Pronociceptive effects of a TRPA1 channel agonist methylglyoxal in healthy control and diabetic animals

Pronociceptive effects of a TRPA1 channel agonist methylglyoxal in healthy control and diabetic... 260Poster-abstracts from SASP 2013 / Scandinavian Journal of Pain 4 (2013) 255–260zolantidine (H2 receptor antagonist), but not with pyrilamine (H1receptor antagonist), reversed the antihypersensitivity effect of histamine. Zolantidine or pyrilamine alone in LC failed to influencepain behavior. The antihypersensitivity effect induced by histaminein LC was reduced also by spinal administration of atipamezole (an␣2 -adrenoceptor antagonist).Conclusions: The results indicate that histamine acting onH2 receptors in the LC attenuates mechanical hypersensitivity inperipheral neuropathy. The histamine-induced descending antihypersensitivity effect is at least partly mediated by noradrenergicpathways acting on the spinal ␣2 -adrenoceptor.http://dx.doi.org/10.1016/j.sjpain.2013.07.015B9Pronociceptive effects of a TRPA1 channelagonistmethylglyoxal in healthy control and diabeticanimalsHanna Viisanen 1 , Maria Lasierra 1 , Hong Wei 1 ,Ari Koivisto 2 ,Karl E. Åkerman 1 , Antti Pertovaara 11Institute of Biomedicine/Physiology, University ofHelsinki, Finland2 Orion Corporation, OrionPharma, FinlandAims: Methylglyoxal (MG), a reactive carbonyl compound generated in diabetes mellitus (DM), activates the TRPA1 ion channel.Here we studied whether MG induces mechanical hypersensitivity or ongoing pain and whether the pronociceptive effect of MG ischanged following its sustained endogenous release in DM.Methods: DM was induced by streptozotocin (50–60 mg/kg i.p.)in the rat. MG and Chembridge-5861528 (CHEM), a selective TRPA1channel antagonist, were administered intraplantarly (i.pl.) in control and diabetic animals. Limb withdrawal to monofilaments wasused as an index of hypersensitivity, and observation of sustainedpain-like behavior and conditioned place-avoidance test were usedto assess ongoing pain. In vitro calcium imaging was used to studywhether MG induces sustained activation of dorsal root ganglion(DRG) neurons of diabetic as well as control animals.Results: MG produced mechanical hypersensitivity and ongoingpain behavior in control animals, which effects were reduced indiabetic animals. CHEM treatment at a dose suppressing the MGinduced mechanical hypersensitivity failed to suppress the MGinduced ongoing pain behavior. MG was able to produce sustainedcalcium inflow in DRG neurons of DM as well as control animals.Conclusions: The results suggest that MG induces hypersensitivity and ongoing pain that are reduced in diabetes mellitus,possibly due to changes caused by the DM-induced sustainedendogenous release of MG. Moreover, the MG-induced mechanical hypersensitivity can be more effectively reversed by a TRPA1antagonist than the MG-induced ongoing pain behavior.http://dx.doi.org/10.1016/j.sjpain.2013.07.016B10Human inducible pluripotent stem cell-derivedsensory neurons express multiple functionalion channels and GPCRsM. Saarnilehto 1 , M. Pekkanen-Mattila 2 , K.Aalto-Setälä 2 ,O. Silvennoinen 2 , A. Koivisto 11In vitro Biology, Orion Pharma, Orion Corporation,Turku, Finland2 Institute of Biotechnology, University of Tampere,FinlandAims: Aim of the study was to characterize functional ion channel and GPCR responses by using selective pharmacological toolsand intracellular calcium imaging from human inducible pluripotent stem cell-derived sensory neurons.Methods: Sensory neurons were generated from human keratinocytes that were reprogrammed to inducible pluripotent stemcells by using standard Yamanaka factors. Inducible pluripotentstem cells were differentiated into sensory neurons by using 2 differentiation protocols (small molecule and PA6 co-culture). Sensoryneurons were loaded with intracellular calcium dye Fluo-4. Singlecell calcium imaging was performed with Photometrics EvolveEM-CCD camera at physiological temperature. Cells were perfusedwith a Ringer solution at 2–3 ml/min into which pharmacologicalcompounds were dissolved. Data was analyzed with Till PhotonicsOffline Analysis program.Results: Most of the results were obtained from PA6 differentiated neurons. 50 s application of 50 mM KCl solution was usedas diagnostic tool to activate voltage-gated calcium channels andthereby evoke intracellular calcium elevation. Functional ASIC,NMDA, kainate and TRPA1 ion channels were present in a subsetof sensory neurons. Majority of sensory neurons showed robustresponses to purinergic stimulation with ATP and histaminergicstimulation with histamine, but not to subtype selective histamineH1, H2 or H4 stimulation suggesting the presence of H3 receptorsubtype All cells responded strongly to protease-activated receptorstimulation with a low dose of trypsin. Interestingly, at single-celllevel notable heterogeneity of ion channel and GPCR responses wasobserved.Conclusions: Our results suggest that iPS-derived sensory neurons will be valuable in further pharmacological studies as well assensory neuropathy disease modeling.http://dx.doi.org/10.1016/j.sjpain.2013.07.017 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Scandinavian Journal of Pain de Gruyter

Pronociceptive effects of a TRPA1 channel agonist methylglyoxal in healthy control and diabetic animals

