Intact sciatic myelinated primary afferent terminals collaterally sprout in the adult rat dorsal horn following section of a neighbouring peripheral nerve

Doubell, Timothy P.; Woolf, Clifford J.

doi:10.1002/(sici)1096-9861(19970331)380:1<95::aid-cne7>3.0.co;2-o

Cited by 61 publications

(45 citation statements)

References 39 publications

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“…IB4 neurons are nociceptive and innervate the epidermis (Hunt and Mantyh, 2001;Lu et al, 2001). Interestingly, IB4 neurons have been shown to have a reduced ability to regenerate in vitro, and following nerve injury in vivo, the projections from IB4 neurons retreat, resulting in hyperalgesia (Doubell et al, 1997;Leclere et al, 2007). This reduced growth capacity could be a feature linked to the high PTEN expression we identified within them, suggesting that PTEN inhibition may have a prominent role in the recovery of nociception after nerve injury.…”

Section: Discussionmentioning

confidence: 99%

PTEN Inhibition to Facilitate Intrinsic Regenerative Outgrowth of Adult Peripheral Axons

Christie¹,

Webber²,

Martinez³

et al. 2010

Journal of Neuroscience

303

283

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In vivo regeneration of peripheral neurons is constrained and rarely complete, and unfortunately patients with major nerve trunk transections experience only limited recovery. Intracellular inhibition of neuronal growth signals may be among these constraints. In this work, we investigated the role of PTEN (phosphatase and tensin homolog deleted on chromosome 10) during regeneration of peripheral neurons in adult Sprague Dawley rats. PTEN inhibits phosphoinositide 3-kinase (PI3-K)/Akt signaling, a common and central outgrowth and survival pathway downstream of neuronal growth factors. While PI3-K and Akt outgrowth signals were expressed and activated within adult peripheral neurons during regeneration, PTEN was similarly expressed and poised to inhibit their support. PTEN was expressed in neuron perikaryal cytoplasm, nuclei, regenerating axons, and Schwann cells. Adult sensory neurons in vitro responded to both graded pharmacological inhibition of PTEN and its mRNA knockdown using siRNA. Both approaches were associated with robust rises in the plasticity of neurite outgrowth that were independent of the mTOR (mammalian target of rapamycin) pathway. Importantly, this accelerated outgrowth was in addition to the increased outgrowth generated in neurons that had undergone a preconditioning lesion. Moreover, following severe nerve transection injuries, local pharmacological inhibition of PTEN or siRNA knockdown of PTEN at the injury site accelerated axon outgrowth in vivo. The findings indicated a remarkable impact on peripheral neuron plasticity through PTEN inhibition, even within a complex regenerative milieu. Overall, these findings identify a novel route to propagate intrinsic regeneration pathways within axons to benefit nerve repair.

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Section: Discussionmentioning

confidence: 99%

PTEN Inhibition to Facilitate Intrinsic Regenerative Outgrowth of Adult Peripheral Axons

Christie¹,

Webber²,

Martinez³

et al. 2010

Journal of Neuroscience

303

283

View full text Add to dashboard Cite

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“…In adult animals, it is well established that projections of IB4-labeled neurons in the dorsal horn regress after PNS lesions (White et al, 1990;Bennett et al, 1998;Bailey and Ribeiro-daSilva, 2006), although projections of CGRP-positive neurons appear less affected. One consequence of the regression of the IB4-labeled axonal projection is that it might allow sprouting of other classes of axons into the denervated territory, which could contribute to hyperalgesia associated with nerve lesions (Doubell et al, 1997), although this hypothesis has been challenged (Bao et al, 2002;Hughes et al, 2003;Shehab et al, 2004). However, in animal models of neuropathic pain, the associated hyperalgesia may be reduced by intrathecal infusions of GDNF (Boucher and McMahon, 2001), and such infusions also prevent the regression of the IB4 labeling in the dorsal horns after PN injury (Bennett et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Impaired Axonal Regeneration by Isolectin B4-Binding Dorsal Root Ganglion NeuronsIn Vitro

