1992; 592: 283-297Crossref PubMed Scopus (268) Google Scholar, 13Kostyuk P.G. Veselovsky N.S. Tsyndrenko A.Y. Neuroscience. 1981; 6: 2423-2430Crossref PubMed Scopus (314) Google Scholar, 14Roy M.L. Narahashi T. J. Neurosci. 1992; 12: 2104-2111Crossref PubMed Google Scholar). At least two TTX-S sodium channel α-subunits, Nav1.6, and Nav1.7, are constitutively expressed in the peripheral nervous system (15Ogata N. Ohishi Y. Jpn. J. Pharmacol. 2002; 88: 365-377Crossref PubMed Scopus (149) Google Scholar). In addition, Nav1.3, a TTX-S sodium channel that is normally expressed during embryonic development, is up-regulated in the peripheral nervous system following nerve injury (16Black J.A. Cummins T.R. Plumpton C. Chen Y.H. Hormuzdiar W. Clare J.J. Waxman S.G. J. Neurophysiol. 1999; 82: 2776-2785Crossref PubMed Scopus (266) Google Scholar). Two TTX-R sodium channels, Nav1.8 (17Akopian A.N. Sivilotti L. Wood J.N. Nature. 1996; 379: 257-262Crossref PubMed Scopus (905) Google Scholar) and Nav1.9 (18Tate S. Benn S. Hick C. Trezise D. John V. Mannion R.J. Costigan M. Plumpton C. Grose D. Gladwell Z. Kendall G. Dale K. Bountra C. Woolf C.J. Nat. Neurosci. 1998; 1: 653-655Crossref PubMed Scopus (261) Google Scholar, 19Dib-Hajj S.D. Tyrrell L. Black J.A. Waxman S.G. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar) have been in DRG neurons and in expression have been implicated in painful diabetic neuropathy K. Plumpton C. T. S. Bountra C. Pain. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, M. H. M. H. Neuroscience. 1999; PubMed Scopus Google Scholar, S.D. E. M. L. J. Neurosci. 1998; PubMed Google Scholar, S.G. Pain. 1999; 6: Full Text PDF PubMed Scopus (149) Google Scholar). TTX-S sodium channels in are of a and one or two 2003; PubMed Scopus Google Scholar, 2002; Scholar, 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, G. Neuroscience. 1999; PubMed Scopus Google Scholar). The of TTX-R sodium channels, is TTX-R sodium M. H. M. H. Neuroscience. 1999; PubMed Scopus Google expression of Nav1.8 and have been in models of diabetic neuropathy M.J. M. Black J.A. Waxman S.G. Neurol. 2002; 52: PubMed Scopus Google Scholar). a of the of TTX-S and TTX-R sodium channels, including phosphorylation been in animal models with painful diabetic neuropathy. In the investigated the expression and of TTX-S and TTX-R sodium channels in small to DRG neurons isolated from diabetic rats with painful neuropathy. We that TTX-S and TTX-R sodium currents increased significantly and the voltage-dependent activation and steady-state inactivation curves were shifted in these DRG TTX-S currents induced by both fast and slow voltage ramps increased significantly in diabetic The expression of Nav1.3 and Nav1.7 increased in DRG from diabetic In the expression of Nav1.6 and Nav1.8 in DRG serine/threonine phosphorylation of Nav1.6 and Nav1.8 and tyrosine phosphorylation of Nav1.6 and Nav1.7 increased in neurons from diabetic rats. We that Nav1.8 phosphorylation in responsible for the increased TTX-R observed in diabetic immunofluorescence observed that the expression of Nav1.7 increased the expression of Nav1.8 in small neurons of diabetic rats with in with These that the function of observed in early painful diabetic neuropathy both TTX-S and TTX-R sodium were by the of on and of to of rats were to the of Diabetes mellitus was induced by a of a of in a rats in the of were for after to were after and the onset of the diabetic was as were for to weeks after of diabetes. with this model that rats with for 4–8 weeks a of abnormalities including nerve increased and activation of the in DRG neurons that were after weeks of (6Srinivasan S. Stevens M. Wiley J.W. Diabetes. 2000; 49: 1932-1938Crossref PubMed Scopus (225) Google Scholar, 7Barber A.J. Lieth E. Khin S.A. Antonetti D.A. Buchanan A.G. Gardner T.W. J. Clin. Investig. 1998; 102: 783-791Crossref PubMed Scopus (1038) Google Scholar). to a of diabetic rats and were for in as were for to this the were and to the mechanical sensitivity of the withdrawal in response to a normally innocuous mechanical stimulus was as J. Neurosci. 