GDNF induces mechanical hyperalgesia in muscle by reducing I(BK) in isolectin B4-positive nociceptors.
We have assessed the mechanism underlying glial cell-derived neurotrophic factor (GDNF)-induced mechanical hyperalgesia in the gastrocnemius muscle, using patch clamp electrophysiology, in vivo electrophysiology and behavioral studies. Cultured isolectin B4-positive (IB4+) dorsal root ganglion neurons that innervated this muscle were held under current clamp; the majority developed an increase in action potential duration (a factor of increase of 2.29±0.24, compared to 1.13±0.17 in control, P<0.01) in response to GDNF (200 ng/ml) by 15 min after application. They also demonstrated a depolarization of resting membrane potential, but without significant changes in rheobase, action potential peak, or after-hyperpolarization. Large-conductance voltage- and calcium-activated potassium (BK) channels, which have recently been shown to play a role in the repolarization of IB4+ nociceptors, were inhibited under voltage clamp, as indicated by a significant reduction in the iberiotoxin-sensitive current. In vivo single-fiber recording from muscle afferents revealed that injection of iberiotoxin into their peripheral nociceptive field caused an increase in nociceptor firing in response to a 60s suprathreshold stimulus (an increase from 392.2±119.8 spikes to 596.1±170.8 spikes, P<0.05). This was observed in the absence of changes in the mechanical threshold. Finally, injection of iberiotoxin into the gastrocnemius muscle produced dose-dependent mechanical hyperalgesia. These data support the suggestion that GDNF induces nociceptor sensitization and mechanical hyperalgesia, at least in part, by inhibiting BK current in IB4+ nociceptors.
Department of Oral and Maxillofacial Surgery, University of California at San Francisco, CA 94143-0440, USA.
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J
Hendrich
P
P
Alvarez
X
X
Chen
J D
JD
Levine
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D005727:Ganglia, Spinal / Q000378:metabolism; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism*; D006023:Glycoproteins / Q000378:metabolism; D006930:Hyperalgesia / Q000503:physiopathology*; D037102:Lectins / Q000378:metabolism; D008297:Male; D018482:Muscle, Skeletal / Q000294:innervation; D009619:Nociceptors / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D053675:Versicans
D051100:Glial Cell Line-Derived Neurotrophic Factor; D006023:Glycoproteins; D037102:Lectins; D024681:Potassium Channels, Calcium-Activated; C508324:Vcan protein, rat; D053675:Versicans