Glial Cell Line-Derived Neurotrophic Factor Family Members Sensitize NociceptorsIn Vitroand Produce Thermal HyperalgesiaIn 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 capsaicinevoked Ca 2ϩ 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 GFR␣3 (for GDNF family receptor ␣) was seen in DRG, and GFR␣3 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.

Inflammatory and neuropathic cold allodynia are selectively mediated by the neurotrophic factor receptor GFRα3

“…The molecular processes whereby NGF/TrkA activation leads to heat hyperalgesia are well-documented (7), but to date, the molecular nature of GFL signaling on nociception has yet to be elucidated. For example, we and others have shown that acute exposure of GFLs, including artemin, in vivo leads to heat hyperalgesia (8,42,45). Similarly, GFLs potentiate capsaicin responses in dissociated DRG neurons recorded by Ca 2+ imaging, showing sensitization of TRPV1 + cells (45).…”

“…For example, we and others have shown that acute exposure of GFLs, including artemin, in vivo leads to heat hyperalgesia (8,42,45). Similarly, GFLs potentiate capsaicin responses in dissociated DRG neurons recorded by Ca 2+ imaging, showing sensitization of TRPV1 + cells (45). However, specific changes in TRPV1 channel activity have not been reported, and the preponderance of data suggests that artemin-induced heat hyperalgesia is caused by increased TRPV1 expression (27,28,46,47).…”

“…What is a remarkable and seminal result of our study is that injury-induced cold allodynia of multiple etiologies is totally dependent on GFRα3, unlike the redundant nature of heat and mechanical pain that signal through a diverse repertoire of cell surface receptors (1). NGF, protons, bradykinin, and histamine, to name a few, are all capable of potentiating TRPV1 responses (7,29,44,45) and responsible for the development of heat hyperalgesia. However, only artemin and NGF induce cold allodynia in a manner similar to that found after injury (8).…”

Le récepteur tyrosine kinase c-Kit

“…Chez l'adulte, ces facteurs neurotrophiques régulent également les propriétés fonctionnelles des nocicepteurs et leur expression est augmentée lors de l'inflammation tissulaire. L'injection de NGF, comme celle de GDNF, d'artémine ou de neurturine, induit une hyperalgé-sie thermique et mécanique, mimant une hyperalgésie inflammatoire [4]. Une des cibles moléculaires de l'effet pro-algique du NGF et de l'artémine est le récepteur TRPV1 (transient receptor potential vanilloid 1) [4][5][6].…”

“…L'injection de NGF, comme celle de GDNF, d'artémine ou de neurturine, induit une hyperalgé-sie thermique et mécanique, mimant une hyperalgésie inflammatoire [4]. Une des cibles moléculaires de l'effet pro-algique du NGF et de l'artémine est le récepteur TRPV1 (transient receptor potential vanilloid 1) [4][5][6]. En effet, il n'existe pas d'hyperalgésie secondaire à l'inflammation ni d'hyperalgésie thermique induites par le NGF chez les souris dont le gène TRPV1 a été invalidé [7][8][9].…”