Leclere¹,

Norman²,

Groutsi³

et al. 2007

J. Neurosci.

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The subpopulation of dorsal root ganglion (DRG) neurons recognized by Griffonia simplicifolia isolectin B4 (IB4) differ from other neurons by expressing receptors for glial cell line-derived neurotrophic factor (GDNF) rather than neurotrophins. Additionally, IB4-labeled neurons do not express the laminin receptor, ␣7-integrin (Gardiner et al., 2005), necessary for optimal axonal regeneration in the peripheral nervous system. In cultures of dissociated DRG neurons of adult mice on laminin, robust spontaneous neurite outgrowth from IB4-negative neurons occurs and is strongly enhanced by previous axotomy. In contrast, IB4-labeled neurons show little neurite outgrowth and do not express GAP 43, even after axotomy or culture with GDNF. Moreover, growth of their axons through collagen gels is impaired compared with other DRG neurons. To determine whether the sparse neurite outgrowth of IB4-labeled neurons is attributable to lack of integrin expression, DRG cultures were infected with a herpes simplex 1 vector encoding ␣7-integrin, but its forced expression failed to promote neurite outgrowth in either IB4-labeled or other DRG neurons or in cultured adult retinal ganglion cells. Forced coexpression of both ␣7-integrin and GAP 43 also failed to promote neurite outgrowth in IB4-labeled neurons. In addition, cultured sciatic nerve segments were found to release much lower levels of GDNF, demonstrated by ELISA, than nerve growth factor. These findings together with their impaired intrinsic axonal regeneration capacity may contribute to the known vulnerability of the IB4-labeled population of DRG neurons to peripheral nerve injury.

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“…It is likely that the mechanisms of pain chronicity develop in the early stages after nerve injury. Indeed, structural plasticity in the nociceptive network, which is considered an important contributor to chronicity of neuropathic pain symptoms such as mechanical pain hypersensitivity, occurs within days after nerve injury (Doubell et al, 1997;Shortland et al, 1997;Woolf et al, 1992Woolf et al, ,1995.…”

Section: Introductionmentioning

confidence: 99%

Neuropathy-Induced Spinal GAP-43 Expression Is Not a Main Player in the Onset of Mechanical Pain Hypersensitivity

Jaken

Gorp

Joosten

et al. 2011

Journal of Neurotrauma

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Structural plasticity within the spinal nociceptive network may be fundamental to the chronic nature of neuropathic pain. In the present study, the spatiotemporal expression of growth-associated protein-43 (GAP-43), a protein which has been traditionally implicated in nerve fiber growth and sprouting, was investigated in relation to mechanical pain hypersensitivity. An L5 spinal nerve transection model was validated by the presence of mechanical pain hypersensitivity and an increase in the early neuronal activation marker cFos within the superficial spinal dorsal horn upon innocuous hindpaw stimulation. Spinal GAP-43 was found to be upregulated in the superficial L5 dorsal horn from 5 up to 10 days after injury. GAP-43 was co-localized with calcitoningene related peptide (CGRP), but not vesicular glutamate transporter-1 (VGLUT-1), IB4, or protein kinase-c (PKC-c), suggesting the regulation of GAP-43 in peptidergic nociceptive afferents. These GAP-43/CGRP fibers may be indicative of sprouting peptidergic fibers. Fiber sprouting largely depends on growth factors, which are typically associated with neuro-inflammatory processes. The putative role of neuropathy-induced GAP-43 expression in the development of mechanical pain hypersensitivity was investigated using the immune modulator propentofylline. Propentofylline treatment strongly attenuated the development of mechanical pain hypersensitivity and glial responses to nerve injury as measured by microglial and astroglial markers, but did not affect neuropathy-induced levels of spinal GAP-43 or GAP-43 regulation in CGRP fibers. We conclude that nerve injury induces structural plasticity in fibers expressing CGRP, which is regarded as a main player in central sensitization. Our data do not, however, support a major role of these structural changes in the onset of mechanical pain hypersensitivity.

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Intact sciatic myelinated primary afferent terminals collaterally sprout in the adult rat dorsal horn following section of a neighbouring peripheral nerve

Cited by 61 publications

References 39 publications

PTEN Inhibition to Facilitate Intrinsic Regenerative Outgrowth of Adult Peripheral Axons

PTEN Inhibition to Facilitate Intrinsic Regenerative Outgrowth of Adult Peripheral Axons

Impaired Axonal Regeneration by Isolectin B4-Binding Dorsal Root Ganglion NeuronsIn Vitro

Neuropathy-Induced Spinal GAP-43 Expression Is Not a Main Player in the Onset of Mechanical Pain Hypersensitivity

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