Article

Roles of cutaneous versus spinal TRPA1 channels in mechanical hypersensitivity in the diabetic or mustard oil-treated non-diabetic rat

Institute of Biomedicine/Physiology, University of Helsinki, Biomedicum Helsinki, POB 63, 00014 Helsinki, Finland.
Neuropharmacology (Impact Factor: 5.11). 12/2009; 58(3):578-84. DOI: 10.1016/j.neuropharm.2009.12.001
Source: PubMed

ABSTRACT

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.

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Available from: Ari-Pekka Koivisto, Dec 16, 2013
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    • "Indeed, the presynaptic facilitative role of TRPA1 in the spinal cord has been addressed [59]. The effects of antagonistic challenges against spinal TRPA1 function were examined and the treatment displayed analgesic outcomes in diverse pain models including SNL, rapid eye movement sleep deprivation , capsaicin-paw injection, formalin-paw injection, and diabetic neuropathy [60] [61] [62]. It was further demonstrated that the pain-facilitating effect of descending excitatory inputs from RVM stimulation or spinal cord 5-HT3 receptor activation was all blunted by TRPA1 antagonism [62]. "
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    • "The capacity of GA to pass through the bloodbrain barrier is important because it could block the actions of some recently identified endogenous TRPA1 ligands in spinal cord that are involved in the maintenance of mechanical allodynia observed in animal models and reduce the allodynia (Buxton 2006; Sisignano et al. 2012; Gregus et al. 2012). Therefore, TRPA1 antagonists that are able to reach the spinal cord seem to have efficacy in reducing the mechanical allodynia associated with neuropathic and inflammatory pain (Chen et al. 2011; da Costa et al. 2009; Wei et al. 2009a, 2012). "
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    • "The spinal TRPA1 channel on central terminals of nociceptive nerve fibers, in contrast, has so far been associated only with modulation of stimulus-evoked pain responses, such as secondary or central hypersensitivity (Da Costa et al., 2010; Kremeyer et al., 2010; Wei et al., 2010a, 2011; Sisignano et al., 2012; Klafke et al., 2012), or a dorsal root reflex-mediated aggravation of cutaneous neurogenic inflammation (Wei et al., 2010b), but not yet with spontaneous pain (Pertovaara and Koivisto, 2011; Wei et al., 2012). In stimulus-evoked neuropathic hypersensitivity the spinal TRPA1 channel has proved to play an important role as shown by the mechanical antihypersensitivity effect induced by spinal administration of a TRPA1 channel antagonist in nerve-injured or diabetic animals (Wei et al., 2010a, 2011). "
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