title: Pronociceptive effects induced by cutaneous application of a transient receptor potential ankyrin 1 (TRPA1) channel agonist methylglyoxal in diabetic animals: comparison with tunicamycin-induced endoplastic reticulum stress.
abstract: 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 MG was administered for the second time in the same but not adjacent plantar sites. Hypersensitivity induced by ER stress was reversed by pharmacological blocking of TRPA1. In vitro patch clamp recording indicated that tunicamycin itself (30 μM) is not a TRPA1 agonist. The results indicate that pain hypersensitivity induced by non-diabetic ER stress as well as that induced by diabetes is mediated TRPA1. Reduction of MG-induced hypersensitivity in diabetes or ER stress may, at least partly, be explained by peripheral mechanisms.
authors: Department of Physiology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
authors: H
authors: H
authors: Viisanen
authors: Orion Corporation, OrionPharma, Turku, Finland.
authors: H
authors: H
authors: Chapman
authors: Department of Physiology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
authors: H
authors: H
authors: Wei
authors: Department of Physiology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
authors: M
authors: M
authors: Lasierra Losada
authors: Orion Corporation, OrionPharma, Turku, Finland.
authors: A
authors: A
authors: Koivisto
authors: Department of Physiology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
authors: K E
authors: KE
authors: Akerman
authors: Department of Physiology, Faculty of Medicine, University of Helsinki, Helsinki, Finland. antti.pertovaara@helsinki.fi.
authors: A
authors: A
authors: Pertovaara
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced*; D008297:Male; D010147:Pain Measurement; D010812:Physical Stimulation; D011765:Pyruvaldehyde / Q000494:pharmacology*; D051381:Rats; D012867:Skin / Q000187:drug effects; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels / Q000819:agonists* / Q000502:physiology; D014415:Tunicamycin / Q000494:pharmacology*
chemical_list: D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; C480976:Trpa1 protein, rat; D014415:Tunicamycin; D011765:Pyruvaldehyde