Re-innervation patterns by peptidergic Substance-P, non-peptidergic P2X3, and myelinated NF-200 nerve fibers in epidermis and dermis of rats with neuropathic pain

Duraku, Liron S.; Hossaini, Mehdi; Schüttenhelm, Barthold N.; Holstege, Jan C.; Baas, Martijn; Ruigrok, Tom J. H.; Walbeehm, Erik T.

doi:10.1016/j.expneurol.2012.11.029

Cited by 41 publications

(59 citation statements)

References 57 publications

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“…Non-footpad areas contained a significantly (p < 0.001) higher density of nonpeptidergic epidermal P2 × 3-IR nerve fibers than did the footpad area. 9 Although the number of epidermal P2 × 3-IR nerve fibers increased after 5 weeks postoperatively, it never reached control levels (p < 0.001); indeed, it never exceeded more than half the density of that of sham-operated rats (Fig. 10).…”

Section: P2 × 3-ir Fibersmentioning

confidence: 86%

“…This notion is supported by the observation of normal responses to the von Frey test, while decreased IENF density was demonstrated in the collateral sprouted skin area compared with sham-operated rats in the spared nerve injury model. 9 Therefore, we believe that after withdrawal of collateral sprouted nerve fibers (after 5 weeks postoperatively), the relation between behavioral and histological data is more evident. This is confirmed by the finding of thermal hypersensitivity, which correlated well with the hyperinnervation by peptidergic epidermal nerve fibers noted at 20 weeks postoperatively.…”

Section: Thermal Hypersensitivity Correlated To Peptidergic Epidermalmentioning

confidence: 92%

“…Although we did not observe a correlation between mechanical hypersensitivity and the density of reinnervated fibers by specific subgroups of sensory nerve fibers, such a correlation was established in a recent study by Duraku et al 9 This discrepancy can be ascribed to differences in the experimental model that was applied. While Duraku et al ligated the nerve proximal from the nerve injury, thereby preventing nerve regeneration, 9 we examined actively regenerating axons following end-to-end reconstruction of the nerve.…”

Section: Thermal Hypersensitivity Correlated To Peptidergic Epidermalmentioning

confidence: 99%

“…45 It is also unclear if these fibers play a role in the pathogenesis of neuropathic pain similar to the spared nerve injury model. 9 While Stankovic et al showed a decrease in density of IENFs 12 weeks after end-to-end reconstruction of the sciatic nerve in rat, 40 the authors of a more recent study demonstrated return of the density of IENFs to control values in less than 9 weeks after reconstruction. 5 However, in humans, improvement of clinical signs can be seen up to 2 years after nerve reconstruction (Dr. E.T.…”

mentioning

confidence: 99%

“…Duraku et al recently showed the importance of the distinction between subgroups of intra-epidermal nerve fibers (IENFs) by extensive collateral sprouting of peptidergic fibers from uninjured nerves, compared with the nonpeptidergic fibers following a spared nerve injury lesion. 8,9 However, regeneration of the different subgroups of IENFs has not yet been described following end-to-end reconstruction, which provides a better outcome compared with nerve graft repair. 45 It is also unclear if these fibers play a role in the pathogenesis of neuropathic pain similar to the spared nerve injury model.…”

mentioning

confidence: 99%

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Long-term follow-up of peptidergic and nonpeptidergic reinnervation of the epidermis following sciatic nerve reconstruction in rats

Kambiz

Duraku

Baas

et al. 2015

JNS

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OBJECT Peripheral nerve injuries are a commonly encountered clinical problem and often result in long-term functional deficits. The current gold standard for transected nerves is an end-to-end reconstruction, which results in the intermittent appearance of neuropathic pain. METHODS To improve our understanding of the relation between this type of reconstruction and neuropathic pain, the authors transected and immediately end-to-end reconstructed the sciatic nerve in rats. The effect of this procedure on neuropathic pain, as measured by thermal and mechanical hypersensitivity at 4 different time points (5, 10, 20, and 30 weeks), was related to the density of peptidergic and nonpeptidergic fiber innervation in the glabrous skin of rats' hind paws. RESULTS Thermal hypersensitivity occurring 20 weeks after reconstruction was accompanied by a significant increase in peptidergic epidermal fibers. However, the lesion-induced reduction in the density of nonpeptidergic epidermal fibers remained decreased at all experimental time points. Moreover, temporal collateral sprouting by undamaged saphenous nerve was visualized using the recently revised Evans blue extravasation technique. Strikingly, as the sciatic nerve repopulated rats' hind paw, the saphenous nerve withdrew to its original territory. CONCLUSIONS The authors conclude that the transient thermal hypersensitivity is related to increased density of epidermal peptidergic fibers, which mainly originate from regenerating fibers. Furthermore, a changed composition in the peptidergic and nonpeptidergic epidermal fibers is demonstrated following end-to-end reconstruction of the sciatic nerve.

