SNS Na+ channel expression increases in dorsal root ganglion neurons in the carrageenan inflammatory pain model

Tanaka, Masaki; Cummins, Theodore R.; Ishikawa, Kuniko; Dib‐Hajj, Sulayman D.; Black, Joel A.; Waxman, Stephen G.

doi:10.1097/00001756-199804200-00003

Cited by 215 publications

(136 citation statements)

References 11 publications

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“…The latter are thought to be the properties of the sensory nerve specific (SNS)/peripheral nerve 3 (PN3) ␣ subunit . Whether or not SNS expression is altered during inflammation (see Okuse et al, 1997;Tanaka et al, 1998), there is evidence that NGF may upregulate TTXS Na ϩ currents and channels (e.g., PN1, ␣I and ␣II and ␤1) (Fjell et al, 1999b;Gould, III et al, 2000). Especially in C-fiber nociceptors, this NGF-dependent upregulation could increase the current density, AP kinetics of nociceptors and CV and may lower AP thresholds leading to reduced withdrawal thresholds (this paper and see Woolf et al, 1994;Djouhri and Lawson, 2001).…”

Section: Possible Ionic Mechanismsmentioning

confidence: 85%

Time Course and Nerve Growth Factor Dependence of Inflammation-Induced Alterations in Electrophysiological Membrane Properties in Nociceptive Primary Afferent Neurons

et al. 2001

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Novel findings of changes in nociceptive dorsal root ganglion (DRG) neurons during hindlimb inflammation induced by complete Freund's adjuvant (CFA) injections in the hindpaw and hindleg are reported. These include increased maximum fiber following frequency in nociceptive C-and A␦-fiber units by 2.7 and 3 times, respectively, and increased incidence of ongoing (spontaneous) activity by 3.3 times (to 54%) and 2.4 times (to 27%), respectively. These changes and the CFA-induced changes in somatic action potential (AP) configuration in nociceptive neurons were incomplete 24 hr after CFA. The nerve growth factor (NGF) dependence of the inflammation-induced changes was examined by injecting a synthetic NGF sequestering protein [tyrosine receptor kinase A Ig2 (trkA Ig2)] with CFA and subsequently into the CFA injection sites. NGF sequestration prevented some CFA-induced changes in nociceptive neurons including: the increased fiber following frequency (C and A␦), the increased proportions of units with ongoing activity (C and A␦), the decreased AP duration (C and A␦), but not the decreased afterhyperpolarization (AHP) durations (C, A␦, and A␣/␤) . AP variables of nociceptive units with spontaneous activity were examined.The time course of electrophysiological changes in nociceptive units is consistent with processes involving altered protein expression and/or retrograde transport of factors. These results (1) implicate NGF in regulating inflammation-induced decreases in AP duration and in increases in firing rate and spontaneous activity but not in decreases in AHP duration and (2) suggest clinical advantages of reducing NGF in some inflammatory pain states. Key words: nociceptive neurons; DRG; hyperalgesia; NGF; firing rate; spontaneous activityInflammation is accompanied by hyperalgesia and allodynia. The underlying neuronal mechanisms are not fully understood, but short-term (hours) changes at more than one level of the nociceptive pathway occur, including sensitization of peripheral terminals and of central pathways (for review, see Millan, 1999). However, it is clear that longer term (days) changes in the electrical properties of the entire primary afferent neuron also occur during inflammation. These include decreased durations both of somatic action potentials (APs) in nociceptive C-and A␦-fiber units and of afterhyperpolarizations (AHPs) in nociceptive A␦ and A␣/␤-fiber neurons . The time course of these changes was not known.Nerve growth factor (NGF) is upregulated in inflamed tissues and transported back to the dorsal root ganglia (DRGs) (Woolf et al., 1994). NGF is implicated in mediating inflammatory hyperalgesia because (1) administration of NGF leads to hyperalgesia in adult rats (Lewin et al

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Section: Possible Ionic Mechanismsmentioning

confidence: 85%

Time Course and Nerve Growth Factor Dependence of Inflammation-Induced Alterations in Electrophysiological Membrane Properties in Nociceptive Primary Afferent Neurons

et al. 2001

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“…If more inflammation was induced in the model we used, this could contribute to the differences in Na ϩ channel expression seen in the two studies. This is because inflammation and inflammatory mediators can increase Na ϩ channel expression (Baker and Wood 2001;Gould et al 1998;Khasar et al 1998;Tanaka et al 1998;Waxman et al 1999.…”

Section: Relationship To Other Studiesmentioning

confidence: 99%

“…We suggest that the increase in TTX-R I Na and TTX-S I Na seen in our experiments may simply reflect increased accumulation of both types of Na ϩ channels in the cell body as a result of in vivo axotomy. This effect may reflect the loss of axons in vivo and perhaps inflammation at the site of injury that would tend to up-regulate Na ϩ channel expression (Baker and Wood 2001;Gould et al 1998;Khasar et al 1998;Tanaka et al 1998;Waxman et al 1999. In summary, it may be supposed that three factors control TTX-R and TTX-S I Na expression in DRG cells after axotomy: loss of retrograde supply of NGF, channel accumulation in the cell body, and up-regulation of channel expression by inflammatory mediators (Gold et al 1996).…”

Section: Relationship To Other Studiesmentioning

confidence: 99%

Changes in Na⁺ Channel Currents of Rat Dorsal Root Ganglion Neurons Following Axotomy and Axotomy-Induced Autotomy