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Publisher
de Gruyter
Copyright
© 2013 Scandiavian Association for the Study of Pain
ISSN
1877-8860
eISSN
1877-8879
D.O.I.
10.1016/j.sjpain.2013.07.016
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Abstract

260Poster-abstracts from SASP 2013 / Scandinavian Journal of Pain 4 (2013) 255–260zolantidine (H2 receptor antagonist), but not with pyrilamine (H1receptor antagonist), reversed the antihypersensitivity effect of histamine. Zolantidine or pyrilamine alone in LC failed to influencepain behavior. The antihypersensitivity effect induced by histaminein LC was reduced also by spinal administration of atipamezole (an␣2 -adrenoceptor antagonist).Conclusions: The results indicate that histamine acting onH2 receptors in the LC attenuates mechanical hypersensitivity inperipheral neuropathy. The histamine-induced descending antihypersensitivity effect is at least partly mediated by noradrenergicpathways acting on the spinal ␣2 -adrenoceptor.http://dx.doi.org/10.1016/j.sjpain.2013.07.015B9Pronociceptive effects of a TRPA1 channelagonistmethylglyoxal in healthy control and diabeticanimalsHanna Viisanen 1 , Maria Lasierra 1 , Hong Wei 1 ,Ari Koivisto 2 ,Karl E. Åkerman 1 , Antti Pertovaara 11Institute of Biomedicine/Physiology, University ofHelsinki, Finland2 Orion Corporation, OrionPharma, FinlandAims: Methylglyoxal (MG), a reactive carbonyl compound generated in diabetes mellitus (DM), activates the TRPA1 ion channel.Here we studied whether MG induces mechanical hypersensitivity or ongoing pain and whether the pronociceptive effect of MG ischanged following its sustained endogenous release in DM.Methods: DM was induced by streptozotocin (50–60 mg/kg i.p.)in the rat. MG and Chembridge-5861528 (CHEM), a selective TRPA1channel antagonist, were administered intraplantarly (i.pl.) in control and diabetic animals. Limb withdrawal to monofilaments wasused as an index of hypersensitivity, and observation of sustainedpain-like behavior and conditioned place-avoidance test were usedto assess ongoing pain. In vitro calcium imaging was used to studywhether MG induces sustained activation of dorsal root ganglion(DRG) neurons of diabetic as well as control animals.Results: MG produced mechanical hypersensitivity and ongoingpain behavior in control animals, which effects were reduced indiabetic animals. CHEM treatment at a dose suppressing the MGinduced mechanical hypersensitivity failed to suppress the MGinduced ongoing pain behavior. MG was able to produce sustainedcalcium inflow in DRG neurons of DM as well as control animals.Conclusions: The results suggest that MG induces hypersensitivity and ongoing pain that are reduced in diabetes mellitus,possibly due to changes caused by the DM-induced sustainedendogenous release of MG. Moreover, the MG-induced mechanical hypersensitivity can be more effectively reversed by a TRPA1antagonist than the MG-induced ongoing pain behavior.http://dx.doi.org/10.1016/j.sjpain.2013.07.016B10Human inducible pluripotent stem cell-derivedsensory neurons express multiple functionalion channels and GPCRsM. Saarnilehto 1 , M. Pekkanen-Mattila 2 , K.Aalto-Setälä 2 ,O. Silvennoinen 2 , A. Koivisto 11In vitro Biology, Orion Pharma, Orion Corporation,Turku, Finland2 Institute of Biotechnology, University of Tampere,FinlandAims: Aim of the study was to characterize functional ion channel and GPCR responses by using selective pharmacological toolsand intracellular calcium imaging from human inducible pluripotent stem cell-derived sensory neurons.Methods: Sensory neurons were generated from human keratinocytes that were reprogrammed to inducible pluripotent stemcells by using standard Yamanaka factors. Inducible pluripotentstem cells were differentiated into sensory neurons by using 2 differentiation protocols (small molecule and PA6 co-culture). Sensoryneurons were loaded with intracellular calcium dye Fluo-4. Singlecell calcium imaging was performed with Photometrics EvolveEM-CCD camera at physiological temperature. Cells were perfusedwith a Ringer solution at 2–3 ml/min into which pharmacologicalcompounds were dissolved. Data was analyzed with Till PhotonicsOffline Analysis program.Results: Most of the results were obtained from PA6 differentiated neurons. 50 s application of 50 mM KCl solution was usedas diagnostic tool to activate voltage-gated calcium channels andthereby evoke intracellular calcium elevation. Functional ASIC,NMDA, kainate and TRPA1 ion channels were present in a subsetof sensory neurons. Majority of sensory neurons showed robustresponses to purinergic stimulation with ATP and histaminergicstimulation with histamine, but not to subtype selective histamineH1, H2 or H4 stimulation suggesting the presence of H3 receptorsubtype All cells responded strongly to protease-activated receptorstimulation with a low dose of trypsin. Interestingly, at single-celllevel notable heterogeneity of ion channel and GPCR responses wasobserved.Conclusions: Our results suggest that iPS-derived sensory neurons will be valuable in further pharmacological studies as well assensory neuropathy disease modeling.http://dx.doi.org/10.1016/j.sjpain.2013.07.017

Journal

Scandinavian Journal of Painde Gruyter

Published: Oct 1, 2013

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