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Section: P2 × 3-ir Fibersmentioning

confidence: 86%

Section: Thermal Hypersensitivity Correlated To Peptidergic Epidermalmentioning

confidence: 92%

Section: Thermal Hypersensitivity Correlated To Peptidergic Epidermalmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Long-term follow-up of peptidergic and nonpeptidergic reinnervation of the epidermis following sciatic nerve reconstruction in rats

Kambiz

Duraku

Baas

et al. 2015

JNS

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The reduction of intraepidermal P2X₃ nerve fiber density correlates with behavioral hyperalgesia in a rat model of nerve injury‐induced pain

Bechakra

Schüttenhelm

Pederzani

et al. 2017

J of Comparative Neurology

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Skin biopsies from patients with neuropathic pain often show changes in epidermal innervation, although it remains to be elucidated to what extent such changes can be linked to a particular subgroup of nerve fibers and how these changes are correlated with pain intensity. Here, we investigated to what extent behavioral signs of hyperalgesia are correlated with immunohistochemical changes of peptidergic and non-peptidergic epidermal nerve fibers in a rat model of nerve injury-induced pain. Rats subjected to unilateral partial ligation of the sciatic nerve developed significant mechanical and thermal hyperalgesia as tested by the withdrawal responses of the ipsilateral footpad to von Frey hairs and hotplate stimulation. At day 14, epidermal nerve fiber density and total epidermal nerve fiber length/mm were significantly and consistently reduced compared to the contralateral side, following testing and re-testing by two blinded observers. The expression of calcitonin gene-related peptide, a marker for peptidergic nerve fibers, was not significantly changed on the ipsilateral side. In contrast, the expression of the P2X receptor, a marker for non-peptidergic nerve fibers, was not only significantly reduced but could also be correlated with behavioral hyperalgesia. When labeling both peptidergic and non-peptidergic nerve fibers with the pan-neuronal marker PGP9.5, the expression was significantly reduced, albeit without a significant correlation with behavioral hyperalgesia. In conjunction, our data suggest that the pathology of the P2X epidermal nerve fibers can be selectively linked to neuropathy, highlighting the possibility that it is the degeneration of these fibers that drives hyperalgesia.

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Longitudinal intravital imaging nerve degeneration and sprouting in the toes of spared nerve injured mice

Yeh

Lee

Hsiung

et al. 2021

J of Comparative Neurology

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Neuropathic pain is pain caused by damage to the somatosensory nervous system. Both degenerating injured nerves and neighboring sprouting nerves can contribute to neuropathic pain. However, the mesoscale changes in cutaneous nerve fibers over time after the loss of the parent nerve has not been investigated in detail. In this study, we followed the changes in nerve fibers longitudinally in the toe tips of mice that had undergone spared nerve injury (SNI). Nav1.8‐tdTomato, Thy1‐GFP and MrgD‐GFP mice were used to observe the small and large cutaneous nerve fibers. We found that peripheral nerve plexuses degenerated within 3 days of nerve injury, and free nerve endings in the epidermis degenerated within 2 days. The timing of degeneration paralleled the initiation of mechanical hypersensitivity. We also found that some of the Nav1.8‐positive nerve plexuses and free nerve endings in the fifth toe survived, and sprouting occurred mostly from 7 to 28 days. The timing of the sprouting of nerve fibers in the fifth toe paralleled the maintenance phase of mechanical hypersensitivity. Our results support the hypotheses that both injured and intact nerve fibers participate in neuropathic pain, and that, specifically, nerve degeneration is related to the initiation of evoked pain and nerve sprouting is related to the maintenance of evoked pain.

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Re-innervation patterns by peptidergic Substance-P, non-peptidergic P2X3, and myelinated NF-200 nerve fibers in epidermis and dermis of rats with neuropathic pain

Cited by 41 publications

References 57 publications

Long-term follow-up of peptidergic and nonpeptidergic reinnervation of the epidermis following sciatic nerve reconstruction in rats

Long-term follow-up of peptidergic and nonpeptidergic reinnervation of the epidermis following sciatic nerve reconstruction in rats

The reduction of intraepidermal P2X₃ nerve fiber density correlates with behavioral hyperalgesia in a rat model of nerve injury‐induced pain

Longitudinal intravital imaging nerve degeneration and sprouting in the toes of spared nerve injured mice

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Re-innervation patterns by peptidergic Substance-P, non-peptidergic P2X3, and myelinated NF-200 nerve fibers in epidermis and dermis of rats with neuropathic pain

Cited by 41 publications

References 57 publications

Long-term follow-up of peptidergic and nonpeptidergic reinnervation of the epidermis following sciatic nerve reconstruction in rats

Long-term follow-up of peptidergic and nonpeptidergic reinnervation of the epidermis following sciatic nerve reconstruction in rats

The reduction of intraepidermal P2X3 nerve fiber density correlates with behavioral hyperalgesia in a rat model of nerve injury‐induced pain

Longitudinal intravital imaging nerve degeneration and sprouting in the toes of spared nerve injured mice

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The reduction of intraepidermal P2X₃ nerve fiber density correlates with behavioral hyperalgesia in a rat model of nerve injury‐induced pain