Correction: Methylglyoxal Evokes Pain by Stimulating TRPA1 (original) (raw)
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Methylglyoxal Evokes Pain by Stimulating TRPA1
PLoS ONE, 2013
Diabetic neuropathy is a severe complication of long-standing diabetes and one of the major etiologies of neuropathic pain. Diabetes is associated with an increased formation of reactive oxygen species and the electrophilic dicarbonyl compound methylglyoxal (MG). Here we show that MG stimulates heterologously expressed TRPA1 in CHO cells and natively expressed TRPA1 in MDCK cells and DRG neurons. MG evokes [Ca 2+ ] i -responses in TRPA1 expressing DRG neurons but is without effect in neurons cultured from Trpa1 2/2 mice. Consistent with a direct, intracellular action, we show that methylglyoxal is significantly more potent as a TRPA1 agonist when applied to the intracellular face of excised membrane patches than to intact cells. Local intraplantar administration of MG evokes a pain response in Trpa1 +/+ but not in Trpa1 2/2 mice. Furthermore, persistently increased MG levels achieved by two weeks pharmacological inhibition of glyoxalase-1 (GLO-1), the rate-limiting enzyme responsible for detoxification of MG, evokes a progressive and marked thermal (cold and heat) and mechanical hypersensitivity in wildtype but not in Trpa1 2/2 mice. Our results thus demonstrate that TRPA1 is required both for the acute pain response evoked by topical MG and for the long-lasting pronociceptive effects associated with elevated MG in vivo. In contrast to our observations in DRG neurons, MG evokes indistinguishable [Ca 2+ ] i -responses in pancreatic bcells cultured from Trpa1 +/+ and Trpa1 2/2 mice. In vivo, the TRPA1 antagonist HC030031 impairs glucose clearance in the glucose tolerance test both in Trpa1 +/+ and Trpa1 2/2 mice, indicating a non-TRPA1 mediated effect and suggesting that results obtained with this compound should be interpreted with caution. Our results show that TRPA1 is the principal target for MG in sensory neurons but not in pancreatic b-cells and that activation of TRPA1 by MG produces a painful neuropathy with the behavioral hallmarks of diabetic neuropathy.
Neurochemical Research, 2012
Diabetes mellitus, a debilitating chronic disease, affects *100 million people. Peripheral neuropathy is one of the most common early complications of diabetes in *66 % of these patients. Altered Ca 2? handling and Ca 2? signaling were detected in a huge variety of preparations isolated from animals with experimentally induced type 1 and 2 diabetes as well as patients suffering from the disease. We reviewed the role of Ca 2? signaling through cation channels and oxidative stress on diabetic neuropathic pain in sensory neurons. The pathogenesis of diabetic neuropathy involves the polyol pathway, advanced glycation end products, oxidative stress, protein kinase C activation, neurotrophism, and hypoxia. Experimental studies with respect to oxidative stress and Ca 2? signaling, inhibitor roles of antioxidants in diabetic neuropathic pain are also summarized in the review. We hypothesize that deficits in insulin, triggers alterations of sensory neurone phenotype that are critical for the development of abnormal Ca 2? homeostasis and oxidative stress and associated mitochondrial dysfunction. The transient receptor potential channels are a large family of proteins with six main subfamilies. The sheer number of different TRPs with distinct functions supports the statement that these channels are involved in a wide range of processes ranging in diabetic neuropathic pain and it seems that the TRPC, TRPM and TRPV groups are mostly responsible from diabetic neuropathic pain. In conclusion, the accumulating evidence implicating Ca 2? dysregulation and over production of oxidative stress products in diabetic neuropathic pains, along with recent advances in understanding of genetic variations in cation channels such as TRP channels, makes modulation of neuronal Ca 2? handling an increasingly viable approach for therapeutic interventions against the painful and degenerative aspects of many diabetic neuropathies.
Nature Medicine, 2012
Pain and hyperalgesia are key danger signals that are evoked by physical insults, noxious chemicals and inflammation. Such danger signals are also present in patients with diabetic neuropathy despite losses in sensory and autonomic functions in these individuals. Whereas the molecular mechanisms underlying inflammatory hyperalgesia are increasingly being unraveled, there is currently only a vague understanding of the mechanisms causing neuropathic pain in metabolic diseases such as diabetes 1 . In general, hyperglycemia has been emphasized as a major risk factor in these diseases; however, normalization of glucose concentrations has shown little benefit in affected individuals 1-3 .
