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Intrathecal NGF Administration Reduces Reactive Astrocytosis and Changes Neurotrophin Receptors Expression Pattern in a Rat Model of Neuropathic Pain

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Abstract

Nerve growth factor (NGF), an essential peptide for sensory neurons, seems to have opposite effects when administered peripherally or directly to the central nervous system. We investigated the effects of 7-days intrathecal (i.t.) infusion of NGF on neuronal and glial spinal markers relevant to neuropathic behavior induced by chronic constriction injury (CCI) of the sciatic nerve. Allodynic and hyperalgesic behaviors were investigated by Von Frey and thermal Plantar tests, respectively. NGF-treated animals showed reduced allodynia and thermal hyperalgesia, compared to control animals. We evaluated on lumbar spinal cord the expression of microglial (ED-1), astrocytic (GFAP and S-100β), and C- and Aδ-fibers (SubP, IB-4 and Cb) markers. I.t. NGF treatment reduced reactive astrocytosis and the density of SubP, IB4 and Cb positive fibers in the dorsal horn of injured animals. Morphometric parameters of proximal sciatic nerve stump fibers and cells in DRG were also analyzed in CCI rats: myelin thickness was reduced and DRG neurons and satellite cells appeared hypertrophic. I.t. NGF treatment showed a beneficial effect in reversing these molecular and morphological alterations. Finally, we analyzed by immunohistochemistry the expression pattern of neurotrophin receptors TrkA, pTrkA, TrkB and p75NTR. Substantial alterations in neurotrophin receptors expression were observed in the spinal cord of CCI and NGF-treated animals. Our results indicate that i.t. NGF administration reverses the neuro-glial morphomolecular changes occurring in neuropathic animals paralleled by alterations in neurotrophin receptors ratio, and suggest that NGF is effective in restoring homeostatic conditions in the spinal cord and maintaining analgesia in neuropathic pain.

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Abbreviations

NGF:

Nerve growth factor

CCI:

Chronic constriction injury

GFAP:

Glial fibrillary acidic protein

SubP:

Substance P

IB-4:

Isolectin B4

Cb:

Calbindin

Trk:

Tyrosine kinase receptor

pTrkA:

Phosphorylated TrkA

p75NTR :

p75 neurotrophin receptor

i.t.:

Intrathecal

DRG:

Dorsal root ganglia

CNS:

Central nervous system

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Acknowledgments

This work was supported by grants from Regione Campania (L.R. N.5 Bando 2003 to M.P.), the Italian Minister of Research and University (PRIN2007 to M.P. and to A.M.C.), Regione Campania (Prog. Spec art 12 E.F. 2000 to M.P.), the CNR (Neurobiotecnologie 2003 to M.P.) and FIRB-ITALBIONET to L.A.

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Authors and Affiliations

  1. Laboratorio di Morfologia delle Reti Neuronali, Dipartimento di Medicina Pubblica Clinica e Preventiva, Seconda Università di Napoli, 80138, Naples, Italy

    Giovanni Cirillo, Carlo Cavaliere, Maria Rosaria Bianco, Antonietta De Simone, Stefania Sellitti & Michele Papa

  2. Laboratorio di Neuroscienze “R. Levi-Montalcini”, Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan, Italy

    Anna Maria Colangelo & Lilia Alberghina

  3. Blueprint Biotech srl, Milano, Italy

    Lilia Alberghina

  4. Department of Medicina Pubblica Clinica e Preventiva, Institute of Human Anatomy, Second University of Naples, 80100, Naples, Italy

    Michele Papa

Authors
  1. Giovanni Cirillo
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  2. Carlo Cavaliere
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  3. Maria Rosaria Bianco
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  4. Antonietta De Simone
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  5. Anna Maria Colangelo
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  6. Stefania Sellitti
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  7. Lilia Alberghina
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  8. Michele Papa
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Correspondence to Michele Papa.

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Cirillo, G., Cavaliere, C., Bianco, M.R. et al. Intrathecal NGF Administration Reduces Reactive Astrocytosis and Changes Neurotrophin Receptors Expression Pattern in a Rat Model of Neuropathic Pain. Cell Mol Neurobiol 30, 51–62 (2010). https://doi.org/10.1007/s10571-009-9430-2

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  • DOI: https://doi.org/10.1007/s10571-009-9430-2

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