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.
Neuroscience Center, University of Helsinki, 00014 Helsinki, Finland.
Päivi H
PH
Lindfors
Vootele
V
Võikar
Jari
J
Rossi
Matti S
MS
Airaksinen
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