1998; PubMed Scopus Google Scholar). to the mechanical stimulus was with a pressure system of a with a of in The is to a display of the as well as of stimulus The rat was in a with a and for was to the of the with a pressure by and the pressure a withdrawal was the was and the pressure to a withdrawal stimuli were to significant in the pressure to a withdrawal in response to this mechanical stimulus was as mechanical thermal rats were in a a on of and to The was a thermal stimulus to the of The latency to withdrawal as the of thermal the was the stimulus was to was with between of to peripheral The withdrawal latency for was by the with the a significant in the latency of withdrawal in response to the thermal stimulus was as the of thermal hyperalgesia K. C. J. Pain. Full Text PDF PubMed Scopus Google Scholar). were isolated from and of the and neurons were to the J. Sima Wiley J.W. J. Neurophysiol. PubMed Scopus Google Scholar). were with in a with and for and for The DRGs were in in for and with in with DRG neurons were on with neurons were in for to the currents were in the were from a and with 100 was to by and was to were The used to currents and The was to and was was to the of sodium currents to the of the voltage Z. Pain. 1999; 81: Full Text Full Text PDF PubMed Scopus Google Scholar). these the potential for was In action potentials were in the M. Cummins T.R. Waxman S.G. J. Neurophysiol. PubMed Scopus Google Scholar). TTX-R sodium currents were isolated from TTX-S currents by to the The was with and were with on the of of a and of with was The potential was and were from by from a potential of the of was as and were was the were and the potentials were the in the and were for after in the steady-state inactivation of TTX-R sodium curves were after the as M. H. M. H. Neuroscience. 1999; PubMed Scopus Google Scholar). TTX-R sodium currents were from a potential of to were a system and on a that was by and steady-state inactivation were with a of the to is the potential is and is the potential for the by the of the the the potential of activation or and the were expressed as were the of and were and to the Plumpton C. S. Mannion R.J. Costigan M. Woolf C.J. Neurosci. 2000; PubMed Scopus Google Scholar). the were with and with DRGs from and of the were for in in and in in for the DRG were on a and immunofluorescence of sodium channels, the were with with in for and with in for least The were with channel and in for for sodium channels used were Nav1.6 Nav1.7 or Nav1.8 from S. with the were with and from for The were with and were with a with a and with and in the and of the from diabetic and rats were and in and of DRG of were with the or a The were and in in the of and for were to the and with the were and with were on and In DRG were on for The were with for and with or The were with for and the The were and with Diabetic and after of STZ, of the rats of level rats level The level of in rats was during the These results are to J. Sima Wiley J.W. J. Neurophysiol. PubMed Scopus Google Scholar). In the mechanical allodynia was by the withdrawal threshold in response to of a Diabetic rats a significant in the pressure to withdrawal as with responses The pressure withdrawal threshold for diabetic rats to following this in responsiveness to mechanical stimuli weeks after the of diabetes. hyperalgesia was by the withdrawal latency to a stimulus to the the in the withdrawal latency to thermal stimulation in of diabetic rats. with diabetic rats to exhibit a significant reduction in the to a withdrawal weeks after of both mechanical allodynia and thermal hyperalgesia for to weeks after the onset of diabetes, the of We significant between and responses to mechanical or thermal stimuli of with of Diabetic with and of TTX-R TTX-R sodium currents DRG neurons were isolated and in the of in the The potential was in DRG neurons from rats and in diabetic rats for The between these two was significant The was in the and in the diabetic of TTX-R in DRG neurons from a diabetic rat weeks after the onset of with The of was significantly in neurons from diabetic rats with The in diabetic neurons was with in neurons and the between these two was significant in the for DRG neurons isolated from diabetic rats was shifted in the with that for was by