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The Journal of Neuroscience, August 16, 2006, 26(33):8588-8599; doi:10.1523/JNEUROSCI.1726-06.2006

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Cellular/Molecular
Glial Cell Line-Derived Neurotrophic Factor Family Members Sensitize Nociceptors In Vitro and Produce Thermal Hyperalgesia In Vivo

Sacha A. Malin,¹ Derek C. Molliver,¹ H. Richard Koerber,² Pamela Cornuet,¹ Rebecca Frye,¹ Kathryn M. Albers,^1,2 and Brian M. Davis^1,2

Departments of ¹Medicine and ²Neurobiology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261

Correspondence should be addressed to Brian M. Davis, Department of Medicine, University of Pittsburgh, S843 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261. Email: bmd1{at}pitt.edu

Nerve growth factor (NGF) has been implicated as an effector of inflammatory pain because it sensitizes primary afferents to noxious thermal, mechanical, and chemical [e.g., capsaicin, a transient receptor potential vanilloid receptor 1 (TRPV1) agonist] stimuli and because NGF levels increase during inflammation. Here, we report the ability of glial cell line-derived neurotrophic factor (GDNF) family members artemin, neurturin and GDNF to potentiate TRPV1 signaling and to induce behavioral hyperalgesia. Analysis of capsaicin-evoked Ca²⁺ transients in dissociated mouse dorsal root ganglion (DRG) neurons revealed that a 7 min exposure to GDNF, neurturin, or artemin potentiated TRPV1 function at doses 10–100 times lower than NGF. Moreover, GDNF family members induced capsaicin responses in a subset of neurons that were previously insensitive to capsaicin. Using reverse transcriptase-PCR, we found that artemin mRNA was profoundly upregulated in response to inflammation induced by hindpaw injection of complete Freund’s adjuvant (CFA): artemin expression increased 10-fold 1 d after CFA injection, whereas NGF expression doubled by day 7. No increase was seen in neurturin or GDNF. A corresponding increase in mRNA for the artemin coreceptor GFR3 (for GDNF family receptor ) was seen in DRG, and GFR3 immunoreactivity was widely colocalized with TRPV1 in epidermal afferents. Finally, hindpaw injection of artemin, neurturin, GDNF, or NGF produced acute thermal hyperalgesia that lasted up to 4 h; combined injection of artemin and NGF produced hyperalgesia that lasted for 6 d. These results indicate that GDNF family members regulate the sensitivity of thermal nociceptors and implicate artemin in particular as an important effector in inflammatory hyperalgesia.

Key words: artemin; NGF; GDNF; neurturin; pain; TRPV1

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Received April 21, 2006; revised July 6, 2006; accepted July 6, 2006.

Correspondence should be addressed to Brian M. Davis, Department of Medicine, University of Pittsburgh, S843 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261. Email: bmd1{at}pitt.edu

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