Pharmacological Research, 2012
Peripheral diabetic neuropathy (PDN) is a devastating complication of diabetes mellitus (DM). Here we test the hypothesis that the transient receptor potential ankyrin 1 (TRPA1) ion channel on primary afferent nerve fibers is involved in the pathogenesis of PDN, due to sustained activation by reactive compounds generated in DM. DM was induced by streptozotocin in rats that were treated daily for 28 days with a TRPA1 channel antagonist (Chembridge-5861528) or vehicle. Laser Doppler flow method was used for assessing axon reflex induced by intraplantar injection of a TRPA1 channel agonist (cinnamaldehyde) and immunohistochemistry to assess substance P-like innervation of the skin. In vitro calcium imaging and patch clamp were used to assess whether endogenous TRPA1 agonists (4-hydroxynonenal and methylglyoxal) generated in DM induce sustained activation of the TRPA1 channel. Axon reflex induced by a TRPA1 channel agonist in the plantar skin was suppressed and the number of substance P-like immunoreactive nerve fibers was decreased 4 weeks after induction of DM. Prolonged treatment with Chembridge-5861528 reduced the DM-induced attenuation of the cutaneous axon reflex and loss of substance P-like immunoreactive nerve fibers. Moreover, in vitro calcium imaging and patch clamp results indicated that reactive compounds generated in DM (4-hydroxynonenal and methylglyoxal) produced sustained activations of the TRPA1 channel, a prerequisite for adverse long-term effects. The results indicate that the TRPA1 channel exerts an important role in the pathogenesis of PDN. Blocking the TRPA1 channel provides a selective disease-modifying treatment of PDN.
Journal of physiology and pharmacology : an official journal of the Polish Physiological Society, 2016
Methylglyoxal (MG) is a reactive carbonyl compound generated in diabetes mellitus. MG is an established transient receptor potential ankyrin 1 (TRPA1) channel agonist that contributes to TRPA1-mediated diabetic pain hypersensitivity. Here we studied whether exposure to diabetes and thereby to elevated endogenous MG modulates hypersensitivity induced by intradermal MG. Moreover, since diabetes induces endoplasmic reticulum (ER) stress, we compared the role of TRPA1 in diabetes and ER stress by assessing whether tunicamycin-induced ER stress, without diabetes, produces TRPA1-mediated pain hypersensitivity and by assessing whether ER stress and diabetes have similar modulatory effects on MG-induced hypersensitivity. In vitro patch clamp recording was performed to assess whether tunicamycin is a TRPA1 agonist. Behavioral tests showed that mechanical hypersensitivity induced by MG is reduced in diabetes and ER stress. In healthy controls, hypersensitivity induced by MG was reduced when M...
Methylglyoxal causes pain and hyperalgesia in human through C-fiber activation
Pain, 2019
The endogenous metabolite methylglyoxal (MG) accumulates in diabetic patients with neuropathic pain. Methylglyoxal could be a mediator of diabetes-induced neuropathic pain through TRPA1 activation and sensitization of the voltage-gated sodium channel subtype 1.8. In this study, we tested the algogenic and sensitizing effect of MG in healthy human subjects using intracutaneous microinjections. The involvement of C fibers was assessed through selective A-fiber nerve block, axon-reflex-erythema, and through single nerve fiber recordings in humans (microneurography). Involvement of the transduction channels TRPA1 and TRPV1 in MG-induced pain sensation was investigated with specific ion channel blockers. We showed for the first time in healthy humans that MG induces pain, axon-reflex-erythema, and long-lasting hyperalgesia through the activation of C nociceptors. Predominantly, the subclass of mechano-insensitive C fibers is activated by MG. A fibers contribute only negligibly to the burning pain sensation. Selective pharmacological blockade of TRPA1 or TRPV1 showed that TRPA1 is crucially involved in MG-induced chemical pain sensation and heat hyperalgesia. In conclusion, the actions of MG through TRPA1 activation on predominantly mechano-insensitive C fibers might be involved in spontaneously perceived pain in diabetic neuropathy and hyperalgesia as well as allodynia.