neurons to or by diabetic neurons to The of activation was by the of the a function The of the of activation was in from diabetic rats. was significantly more the for neurons The voltage of steady-state inactivation was to a is the of steady-state inactivation and is the The of steady-state inactivation were in neurons from diabetic rats and in The between these was significant the steady-state inactivation of TTX-R currents was shifted in DRG neurons from diabetic rats with DRG from Diabetic in TTX-S and DRG neurons were by a to for and to potentials from to in demonstrates the for the of DRG neurons isolated from and diabetic rats. The of was in from rats and in diabetic rats for currents for diabetic neurons were with for We observed increased action potential in DRG neurons isolated from diabetic rats with In the potential was and the action potential was by of for to the the most of the action potential of the of J. Neurosci. 2002; PubMed Google Scholar). The of the action potentials a on the the activation of neurons to as J. Scopus Google Scholar, L. L. J. 1998; Scopus Google Scholar). The of the action potential was significantly in diabetic neurons with for The of the action potential was significantly in diabetic neurons in as demonstrated in for These results suggest that diabetic DRG neurons are more to action potential stimulation the of and TTX-R by voltage to The TTX-S was by the currents after from the currents in the of The of the TTX-S the of TTX-R that the activation of TTX-S is more The for TTX-S in DRG neurons from and diabetic rats is in The for TTX-S was in from diabetic is significantly more that for neurons The of activation of TTX-S were and with a as in The of voltage-dependent activation for TTX-S was in from rats and in from diabetic rats. The between these was significant The for the TTX-S activation curves were of for diabetic neurons and for and the between these was significant and in DRG from Diabetic threshold currents the of DRG sodium currents in DRG neurons in response to a slow voltage from to over a to more the in the was increased to from to currents by this were in neurons from diabetic rats in the currents were to the was in neurons from diabetic rats with the In diabetic the was was in neurons for the fast DRG neurons were to from a of in the fast in diabetic neurons was the The by fast voltage was in and in diabetic neurons We the of in diabetic neurons 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). a to for to from to were used to the in neurons to by a to DRG neurons a this were significant in this observed between diabetic and currents were in small DRG neurons from or diabetic rats. Diabetic with in in DRG the observed increases in TTX-S and TTX-R in diabetic neurons to sodium channel of DRGs and the expression of sodium channels by results that the expression of TTX-S and TTX-R sodium channel were in DRGs of diabetic rats In with results M.J. M. Black J.A. Waxman S.G. Neurol. 2002; 52: PubMed Scopus Google observed that the expression of Nav1.8 significantly in diabetic DRGs with In to M.J. M. Black J.A. Waxman S.G. Neurol. 2002; 52: PubMed Scopus Google that the expression of Nav1.6 in diabetic DRGs and The expression of Nav1.3 and Nav1.7 increased significantly in DRGs from diabetic rats with for These increases were and Nav1.3 and Nav1.7, in DRGs from diabetic rats as with the of in DRG in the observed that Nav1.6 was expressed in small and DRG neurons in both and diabetic rats. We that Nav1.6 was in and in diabetic the in Nav1.6 expression observed in was the DRG were for Nav1.6 in rats and in diabetic rats was significant The of Nav1.6 expression small and neurons to in diabetes. of the neurons that were were for of Plumpton C. S. Mannion R.J. Costigan M. Woolf C.J. Neurosci. 2000; PubMed Scopus Google Scholar, J.A. M. Waxman S.G. Brain Res. Brain Res. 2002; PubMed Scopus Google Scholar) in and diabetic of neurons that are for sodium channel and in DRGs from and diabetic significant between and diabetic rats significant between and diabetic rats significant between and diabetic rats significant between and diabetic rats significant between and diabetic rats in a Nav1.7 is expressed in small DRG neurons J.D. D. S.R. Brain Res. 2000; PubMed Scopus Google Scholar, L. S.R. J. 2003; Scopus Google and a slow onset of inactivation T.R. Waxman S.G. J. Neurosci. 