Deficient nonpeptidergic epidermis innervation and reduced inflammatory pain in glial cell line-derived neurotrophic factor family receptor alpha2 knock-out mice.
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 alpha2 (GFRalpha2) 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 (approximately 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 GFRalpha2. In GFRalpha2 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 GFRalpha2-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 GFRalpha2-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 GFRalpha2 signaling in maintaining the size and terminal innervation of the nonpeptidergic class of cutaneous nociceptors in vivo.
Lindfors
Päivi H
PH
Neuroscience Center, University of Helsinki, 00014 Helsinki, Finland.
Võikar
Vootele
V
Rossi
Jari
J
Airaksinen
Matti S
MS
D000818:Animals; D002452:Cell Count; D002460:Cell Line; D004817:Epidermis / Q000294:innervation*; D005727:Ganglia, Spinal / Q000502:physiology / Q000503:physiopathology; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000502:physiology; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006358:Hot Temperature; D007249:Inflammation / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D009457:Neuroglia / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000502:physiology; D010146:Pain / Q000503:physiopathology
C494991:Gfra2 protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors