Unmyelinated primary afferents from adjacent spinal nerves intermingle in the spinal dorsal horn: A possible mechanism contributing to neuropathic pain

Shehab, Safa; Al-Marashda, Khadija; Al-Zahmi, Amal; Abdul-Kareem, Afaf; Al-Sultan, M. A. H.

doi:10.1016/j.brainres.2008.02.089

Cited by 23 publications

(33 citation statements)

References 41 publications

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“…Both IB4 and WGA labelling produced similar results, with the central terminals of labelled afferents for both tracers arborising principally in lamina II. Although this finding is entirely consistent with previous studies where the labelling patterns of both tracers have been compared (Robertson and Grant, 1985;LaMotte et al, 1991;Kitchener et al, 1994;Wang et al, 1994;Gerke and Plenderleith, 2004;Shehab et al, 2008;Shehab, 2009) and also those reporting that C fibres terminate mainly in lamina II (Sugiura et al, 1986(Sugiura et al, , 1989Willis and Coggeshall, 1991;Ribeiro-daSilva, 2004), we have used IB4 for the main part of this study to label C-fibres selectively because (i) WGA was also shown to stain myelinated fibres as illustrated by labelling of terminals in the gracile nucleus and motor neurons in the ventral horn, and (ii) unlike WGA, IB4 does not exhibit any sign of trans-synaptic labelling (Robertson and Grant, 1985;Weinberg et al, 1990;LaMotte et al, 1991;Kitchener et al, 1993).…”

Section: Technical Issuessupporting

confidence: 92%

“…Other factors which might affect the extent of central labelling include the concentrations of tracer injected and the post-injection survival period. We routinely use both concentrations of the tracers and post-injection survival periods that are in line with many other investigators (Swett and Woolf, 1985;Valtschanoff et al, 1992;Kitchener et al, 1993;Wang et al, 1994;Tong et al, 1999;Kitao et al, 2002;Shehab et al, 2003Shehab et al, , 2004Shehab et al, , 2008Jancsó et al, 2004;Shehab, 2009). By comparing these technical parameters with those used by Liu et al (1995) which are not too dissimilar, it is difficult to explain why they failed to obtain adequate labelling with combined injections whereas we succeeded.…”

Section: Comparison With Other Workmentioning

confidence: 54%

“…In spinal cord sections, CTb-labelled terminals are found in laminae I and II inner (IIi) to IX, but are normally very sparse in the outer part of lamina II (IIo) (Robertson and Grant, 1985;LaMotte et al, 1991;Grant, 1990, 1991;Woolf et al, 1992;Shehab et al, 2003Shehab et al, , 2004Shehab, 2009). In contrast, the central terminals of WGA-or IB4-labelled afferents terminate preferentially in lamina II (Swett and Woolf, 1985;Robertson and Grant, 1985;LaMotte et al, 1991;Kitchener et al, 1993Kitchener et al, ,1994Wang et al, 1994;Fullmer et al, 2004;Shehab et al, 2008;Shehab, 2009). While these studies illustrate that both myelinated and unmyelinated primary afferents can be labelled selectively using single injections of CTb, WGA or IB4, attempts to label both populations simultaneously with co-injections of CTb and WGA have been variable (LaMotte et al, 1991;Liu et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

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Simultaneous identification of unmyelinated and myelinated primary somatic afferents by co-injection of isolectin B4 and Cholera toxin subunit B into the sciatic nerve of the rat

Shehab

Hughes

2011

Journal of Neuroscience Methods

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Section: Technical Issuessupporting

confidence: 92%

Section: Comparison With Other Workmentioning

confidence: 54%

Section: Introductionmentioning

confidence: 99%

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Simultaneous identification of unmyelinated and myelinated primary somatic afferents by co-injection of isolectin B4 and Cholera toxin subunit B into the sciatic nerve of the rat

Shehab

Hughes

2011

Journal of Neuroscience Methods

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“…However, a proportion of afferents project in Lissauer's tract to up to two spinal segments rostrally and one spinal segment caudally. The L4 dorsal horn not only receives afferents from L4, but also from ligated L5/L6 dorsal roots (Besse et al, 1991;Shehab et al, 2008). This may contribute to the small, but statistically significant elevation of ␣ 2 ␦-1 in ipsilateral L4 after SNL.…”