1998; PubMed Google Scholar). In with results that the level of Nav1.7 increased in small and DRG neurons from diabetic rats with of DRG neurons were for Nav1.7 in rats with in diabetic rats of The of the neurons that for both Nav1.7 and was in rats and in diabetic rats. this was significant that the in Nav1.7 expression was in These are the of in Nav1.7 expression in painful diabetic neuropathy. Nav1.8 is expressed in and DRGs and been implicated in the of neuropathic pain S.G. S. Cummins T.R. Black J.A. Proc. Natl. Acad. Sci. U. S. A. 1999; PubMed Scopus Google Scholar, J. Pharmacol. PubMed Scopus Google Scholar). demonstrated in the level of Nav1.8 staining in DRGs from diabetic rats with in with results and with the results of M.J. M. Black J.A. Waxman S.G. Neurol. 2002; 52: PubMed Scopus Google Scholar). The of neurons expressed Nav1.8 in Based on the neurons of neurons were for Nav1.8 in rats. significantly to in diabetic rats that for both Nav1.8 and were of the in rats and of the in diabetic rats both the of Nav1.8 expression and the of neurons Nav1.8 with the onset of diabetic neuropathy increased TTX-R of Both TTX-S and TTX-R in DRG from Diabetic of TTX-R sodium channels results in increased sodium and this play a in 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, S.G. S. Cummins T.R. Black J.A. Proc. Natl. Acad. Sci. U. S. A. 1999; PubMed Scopus Google Scholar, Levine J.D. J. Neurosci. 1998; PubMed Google Scholar). in diabetic neuropathy in sodium channel DRG with or and the by channel We the in the The results of both of were and the were demonstrated in increased level of for Nav1.8 was in DRG from diabetic rats with Nav1.8 increased in DRGs from diabetic rats with the for tyrosine phosphorylation of Nav1.8 was observed in DRGs from or diabetic rats. In was observed for Nav1.6 and Nav1.7 and this tyrosine phosphorylation to increased in diabetic rats. of Nav1.6 and Nav1.7 were and the level of increased for both in diabetic rats with for both In addition, increased level of phosphorylation of Nav1.6 was observed in diabetic rats of Nav1.7 were observed in DRGs from rats and a was in DRGs from diabetic rats that phosphorylation of Nav1.6, Nav1.7, and Nav1.8 is increased in DRGs of diabetic that in serine/threonine and tyrosine phosphorylation of voltage-gated sodium channels play a in of painful stimuli in diabetic neuropathy. TTX-R sodium currents have been implicated in chronic pain, including diabetic neuropathy. We that results one of the of TTX-S and TTX-R sodium channel expression and including phosphorylation in diabetic neuropathy. that both TTX-S and TTX-R sodium currents increased in small DRG neurons from diabetic rats and that these increases in with the development of hyperalgesia and allodynia in early diabetes. The expression of TTX-S and TTX-R channel were in diabetic rats. of Nav1.8 significantly as by both of DRG and of DRG suggest that the development of in this model in the of neurons that decreases in the level of Nav1.8 expression in neurons with In to Nav1.8 observed a in the expression of Nav1.7 that the development of hyperalgesia and We observed in the of neurons in the DRG, in the of the Nav1.7 in and in Nav1.7 expression in of DRG These results that both TTX-S and TTX-R sodium channels play important roles in the development of early painful diabetic neuropathy. We observed a significant in TTX-R sodium and increased phosphorylation of Nav1.8 in DRG neurons isolated from diabetic rats. These with the results from M. H. M. H. Neuroscience. 1999; PubMed Scopus Google Scholar, M.J. M. Black J.A. Waxman S.G. Neurol. 