Institute of Biomedicine/Physiology, University of Helsinki, Biomedicum Helsinki, POB 63, 00014 Helsinki, Finland.
Neuropharmacology. 2010 Mar;58(3):578-84. doi: 10.1016/j.neuropharm.2009.12.001. Epub 2009 Dec 29.
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.
先前的研究结果表明，腹腔内给予 TRPA1 通道拮抗剂可减轻糖尿病性过敏。我们研究了糖尿病动物中 TRPA1 通道拮抗剂引起的抗敏作用是否通过作用于皮肤或脊髓中的 TRPA1 通道来解释，或者两者兼而有之。为了进行比较，我们还确定了皮肤和脊髓 TRPA1 通道在健康对照者中由涂用芥子油引起的过敏敏化发展中的作用。链脲佐菌素诱导大鼠发生糖尿病。通过单丝和足底压力诱发的肢体退缩反应评估过敏。鞘内（i.t.）给予 Chembridge-5861528（CHEM，TRPA1 通道拮抗剂）2.5-5.0μg/大鼠可显著减轻糖尿病性过敏，而腹腔内（i.pl.）给予 20μg CHEM 则可减轻糖尿病性过敏。在对照组中，腹腔内给予 CHEM（20μg）在芥子油处理部位产生微弱的抗敏作用。在对照组中，i.t.给予 CHEM（10μg）在芥子油处理区域（继发性痛觉过敏部位）产生强烈的抗敏作用，而在芥子油处理区域（原发性痛觉过敏部位）则无法影响过敏。用体外膜片钳记录验证了 CHEM 对大鼠 TRPA1 通道的可逆拮抗作用。结果表明，虽然皮肤 TRPA1 通道有助于糖尿病或局部涂用芥子油引起的机械性过敏，但脊髓 TRPA1 通道可能位于初级传入神经纤维的中枢末端，在这些情况下对维持机械性过敏起着重要作用。
