The TRPV1/2/3 activator 2-aminoethoxydiphenyl borate sensitizes native nociceptive neurons to heat in wildtype but not TRPV1 deficient mice.
TRPV1 gene disruption results in a loss of capsaicin and proton responsiveness, but has minimal effects on heat-induced nocifensive behavior, suggesting that sensory transduction of heat is independent of TRPV1. TRPV3, another heat-activated ion channel but insensitive to capsaicin, was shown to be expressed in keratinocytes as well as in sensory neurons projecting to the skin. Recently, 2-aminoethoxydiphenyl borate was introduced as a TRPV3 agonist, but its selectivity was questioned by showing that it activated recombinant TRPV1 and TRPV2 as well. We used the isolated mouse skin-saphenous nerve preparation and whole-cell patch-clamping of cultured dorsal root ganglia neurons from TRPV1-/- and wildtype mice. We found no phenotypic differences between the heat responses of polymodal C-fibers, whereas cultured dorsal root ganglia neurons of TRPV1-/- hardly showed any heat-activated currents. Only C-fibers of wildtype but not TRPV1-/- mice were clearly sensitized to heat by 2-aminoethoxydiphenyl borate 10 and 100 microM; heat-activated current in wildtype neurons was only facilitated at 100 microM. Noxious heat-induced calcitonin gene-related peptide release showed clear deficits (<50%) in TRPV1 deficient skin, but the stimulated calcitonin gene-related peptide release from the isolated skull dura was unaffected. In both models, 2-aminoethoxydiphenyl borate was able to potentiate the heat response (46 degrees C, 5 min) in a concentration-dependent manner, again, only in wildtype but not TRPV1-/- mice, suggesting that TRPV2/3 are not involved in this sensitization to heat. The results further suggest that TRPV1 is not responsible for the normal heat response of native nociceptors but plays the essential role in thermal sensitization and a prominent one in controlling dermal calcitonin gene-related peptide release, i.e. neurogenic inflammation.
Zimmermann
K
K
Department of Physiology and Pathophysiology, Friedrich-Alexander-University Erlangen-Nuremberg, Universitaetsstrasse 17, D-91054 Erlangen, Germany. zimmermann@physiologie1.uni-erlangen.de
Leffler
A
A
Fischer
M M J
MM
Messlinger
K
K
Nau
C
C
Reeh
P W
PW
D000818:Animals; D001896:Boron Compounds / Q000494:pharmacology*; D015740:Calcitonin Gene-Related Peptide / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D006358:Hot Temperature; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009619:Nociceptors / Q000187:drug effects* / Q000378:metabolism; D009924:Organ Culture Techniques; D010146:Pain / Q000378:metabolism / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D012867:Skin / Q000187:drug effects / Q000294:innervation / Q000378:metabolism; D050916:TRPV Cation Channels / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*
D001896:Boron Compounds; D050916:TRPV Cation Channels; C109986:2-aminoethoxydiphenyl borate; D015740:Calcitonin Gene-Related Peptide