2002; 52: PubMed Scopus Google a for Nav1.8 channel in painful diabetic neuropathy. The level of serine/threonine phosphorylation of Nav1.8 increased DRGs from diabetic the that phosphorylation of sodium channels is in channel in animal models and for the that sodium channel phosphorylation contributes to painful diabetic neuropathy. The observed phosphorylation in diabetic model the of the in TTX-R observed in diabetic rats phosphorylation of Nav1.8 increased TTX-R currents in both and K. M. M. J. Neurophysiol. PubMed Scopus Google Scholar, K. Wood J.N. J. 1999; Scopus Google Scholar). We that phosphorylation of sites on the the voltage-dependent activation and inactivation or of the channel the of channels into the and increases the TTX-R In on the inactivation of the TTX-R of the TTX-R observed in DRG neurons to Nav1.8 Nav1.9 inactivation with The of Nav1.9 to in diabetic neuropathy a that of this channel effects on thermal hyperalgesia or tactile in the neuropathic rat J. D. S. L. S. L. Proc. Natl. Acad. Sci. U. S. A. 1999; PubMed Scopus Google Scholar). the that TTX-R channels are the that are in painful diabetic neuropathy. that to nerve reverses neuropathic pain K. J.M. Brain Res. 2000; PubMed Scopus Google Scholar). In nerve injury thermal hyperalgesia and tactile after that neuropathic pain is and the of Nav1.8 J. Pharmacol. PubMed Scopus Google Scholar, V. Wood J.N. 12: PubMed Scopus Google Scholar). these results suggest that TTX-S channels contribute to neuropathic pain. We observed that TTX-S contributes of the in small DRG neurons from both and diabetic rats. In diabetic the TTX-S currents increased significantly and the voltage of activation shifted in the the of TTX-S currents to the threshold and of action potentials is to to small in the potential J. Neurosci. 2002; PubMed Google the increased and of the activation of TTX-S in a to the of action potentials in with a potential the observed in diabetic rats. The activation of TTX-S currents in diabetic rats are to channels to more the TTX-S channels, Nav1.7 slow activation and inactivation and slow T.R. Waxman S.G. J. Neurosci. 1998; PubMed Google Scholar). In diabetic the increased expression of Nav1.7, in the threshold in these neurons M. Cummins T.R. Waxman S.G. J. Neurophysiol. PubMed Scopus Google Scholar) that expressed of neurons generate more responses to in diabetic rats with of the increased currents The increased expression of Nav1.7 in diabetic rats the of the action potential and the L. S.R. J. 2003; Scopus Google Scholar). that phosphorylation of Nav1.7 in a voltage sensitivity and or a that is by a in the steady-state activation K. M. M. J. Neurophysiol. PubMed Scopus Google Scholar). In activation of Nav1.7 of Nav1.7 channels or the A. T. H. H. PubMed Scopus Google Scholar). In to these observed increased Nav1.7 currents and increased phosphorylation of Nav1.7 and significantly in DRGs isolated from diabetic rats. We that of Nav1.7 phosphorylation channel function and expression in DRG neurons in with or Nav1.7 currents to Nav1.7 currents a of on channel function K. M. M. J. Neurophysiol. PubMed Scopus Google Scholar). the that tyrosine Nav1.7 in to and been that tyrosine phosphorylation by tyrosine sodium channel currents in S.G. J. Neurosci. 1998; PubMed Google Scholar) and of sodium channel function Y. T. Nat. Neurosci. 2000; PubMed Scopus Google Scholar). this of tyrosine phosphorylation of tyrosine fast sodium currents in J. J. 2003; PubMed Scopus Google Scholar). the of tyrosine phosphorylation in sodium channel Nav1.7 in diabetic neuropathy, to Nav1.6, that is expressed in both small and DRG neurons The expression of Nav1.6 channel in of diabetic DRG neurons was in the of neurons Nav1.6 or in expression in as by We observed phosphorylation of Nav1.6 and the level of tyrosine phosphorylation increased in DRGs isolated from diabetic rats. phosphorylation of Nav1.6 channels been implicated in the of J. Neurosci. PubMed Scopus Google Scholar, 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). currents in small DRG neurons from or diabetic rats this that this In this demonstrates that the function of TTX-S and TTX-R sodium channels are increased in early diabetic neuropathy contribute to the of painful diabetic neuropathy. These sodium currents are with increased phosphorylation both serine/threonine and tyrosine generation of or for TTX-S sodium channels to the of of TTX-S channels to the development of thermal hyperalgesia and mechanical allodynia in painful diabetic neuropathy, the for
Hong et al. (Thu,) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: