Glial cell line-derived neurotrophic factor acutely modulates the excitability of rat small-diameter trigeminal ganglion neurons

Irritable bowel syndrome is characterized by colorectal hypersensitivity and contributed to by sensitized mechanosensitive primary afferents and recruitment of mechanoinsensitive (silent) afferents. Neurotrophic factors are well known to orchestrate dynamic changes in the properties of sensory neurons. Although pain modulation by proteins in the glial cell line-derived neurotrophic factor (GDNF) family has been documented in various pathophysiological states, their role in colorectal hypersensitivity remains unexplored. Therefore, we investigated the involvement of the GDNF family receptor α-3 (GFRα3) signaling in visceral hypersensitivity by quantifying visceromotor responses (VMR) to colorectal distension before and after intracolonic treatment with 2,4,6-trinitrobenzene sulfonic acid (TNBS). Baseline responses to colorectal distension did not differ between C57BL/6 and GFRα3 knockout (KO) mice. Relative to intracolonic saline treatment, TNBS significantly enhanced the VMR to colorectal distension in C57BL/6 mice 2, 7, 10, and 14 days posttreatment, whereas TNBS-induced visceral hypersensitivity was significantly suppressed in GFRα3 KO mice. The proportion of GFRα3 immunopositive thoracolumbar and lumbosacral colorectal dorsal root ganglion neurons was significantly elevated 2 days after TNBS treatment. In single fiber recordings, responses to circumferential stretch of colorectal afferent endings in C57BL/6 mice were significantly increased (sensitized) after exposure to an inflammatory soup, whereas responses to stretch did not sensitize in GFRα3 KO mice. These findings suggest that enhanced GFRα3 signaling in visceral afferents may contribute to development of colorectal hypersensitivity.

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Regulation of nociceptive neurons by nerve growth factor and glial cell line derived neurotrophic factor

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y02-034 ◽

2002 ◽

Vol 80 (5) ◽

pp. 495-505 ◽

Cited By ~ 116

Author(s):

J V Priestley ◽

G J Michael ◽

S Averill ◽

M Liu ◽

N Willmott

Keyword(s):

Nerve Growth Factor ◽

Growth Factor ◽

Dorsal Root Ganglion ◽

Cell Line ◽

Glial Cell ◽

Neurotrophic Factor ◽

Dorsal Root ◽

Small Diameter ◽

Nerve Growth ◽

Nociceptive Neurons

Nociceptive dorsal root ganglion (DRG) cells can be divided into three main populations, namely (1) small diameter non-peptide-expressing cells, (2) small-diameter peptide-expressing (calcitonin gene related peptide (CGRP), substance P) cells, and (3) medium-diameter peptide-expressing (CGRP) cells. The properties of these cell populations will be reviewed, with a special emphasis on the expression of the vanilloid (capsaicin) receptor VR1 and its regulation by growth factors. Cells in populations 1 and 2 express VR1, a nonselective channel that transduces certain nociceptive stimuli and that is crucial to the functioning of polymodal nociceptors. Cells in population 1 can be regulated by glial cell line derived neurotrophic factor (GDNF) and those in populations 2 and 3 by nerve growth factor (NGF). In vivo, DRG cells express a range of levels of VR1 expression and VR1 is downregulated after axotomy. However, treatment with NGF or GDNF can prevent this downregulation. In vitro, DRG cells also show a range of VR1 expression levels that is NGF and (or) GDNF dependent. Functional studies indicate that freshly dissociated cells also show differences in sensitivity to capsaicin. The significance of this is not known but may indicate a difference in the physiological role of cells in populations 1 and 2.Key words: nociceptors, CGRP, IB4, vanilloid, dorsal root ganglion.

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