Abdulla

Smith

2002

Journal of Neurophysiology

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Abdulla, Fuad A. and Peter A. Smith. Changes in Na ϩ channel currents of rat dorsal root ganglion neurons following axotomy and axotomy-induced autotomy. J Neurophysiol 88: 2518 -2529, 2002; 10.1152/jn.00913.2001. Section of rat sciatic nerve (axotomy) increases the excitability of neurons in the L 4 -L 5 dorsal root ganglia (DRG). These changes are more pronounced in animals that exhibit a self-mutilatory behavior known as autotomy. We used whole cell recording to examine changes in the tetrodotoxin-sensitive (TTX-S) and the tetrodotoxin-resistant (TTX-R) components of sodium channel currents (I Na ) that may contribute to axotomy-induced increases in excitability. Cells were initially divided on the basis of size into "large," "medium," and "small" groups. TTX-S I Na predominated in "large" cells, whereas TTX-R I Na predominated in some, but not all "small cells." "Small" cells were therefore subdivided into "smallslow" cells, which predominately exhibited TTX-R I Na and "small fast" cells that exhibited more TTX-S I Na . In contrast to results obtained in other laboratories, where slightly different experimental procedures were used, we found that axotomy increased TTX-R and/or TTX-S I Na and slowed inactivation. The effects were greatest in "small-slow" cells and least in "large" cells. The changes promoted by axotomy were expressed more clearly in animals that exhibited autotomy. Also, the presence of autotomy correlated with a shift in the properties of I Na in "large" rather than "small-slow," putative nociceptive cells. These trends parallel previous observations on axotomyinduced increases in excitability, spike height, and spike width that are also greatest in "small" cells and least in "large" cells. In addition, the presence of autotomy correlates with an increase in excitability of "large" rather than "small" cells. Increases in TTX-R and TTX-S I Na thus coincide with axotomy-induced increases in excitability and alterations in spike shape across the whole population of sensory neurons. Injury-induced changes of this type are likely associated with the onset of chronic pain in humans.

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“…Reported alterations in the expression of both Na v 1.8 and Na v 1.9 in response to chronic constriction injury (CCI) are conflicting (Novakovic et al, 1998;Dib-Hajj et al, 1999;Decosterd et al, 2002), and the channels respond differently to inflammation (Tanaka et al, 1998;Black et al, 2004;Gould et al, 2004). This may be due to the complexity of the CCI model which produces preferential axotomy of large sized DRG neurons and exposure of the remaining intact axons to an inflammatory environment (Bennett and Xie, 1988;Kajander and Bennett, 1992) with increased levels of nerve growth factor (NGF) that increase injury-induced expression of these channels Fjell et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Neurotrophin-3 significantly reduces sodium channel expression linked to neuropathic pain states

Wilson-Gerwing

Stucky

McComb

et al. 2008

Experimental Neurology

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Neuropathic pain resulting from chronic constriction injury (CCI) is critically linked to sensitization of peripheral nociceptors. Voltage gated sodium channels are major contributors to this state and their expression can be upregulated by nerve growth factor (NGF). We have previously demonstrated that neurotrophin-3 (NT-3) acts antagonistically to NGF in modulation of aspects of CCI-induced changes in trkA-associated nociceptor phenotype and thermal hyperalgesia. Thus, we hypothesized that exposure of neurons to increased levels of NT-3 would reduce expression of Na v 1.8 and Na v 1.9 in DRG neurons subject to CCI. In adult male rats, Na v 1.8 and Na v 1.9 mRNAs are expressed at high levels in predominantly small to medium size neurons. One week following CCI, there is reduced incidence of neurons expressing detectable Na v 1.8 and Na v 1.9 mRNA, but without a significant decline in mean level of neuronal expression, and similar findings observed immunohistochemically. There is also increased accumulation/redistribution of channel protein in the nerve most apparent proximal to the first constriction site. Intrathecal infusion of NT-3 significantly attenuates neuronal expression of Na v 1.8 and Na v 1.9 mRNA contralateral and most notably, ipsilateral to CCI, with a similar impact on relative protein expression at the level of the neuron and constricted nerve. We also observe reduced expression of the common neurotrophin receptor p75 in response to CCI that is not reversed by NT-3 in small to medium sized neurons and may confer an enhanced ability of NT-3 to signal via trkA, as has been previously shown in other cell types. These findings are consistent with an analgesic role for NT-3.

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SNS Na+ channel expression increases in dorsal root ganglion neurons in the carrageenan inflammatory pain model

Cited by 215 publications

References 11 publications

Time Course and Nerve Growth Factor Dependence of Inflammation-Induced Alterations in Electrophysiological Membrane Properties in Nociceptive Primary Afferent Neurons

Time Course and Nerve Growth Factor Dependence of Inflammation-Induced Alterations in Electrophysiological Membrane Properties in Nociceptive Primary Afferent Neurons

Changes in Na⁺ Channel Currents of Rat Dorsal Root Ganglion Neurons Following Axotomy and Axotomy-Induced Autotomy

Neurotrophin-3 significantly reduces sodium channel expression linked to neuropathic pain states

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SNS Na+ channel expression increases in dorsal root ganglion neurons in the carrageenan inflammatory pain model

Cited by 215 publications

References 11 publications

Time Course and Nerve Growth Factor Dependence of Inflammation-Induced Alterations in Electrophysiological Membrane Properties in Nociceptive Primary Afferent Neurons

Time Course and Nerve Growth Factor Dependence of Inflammation-Induced Alterations in Electrophysiological Membrane Properties in Nociceptive Primary Afferent Neurons

Changes in Na+ Channel Currents of Rat Dorsal Root Ganglion Neurons Following Axotomy and Axotomy-Induced Autotomy

Neurotrophin-3 significantly reduces sodium channel expression linked to neuropathic pain states

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Changes in Na⁺ Channel Currents of Rat Dorsal Root Ganglion Neurons Following Axotomy and Axotomy-Induced Autotomy