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


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 ( administrations. In controls, 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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    ABSTRACT: TRPV1 is well known as a sensor ion channel that transduces a potentially harmful environment into electrical depolarization of the peripheral terminal of the nociceptive primary afferents. Although TRPV1 is also expressed in central regions of the nervous system, its roles in the area remain unclear. A series of recent reports on the spinal cord synapses have provided evidence that TRPV1 plays an important role in synaptic transmission in the pain pathway. Particularly, in pathologic pain states, TRPV1 in the central terminal of sensory neurons and interneurons is suggested to commonly contribute to pain exacerbation. These observations may lead to insights regarding novel synaptic mechanisms revealing veiled roles of spinal cord TRPV1 and may offer another opportunity to modulate pathological pain by controlling TRPV1. In this review, we introduce historical perspectives of this view and details of the recent promising results. We also focus on extended issues and unsolved problems to fully understand the role of TRPV1 in pathological pain. Together with recent findings, further efforts for fine analysis of TRPV1’s plastic roles in pain synapses at different levels in the central nervous system will promote a better understanding of pathologic pain mechanisms and assist in developing novel analgesic strategies.
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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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    ABSTRACT: The transient receptor potential ankyrin 1 (TRPA1) has been identified as a relevant target for the development of novel analgesics. Gallic acid (GA) is a polyphenolic compound commonly found in green tea and various berries and possesses a wide range of biological activities. The goal of this study was to identify GA as a TRPA1 antagonist and observe its antinociceptive effects in different pain models. First, we evaluated the ability of GA to affect cinnamaldehyde-induced calcium influx. Then, we observed the antinociceptive and antiedematogenic effects of GA (3-100 mg/kg) oral administration after the intraplantar ( injection of TRPA1 agonists (allyl isothiocyanate, cinnamaldehyde, or hydrogen peroxide-H2O2) in either an inflammatory pain model (carrageenan injection) or a neuropathic pain model (chronic constriction injury) in male Swiss mice (25-35 g). GA reduced the calcium influx mediated by TRPA1 activation. Moreover, the oral administration of GA decreased the spontaneous nociception triggered by allyl isothiocyanate, cinnamaldehyde, and H2O2. Carrageenan-induced allodynia and edema were largely reduced by the pretreatment with GA. Moreover, the administration of GA was also capable of decreasing cold and mechanical allodynia in a neuropathic pain model. Finally, GA was absorbed after oral administration and did not produce any detectable side effects. In conclusion, we found that GA is a TRPA1 antagonist with antinociceptive properties in relevant models of clinical pain without detectable side effects, which makes it a good candidate for the treatment of painful conditions.
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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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