Anatomical evidence supporting the potential for modulation by multiple neurotrophins in the majority of adult lumbar sensory neurons

Karchewski, Laurie A.; Kim, F.A.; Johnston, Jayne M.; McKnight, R.M.; Verge, Valerie M. K.

doi:10.1002/(sici)1096-9861(19991018)413:2<327::aid-cne11>3.0.co;2-3

Cited by 76 publications

(61 citation statements)

References 66 publications

(97 reference statements)

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“…Qualitative examination of p75 mRNA expression in DRG subjected to one week unilateral CCI with or without NT-3 infusion begun at the time of injury, revealed that in intact DRG neurons p75 is heterogenously expressed at moderate to high levels across all size ranges of neurons (Figure 8), consistent with that previously reported (Verge et al, 1992,Karchewski et al, 1999. CCI results in a dramatic reduction in neuronal p75 expression (Figure 8).…”

Section: Expression Of the Common Neurotrophin Receptor P75 Is Alteresupporting

confidence: 86%

“…This insert region does not appear to affect the receptor's binding specificity or functional response to NGF, but can confer enhanced responsiveness of the receptor to NT-3 (Barker et al, 1993;Clary et al, 1994). We have shown virtually all trkA sensory neurons to co-express both isoforms, thus providing an anatomical substrate for this interaction (Karchewski et al, 1999). In addition, because in other cell types p75 has been shown to inhibit NT-3 signaling via trkA (Mischel et al, 2001), our observed downregulation of neuronal p75 expression following CCI may allow for enhanced signaling via trkA by NT-3.…”

Section: Potential Mechanisms Of Modulation Of Sodium Channel Expressmentioning

confidence: 68%

“…Our previous studies have demonstrated that DRG neurons co-express two isoforms of trkA, one that selectively binds and is activated by NGF and one with a 6 amino acid insert in the extracellular domain that binds and is activated by both NGF and NT-3 (Karchewski et al, 1999;Barker et al, 1993;Clary and Reichardt 1994). In other cell models, the common neurotrophin receptor, p75, inhibits NT-3 signaling through trkA (Mischel et al, 2001).…”

Section: Expression Of the Common Neurotrophin Receptor P75 Is Alterementioning

confidence: 99%

“…NT-3 can mitigate many aspects of trkAassociated nociceptive phenotype in vivo, including effecting a notable reduction in expression of trkA, NGF high-affinity binding sites, BDNF, substance P, and PACAP in the nociceptive subpopulation (Jongsma Wallin et al, 2001;Karchewski et al, 2002;Gratto and Verge, 2003). Up to half of trkA neurons express a low level of the cognate NT-3 receptor, trkC, while all express the common neurotrophin receptor p75 (Karchewski et al, 1999). It is unlikely that NT-3 signaling by trkC greatly influences the anti-nociceptive responses observed in intact neurons, because the downregulation of BDNF, substance P, and PACAP occurs predominantly in the subpopulation of trkA neurons that lack trkC and express the neuropeptide substance P (Jongsma Wallin et al, 2001;Karchewski et al, 2002;Gratto and Verge, 2003).…”

Section: Potential Mechanisms Of Modulation Of Sodium Channel Expressmentioning

confidence: 99%

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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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Section: Expression Of the Common Neurotrophin Receptor P75 Is Alteresupporting

confidence: 86%

Section: Potential Mechanisms Of Modulation Of Sodium Channel Expressmentioning

confidence: 68%

Section: Expression Of the Common Neurotrophin Receptor P75 Is Alterementioning

confidence: 99%

Section: Potential Mechanisms Of Modulation Of Sodium Channel Expressmentioning

confidence: 99%

See 2 more Smart Citations

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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“…The p75 neurotrophin receptor is expressed throughout the neurons in lumbar DRG and is usually coexpressed with trks. The type of trk expressed is dependent upon the cell type: trkA is expressed in small-to-mediumsized cells, trkB is expressed in medium-to-large-sized cells and trkC is expressed in large A cells [48]. Although the neurotrophic receptor expression has not been reported in A and B cells, it is most likely that part of the small B cells coexpress trkA and the p75 receptor.…”

