A novel control mechanism based on GDNF modulation of somatostatin release from sensory neurones.
Small-diameter sensory neurones found in the rat dorsal root ganglia (DRG) include cells sensitive to glial cell line-derived neurotrophic factor (GDNF), which express the inhibitory peptide somatostatin (SOM). Here we addressed the functional relationship between GDNF and sensory neurone-derived SOM. Topical application of GDNF through the rat isolated dorsal horn of the spinal cord promoted activity-induced release of SOM from central terminals of sensory neurones. Once released by sensory neurones, SOM is known to act, at least in part, by opposing the action of Substance P (SP) in neurogenic inflammation. Therefore, we evaluated GDNF ability to modulate two well-documented effects of peripherally and centrally administered SP. Local application of GDNF in the mouse air pouch reduced SP-induced leukocyte migration. This effect of GDNF was mimicked by the SOM analog octreotide (OCT) and required intact SOM neuronal pools. Intrathecal injection of GDNF activated rat lumbar dorsal horn neurones and inhibited intrathecal SP-induced thermal hypersensitivity. This effect of GDNF was reversed by the SOM antagonist c-SOM and mimicked by OCT. In conclusion we propose GDNF regulation of neuronal SOM release as a novel mechanism that, if explored, may lead to new therapeutic strategies based on local release of somatostatin.
Malcangio
Marzia
M
Neuroscience Research Centre, Guy's, King's and St Thomas' School of Biomedical Sciences, King's College London, London SE1 1UL, UK. Marzia.Malcangio@kcl.ac.uk
Getting
Stephen J
SJ
Grist
John
J
Cunningham
Joanna R
JR
Bradbury
Elizabeth J
EJ
Charbel Issa
Peter
P
Lever
Isobel J
IJ
Pezet
Sophie
S
Perretti
Mauro
M
D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D046508:Culture Techniques; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006358:Hot Temperature; D007700:Kinetics; D051379:Mice; D008959:Models, Neurological; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D013004:Somatostatin / Q000378:metabolism*; D013373:Substance P / Q000037:antagonists & inhibitors; D013569:Synapses / Q000378:metabolism
C495040:Gdnf protein, mouse; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D013373:Substance P; D013004:Somatostatin