Section: Discussionmentioning

confidence: 99%

The Increased Trafficking of the Calcium Channel Subunit α₂δ-1 to Presynaptic Terminals in Neuropathic Pain Is Inhibited by the α₂δ Ligand Pregabalin

Bauer

Nieto-Rostro²,

Rahman³

et al. 2009

J. Neurosci.

383

378

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Neuropathic pain results from damage to the peripheral sensory nervous system, which may have a number of causes. The calcium channel subunit ␣ 2 ␦-1 is upregulated in dorsal root ganglion (DRG) neurons in several animal models of neuropathic pain, and this is causally related to the onset of allodynia, in which a non-noxious stimulus becomes painful. The therapeutic drugs gabapentin and pregabalin (PGB), which are both ␣ 2 ␦ ligands, have antiallodynic effects, but their mechanism of action has remained elusive. To investigate this, we used an in vivo rat model of neuropathy, unilateral lumbar spinal nerve ligation (SNL), to characterize the distribution of ␣ 2 ␦-1 in DRG neurons, both at the light-and electron-microscopic level. We found that, on the side of the ligation, ␣ 2 ␦-1 was increased in the endoplasmic reticulum of DRG somata, in intracellular vesicular structures within their axons, and in the plasma membrane of their presynaptic terminals in superficial layers of the dorsal horn. Chronic PGB treatment of SNL animals, at a dose that alleviated allodynia, markedly reduced the elevation of ␣ 2 ␦-1 in the spinal cord and ascending axon tracts. In contrast, it had no effect on the upregulation of ␣ 2 ␦-1 mRNA and protein in DRGs. In vitro, PGB reduced plasma membrane expression of ␣ 2 ␦-1 without affecting endocytosis. We conclude that the antiallodynic effect of PGB in vivo is associated with impaired anterograde trafficking of ␣ 2 ␦-1, resulting in its decrease in presynaptic terminals, which would reduce neurotransmitter release and spinal sensitization, an important factor in the maintenance of neuropathic pain.

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“…This increase was observed in the superficial dorsal horn of the lumbar spinal cord. We propose that the innocuous stimuli are transmitted to a sensitized lumbar spinal cord via the intact L4 nerve, which is known to innervate multiple levels of the spinal cord (L2-L5 levels; Shehab et al, 2008). Although it is tempting to link structural plasticity, particularly that related to CGRP, a well-known sensitizing molecule, to neuropathy-induced pain hypersensitivity, we still lack extensive knowledge about this scientific niche.…”

Section: Spinal Gap-43 Expression and Nerve Injurymentioning

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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Unmyelinated primary afferents from adjacent spinal nerves intermingle in the spinal dorsal horn: A possible mechanism contributing to neuropathic pain

Cited by 23 publications

References 41 publications

Simultaneous identification of unmyelinated and myelinated primary somatic afferents by co-injection of isolectin B4 and Cholera toxin subunit B into the sciatic nerve of the rat

Simultaneous identification of unmyelinated and myelinated primary somatic afferents by co-injection of isolectin B4 and Cholera toxin subunit B into the sciatic nerve of the rat

The Increased Trafficking of the Calcium Channel Subunit α₂δ-1 to Presynaptic Terminals in Neuropathic Pain Is Inhibited by the α₂δ Ligand Pregabalin

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

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Unmyelinated primary afferents from adjacent spinal nerves intermingle in the spinal dorsal horn: A possible mechanism contributing to neuropathic pain

Cited by 23 publications

References 41 publications

Simultaneous identification of unmyelinated and myelinated primary somatic afferents by co-injection of isolectin B4 and Cholera toxin subunit B into the sciatic nerve of the rat

Simultaneous identification of unmyelinated and myelinated primary somatic afferents by co-injection of isolectin B4 and Cholera toxin subunit B into the sciatic nerve of the rat

The Increased Trafficking of the Calcium Channel Subunit α2δ-1 to Presynaptic Terminals in Neuropathic Pain Is Inhibited by the α2δ Ligand Pregabalin

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

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The Increased Trafficking of the Calcium Channel Subunit α₂δ-1 to Presynaptic Terminals in Neuropathic Pain Is Inhibited by the α₂δ Ligand Pregabalin