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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    • "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.
    Archiv für Experimentelle Pathologie und Pharmakologie 04/2014; 387(7). DOI:10.1007/s00210-014-0978-0 · 2.47 Impact Factor
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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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    ABSTRACT: Transient receptor potential ankyrin 1 (TRPA1) channel antagonists have suppressed mechanical hypersensitivity in peripheral neuropathy, while their effect on ongoing neuropathic pain is not yet known. Here we assessed whether blocking the TRPA1 channel induces place-preference, an index for the relief of ongoing pain, in two experimental rat models of peripheral neuropathy. Diabetic neuropathy was induced by streptozotocin and spared nerve injury (SNI) model of neuropathy by ligation of two sciatic nerve branches. Conditioned place-preference (CPP) paradigm involved pairing of the drug treatment with one of the chambers of a CPP device once or four times, and the time spent in each chamber was recorded after conditioning sessions to reveal place-preference. The mechanical antihypersensitivity effect was assessed by the monofilament test immediately after the conditioning sessions. Intraperitoneally (30 mg/kg; diabetic and SNI model) or intrathecally (10 μg; diabetic model) administered Chembridge-5861528 (CHEM) was used as a selective TRPA1 channel antagonist. In diabetic and SNI models of neuropathy, CHEM failed to induce CPP at a dose that significantly attenuated mechanical hypersensitivity, independent of the route of drug administration or number of successive conditioning sessions. Intrathecal clonidine (an α(2)-adrenoceptor agonist; 10 μg), in contrast, induced CPP in SNI but not control animals. The results indicate that ongoing pain, as revealed by CPP, is less sensitive to treatment by the TRPA1 channel antagonist than mechanical hypersensitivity in peripheral neuropathy.
    Pharmacology Biochemistry and Behavior 12/2012; 104(1). DOI:10.1016/j.pbb.2012.12.014 · 2.78 Impact Factor
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    • "In contrast, pre-injection of an equivalent concentration of AITC (15 mM) caused a significant reduction in paw withdrawal threshold, indicative of hyperalgesia (Figure 1C). These results are similar to studies showing that AITC and cinnamaldehyde induce significant mechanical hyperalgesia in rats [24,25]. Furthermore, our data also suggest disparate in vivo effects of the two TRPA1 agonists 15d-PGJ2 and AITC. "
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    ABSTRACT: Background The Transient Receptor Potential (TRP) ion channel TRPA1 is a key player in pain pathways. Irritant chemicals activate ion channel TRPA1 via covalent modification of N-terminal cysteines. We and others have shown that 15-Deoxy-Δ12, 14-prostaglandin J2 (15d-PGJ2) similarly activates TRPA1 and causes channel-dependent nociception. Paradoxically, 15d-PGJ2 can also be anti-nociceptive in several pain models. Here we hypothesized that activation and subsequent desensitization of TRPA1 in dorsal root ganglion (DRG) neurons underlies the anti-nociceptive property of 15d-PGJ2. To investigate this, we utilized a battery of behavioral assays and intracellular Ca2+ imaging in DRG neurons to test if pre-treatment with 15d-PGJ2 inhibited TRPA1 to subsequent stimulation. Results Intraplantar pre-injection of 15d-PGJ2, in contrast to mustard oil (AITC), attenuated acute nocifensive responses to subsequent injections of 15d-PGJ2 and AITC, but not capsaicin (CAP). Intraplantar 15d-PGJ2—administered after the induction of inflammation—reduced mechanical hypersensitivity in the Complete Freund’s Adjuvant (CFA) model for up to 2 h post-injection. The 15d-PGJ2-mediated reduction in mechanical hypersensitivity is dependent on TRPA1, as this effect was absent in TRPA1 knockout mice. Ca2+ imaging studies of DRG neurons demonstrated that 15d-PGJ2 pre-exposure reduced the magnitude and number of neuronal responses to AITC, but not CAP. AITC responses were not reduced when neurons were pre-exposed to 15d-PGJ2 combined with HC-030031 (TRPA1 antagonist), demonstrating that inhibitory effects of 15d-PGJ2 depend on TRPA1 activation. Single daily doses of 15d-PGJ2, administered during the course of 4 days in the CFA model, effectively reversed mechanical hypersensitivity without apparent tolerance or toxicity. Conclusions Taken together, our data support the hypothesis that 15d-PGJ2 induces activation followed by persistent inhibition of TRPA1 channels in DRG sensory neurons in vitro and in vivo. Moreover, we demonstrate novel evidence that 15d-PGJ2 is analgesic in mouse models of pain via a TRPA1-dependent mechanism. Collectively, our studies support that TRPA1 agonists may be useful as pain therapeutics.
    Molecular Pain 09/2012; 8(1):75. DOI:10.1186/1744-8069-8-75 · 3.65 Impact Factor
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