Glial cell line-derived neurotrophic factor family members sensitize nociceptors in vitro and produce thermal hyperalgesia in vivo
- PMID: 16914685
- PMCID: PMC6674355
- DOI: 10.1523/JNEUROSCI.1726-06.2006
Glial cell line-derived neurotrophic factor family members sensitize nociceptors in vitro and produce thermal hyperalgesia in vivo
Abstract
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 GFRalpha3 (for GDNF family receptor alpha) was seen in DRG, and GFRalpha3 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.
Figures









Similar articles
-
Effects of the neurotrophic factor artemin on sensory afferent development and sensitivity.Sheng Li Xue Bao. 2008 Oct 25;60(5):565-70. Sheng Li Xue Bao. 2008. PMID: 18958361 Free PMC article.
-
Artemin growth factor increases nicotinic cholinergic receptor subunit expression and activity in nociceptive sensory neurons.Mol Pain. 2014 May 22;10:31. doi: 10.1186/1744-8069-10-31. Mol Pain. 2014. PMID: 24886596 Free PMC article.
-
Peripherally increased artemin is a key regulator of TRPA1/V1 expression in primary afferent neurons.Mol Pain. 2015 Mar 8;11:8. doi: 10.1186/s12990-015-0004-7. Mol Pain. 2015. PMID: 25889103 Free PMC article.
-
Postnatal roles of glial cell line-derived neurotrophic factor family members in nociceptors plasticity.Sheng Li Xue Bao. 2008 Oct 25;60(5):571-8. Sheng Li Xue Bao. 2008. PMID: 18958362 Free PMC article. Review.
-
Neurotrophins and hyperalgesia.Proc Natl Acad Sci U S A. 1999 Jul 6;96(14):7693-6. doi: 10.1073/pnas.96.14.7693. Proc Natl Acad Sci U S A. 1999. PMID: 10393882 Free PMC article. Review.
Cited by
-
Protein kinase A anchoring via AKAP150 is essential for TRPV1 modulation by forskolin and prostaglandin E2 in mouse sensory neurons.J Neurosci. 2008 May 7;28(19):4904-17. doi: 10.1523/JNEUROSCI.0233-08.2008. J Neurosci. 2008. PMID: 18463244 Free PMC article.
-
Increased function of the TRPV1 channel in small sensory neurons after local inflammation or in vitro exposure to the pro-inflammatory cytokine GRO/KC.Neurosci Bull. 2012 Apr;28(2):155-64. doi: 10.1007/s12264-012-1208-8. Neurosci Bull. 2012. PMID: 22466126 Free PMC article.
-
A ligand-receptor interactome platform for discovery of pain mechanisms and therapeutic targets.Sci Signal. 2021 Mar 16;14(674):eabe1648. doi: 10.1126/scisignal.abe1648. Sci Signal. 2021. PMID: 33727337 Free PMC article.
-
The transient receptor potential channel TRPA1: from gene to pathophysiology.Pflugers Arch. 2012 Nov;464(5):425-58. doi: 10.1007/s00424-012-1158-z. Epub 2012 Sep 22. Pflugers Arch. 2012. PMID: 23001121 Review.
-
Cytokine activin C ameliorates chronic neuropathic pain in peripheral nerve injury rodents by modulating the TRPV1 channel.Br J Pharmacol. 2020 Dec;177(24):5642-5657. doi: 10.1111/bph.15284. Epub 2020 Nov 16. Br J Pharmacol. 2020. PMID: 33095918 Free PMC article.
References
-
- Amann R, Schuligoi R, Herzeg G, Donnerer J (1995). Intraplantar injection of nerve growth factor into the rat hindpaw: local edema and effects on thermal nociceptive threshold. Pain 64:323–329. - PubMed
-
- Andreev N, Dimitrieva N, Koltzenburg M, McMahon SB (1995). Peripheral administration of nerve growth factor in the adult rat produces a thermal hyperalgesia that requires the presence of sympathetic post-ganglionic neurones. Pain 63:109–115. - PubMed
-
- Baloh RH, Tansey MG, Golden JP, Creedon DJ, Heuckeroth RO, Keck CL, Zimonjic DB, Popescu NC, Johnson EM Jr, Milbrandt J (1997). TrnR2, a novel receptor that mediates neurturin and GDNF signaling through Ret. Neuron 18:793–802. - PubMed
-
- Baudet C, Mikaels A, Westphal H, Johansen J, Johansen TE, Ernfors P (2000). Positive and negative interactions of GDNF, NTN and ART in developing sensory neuron subpopulations, and their collaboration with neurotrophins. Development 127:4335–4344. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases
Miscellaneous