Section: Discussionmentioning

confidence: 99%

The role of the p75 neurotrophin receptor in the morphology of dorsal root ganglion cells in streptozotocin diabetic mice: effects of sciatic nerve crush

Jiang

Jakobsen

2004

Diabetologia

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Aims/hypothesis. Neuronal dorsal root ganglion (DRG) cells seem to be vulnerable in diabetes. The aim of this study was to determine whether the p75 neurotrophin receptor stimulates perikaryal shrinkage and neuronal death, and further accelerates neuronal DRG cell loss after axotomy in a mouse model of diabetes. Methods. Nine non-diabetic BALB/c p75 +/+ mice, seven diabetic BALB/c p75 +/+ mice, nine non-diabetic p75 −/− mice and nine diabetic p75 −/− mice received a unilateral sciatic nerve crush 1 to 2 days after streptozotocin treatment. Tissues were fixed 28 days later by vascular perfusion, and the volume and number of the fifth lumbar DRG neurons were obtained using assumption-free stereological techniques. Results. In diabetic p75 +/+ mice there was a 9% reduction in the perikaryal volume of the DRG A cells (p<0.05) and a 10% reduction in the perikaryal volume of the DRG B cells (p<0.05) on the non-crushed side compared with in non-diabetic p75 +/+ mice. However, neuronal cell number was not reduced. Conversely, no perikaryal shrinkage of A cells or B cells occurred on the non-crushed side in diabetic p75 −/− mice, and no neuronal cell loss was observed. Following nerve crush, there was a loss of B cells in non-diabetic p75 +/+ mice (37±6%) and in diabetic p75 +/+ mice (36±4%). In non-diabetic p75 −/− mice, no neuronal cell loss occurred after crush, whereas in diabetic p75 −/− mice the loss of B cells (14±4%) was small but significant (p<0.02). Conclusions/interpretation. In experimental diabetes the p75 neurotrophin receptor is involved in neuronal DRG cell body shrinkage without loss of neuronal DRG cells. Following sciatic nerve crush, DRG cell loss is not accelerated in diabetic p75 +/+ mice.

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Differential effects of NGF and NT-3 on embryonic trigeminal axon growth patterns

2000

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We examined the effects of neurotrophins nerve growth factor (NGF) and neurotrophin-3 (NT-3) on trigeminal axon growth patterns. Embryonic (E13-15) wholemount explants of the rat trigeminal pathway including the whisker pads, trigeminal ganglia, and brainstem were cultured in serum-free medium (SFM) or SFM supplemented with NGF or NT-3 for 3 days. Trigeminal axon growth patterns were analyzed with the use of lipophilic tracer DiI. In wholemount cultures grown in SFM, trigeminal axon projections, growth patterns, and differentiation of peripheral and central targets are similar to in vivo conditions. We show that in the presence of NGF, central trigeminal axons leave the tract and grow into the surrounding brainstem regions in the elongation phase without any branching. On the other hand, NT-3 promotes precocious development of short axon collaterals endowed with focal arbors along the sides of the central trigeminal tract. These neurotrophins also affect trigeminal axon growth within the whisker pad. Additionally, we cultured dissociated trigeminal ganglion cells in the presence of NGF, NT-3, or NGF+NT-3. The number of trigeminal ganglion cells, their size distribution under each condition were charted, and axon growth was analyzed following immunohistochemical labeling with TrkA and parvalbumin antibodies. In these cultures too, NGF led to axon elongation and NT-3 to axon arborization. Our in vitro analyses suggest that aside from their survival promoting effects, NGF and NT-3 can differentially influence axon growth patterns of embryonic trigeminal neurons.

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Anatomical evidence supporting the potential for modulation by multiple neurotrophins in the majority of adult lumbar sensory neurons

Cited by 76 publications

References 66 publications

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

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

The role of the p75 neurotrophin receptor in the morphology of dorsal root ganglion cells in streptozotocin diabetic mice: effects of sciatic nerve crush

Differential effects of NGF and NT-3 on embryonic trigeminal axon growth patterns

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