Roles of cutaneous versus spinal TRPA1 channels in mechanical hypersensitivity in the diabetic or mustard oil-treated non-diabetic rat.
Previous results indicate that intaperitoneal administration of a TRPA1 channel antagonist attenuates diabetic hypersensitivity. We studied whether the antihypersensitivity effect induced by a TRPA1 channel antagonist in diabetic animals is explained by action on the TRPA1 channel in the skin, the spinal cord, or both. For comparison, we determined the contribution of cutaneous and spinal TRPA1 channels to development of hypersensitivity induced by topical administration of mustard oil in healthy controls. Diabetes mellitus was induced by streptozotocin in the rat. Hypersensitivity was assessed by the monofilament- and paw pressure-induced limb withdrawal response. Intrathecal (i.t.) administration of Chembridge-5861528 (CHEM, a TRPA1 channel antagonist) at doses 2.5-5.0 microg/rat markedly attenuated diabetic hypersensitivity, whereas 20 microg of CHEM was needed to produce a weak attenuation of diabetic hypersensitivity with intraplantar (i.pl.) administrations. In controls, i.pl. administration of CHEM (20 microg) produced a weak antihypersensitivity effect at the mustard oil-treated site. I.t. administration of CHEM (10 microg) in controls produced a strong antihypersensitivity effect adjacent to the mustard oil-treated area (site of secondary hyperalgesia), while it failed to influence hypersensitivity at the mustard oil-treated area (site of primary hyperalgesia). A reversible antagonism of the rat TRPA1 channel by CHEM was verified using in vitro patch clamp recordings. The results suggest that while cutaneous TRPA1 channels contribute to mechanical hypersensitivity induced by diabetes or topical mustard oil, spinal TRPA1 channels, probably on central terminals of primary afferent nerve fibers, play an important role in maintenance of mechanical hypersensitivity in these conditions.
Wei
Hong
H
Institute of Biomedicine/Physiology, University of Helsinki, Biomedicum Helsinki, POB 63, 00014 Helsinki, Finland.
Chapman
Hugh
H
Saarnilehto
Marja
M
Kuokkanen
Katja
K
Koivisto
Ari
A
Pertovaara
Antti
A
D000447:Aldehydes / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D017487:Ankyrins; D000959:Antihypertensive Agents / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism*; D002461:Cell Line, Transformed; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003929:Diabetic Neuropathies / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D009149:Mustard Plant / Q000009:adverse effects; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010938:Plant Oils / Q000009:adverse effects; D051381:Rats; D017208:Rats, Wistar; D012867:Skin / Q000294:innervation / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; D013997:Time Factors; D014162:Transfection
D000447:Aldehydes; D017487:Ankyrins; D000959:Antihypertensive Agents; D015220:Calcium Channels; D015853:Cysteine Proteinase Inhibitors; D010938:Plant Oils; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; C480976:Trpa1 protein, rat; C027576:4-hydroxy-2-nonenal; C027793:mustard oil