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The Journal of Neuroscience, February 15, 2006, 26(7):1953-1960; doi:10.1523/JNEUROSCI.4065-05.2006

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Development/Plasticity/Repair
Deficient Nonpeptidergic Epidermis Innervation and Reduced Inflammatory Pain in Glial Cell Line-Derived Neurotrophic Factor Family Receptor 2 Knock-Out Mice

Päivi H. Lindfors, Vootele Võikar, Jari Rossi, and Matti S. Airaksinen

Neuroscience Center, University of Helsinki, 00014 Helsinki, Finland

Correspondence should be addressed to Matti S. Airaksinen, Neuroscience Center, Viikinkaari 4, University of Helsinki, 00014 Helsinki, Finland. Email: mairaksi{at}operoni.helsinki.fi

Most unmyelinated nociceptive neurons that mediate pain and temperature sensation from the skin bind isolectin B4 (IB4)-lectin and express Ret, the common signaling component of glial cell line-derived neurotrophic factor (GDNF) family. One of these factors, neurturin, is expressed in the epidermis, whereas its GDNF family receptor 2 (GFR2) is expressed in the majority of unmyelinated Ret-positive sensory neurons. However, the physiological roles of endogenous neurturin signaling in primary sensory neurons are poorly understood. Here, we show that the vast majority (85%) of IB4 binding and P2X₃ purinoreceptor-positive neurons, but virtually none of the calcitonin gene-related peptide (CGRP) or vanilloid receptor transient receptor potential vanilloid 1-positive neurons in mouse dorsal root ganglion (DRG) express GFR2. In GFR2 knock-out (KO) mice, the IB4-binding and P2X₃-positive DRG neurons were present but reduced in size, consistent with normal number but reduced caliber of unmyelinated axons in a cutaneous nerve. Strikingly, nonpeptidergic (CGRP-negative) free nerve endings in footpad epidermis were >70% fewer in GFR2-KO mice than in their wild-type littermates. In contrast, the density of CGRP-positive epidermal innervation remained unaffected. In the formalin test, the KO mice showed a normal acute response but a markedly attenuated persistent phase, indicating a deficit in inflammatory pain response. Behavioral responses of GFR2-KO mice to innocuous warm and noxious heat were not blunted; the mice were actually markedly hypersensitive to noxious cold in tail immersion test. Overall, our results indicate a critical role for endogenous GFR2 signaling in maintaining the size and terminal innervation of the nonpeptidergic class of cutaneous nociceptors in vivo.

Key words: cold hyperalgesia; cutaneous C-fiber innervation; formalin test; IB4-lectin; neurturin; noxious heat sensation

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Received Sept. 24, 2005; revised Jan. 4, 2006; accepted Jan. 5, 2006.

Correspondence should be addressed to Matti S. Airaksinen, Neuroscience Center, Viikinkaari 4, University of Helsinki, 00014 Helsinki, Finland. Email: mairaksi{at}operoni.helsinki.fi

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