Spinal nerve ligation in mouse upregulates TRPV1 heat function in injured IB4-positive nociceptors.
Peripheral nerve injury leads to neuropathic pain, but the underlying mechanisms are not clear. The TRPV1 channel expressed by nociceptors is one receptor for noxious heat and inflammatory molecules. Lumbar 4 (L4) spinal nerve ligation (SNL) in mice induced persistent heat hyperalgesia 4 to 10 days after injury. The heat hypersensitivity was completely reversed by the TRPV1 antagonist A-425619. Furthermore, DRG neurons were isolated from the injured L4 ganglia or adjacent L3 ganglia 4 to 10 days after L4 SNL. Whole-cell patch-clamp recordings were performed and heat stimuli (22 degrees C to 50 degrees C/3 s) were applied to the soma. Neurons were classified by soma size and isolectin-B4 (IB4) binding. Among directly injured L4 neurons, SNL increased the percentage of small-diameter IB4-positive neurons that were heat-sensitive from 13% (naive controls) to 56% and conversely decreased the proportion of small IB4-negative neurons that were heat-sensitive from 66% (naive controls) to 34%. There was no change in IB4 binding in neurons from the injured ganglia. Surprisingly, in neurons from the adjacent L3 ganglia, SNL had no effect on the heat responsiveness of either IB4-positive or negative small neurons. Also, SNL had no effect on heat responses in medium-large-diameter neurons from either the injured or adjacent ganglia.


CONCLUSIONS
TRPV1 function is upregulated in IB4-positive sensory neurons, and TRPV1 is responsible for the behavioral heat hypersensitivity in the spinal nerve ligation model. Because IB4-positive neurons may contribute to the emotional perception of pain, TRPV1 antagonists, targeting both sensory and affective pain components, could have broad analgesic effects.
Vilceanu
Daniel
D
Department of Cell Biology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226-0509, USA.
Honore
Prisca
P
Hogan
Quinn H
QH
Stucky
Cheryl L
CL
D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D006358:Hot Temperature; D007546:Isoquinolines / Q000494:pharmacology; D037102:Lectins / Q000378:metabolism*; D008159:Lumbar Vertebrae; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009437:Neuralgia / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology*; D009619:Nociceptors / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D018373:Peripheral Nervous System Agents / Q000494:pharmacology; D011897:Random Allocation; D013127:Spinal Nerves / Q000293:injuries*; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
C503120:1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea; D007546:Isoquinolines; D037102:Lectins; D018373:Peripheral Nervous System Agents; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D014508:Urea