Analgesic effect of dimethyl trisulfide in mice is mediated by TRPA1 and sst 4 receptors

Pozsgai, Gábor; Payrits, Maja; Sághy, Éva; Sebestyen-Batai, Reka; Steen, E. M.; Szöke, Éva; Szepes, Zoltán; Solymár, Margit; Garami, András; Orvos, Péter; Tálosi, László; Helyes, Zsuzsanna; Pintér, Erika

doi:10.1016/j.niox.2017.01.012

Cited by 31 publications

(50 citation statements)

References 66 publications

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“…H 2 S attenuates or enhances the inflammatory processes in animal models depending of the type of inflammation and H 2 S-concentration. H 2 S has several different actions [ 37 ]: it modifies proteins by S-sulfhydration [ 38 ], acts on ezymes (e.g., cytochrome c oxidase, kinases), and has influence on ion channels (e.g., L-type Ca 2+ channels, chloride channels, transient receptor potential ankyrin 1 (TRPA1) ion channel, and K ATP channel) [ 35 , 36 , 39 – 42 ]. Since we know that the capsaicin-sensitive sensory nerves densely innervate the joints and the TRPA1 receptors, expressed on these nerve terminals, a key molecule of nociception and local inflammatory responses [ 43 ], these ion channels can be a possible link between the mineral water and pain perception.…”

Section: Discussionmentioning

confidence: 99%

Investigation of Lake Hévíz Mineral Water Balneotherapy and Hévíz Mud Treatment in Murine Osteoarthritis and Rheumatoid Arthritis Models

Tékus

Borbély

Kiss

et al. 2018

Evidence-Based Complementary and Alternative Medicine

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Arthritic diseases are the most frequent causes of chronic pain and disability. Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial inflammation and progressive structural joint damage. Osteoarthritis is a degenerative process of the articular cartilage associated with hypertrophic changes in the bone. The aim of the present study was to investigate the anti-inflammatory and analgesic effects of Hévíz thermal water and mud in monosodium iodoacetate- (MIA-) (25 mg/ml, 20 μl i.a.) induced osteoarthritis and Complete Freund's adjuvant- (CFA-) (1 mg/ml, 50–50 μl s.c) induced rheumatoid arthritis murine models. The mechanonociceptive threshold of female NMRI mice (n=6– 8 mice/ group) was measured by aesthesiometry, and paw volume was monitored with plethysmometry, knee joint diameter with digital micrometer, and dynamic weight bearing on the hind limbs with a Bioseb instrument. Periarticular bone destruction was assessed by SkyScan 1176 in vivo micro-CT. Inflammatory cytokines were detected by ELISA in plasma samples. Treatments (30 min, every working day) with tap water, sand, and a combined therapy of tap water and sand served as controls. Hévíz medicinal water and combined treatment with water and mud significantly decreased the mechanical hyperalgesia and knee oedema in MIA-induced osteoarthritis model. However, balneotherapy did not influence mechanical hyperalgesia, weight bearing, or oedema formation induced by CFA. Neither medicinal water nor mud treatment ameliorated deep structural damage of the bones or the joints in the animal models. On the basis of the present findings, we conclude that balneotherapy is an effective complementary treatment to reduce the pain sensation and swelling in degenerative joint diseases such as osteoarthritis. Our experimental data are in agreement with the previous human studies that also confirmed antinociceptive and anti-inflammatory effects of thermal water and Hévíz mud treatments.

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Section: Discussionmentioning

confidence: 99%

Investigation of Lake Hévíz Mineral Water Balneotherapy and Hévíz Mud Treatment in Murine Osteoarthritis and Rheumatoid Arthritis Models

Tékus

Borbély

Kiss

et al. 2018

Evidence-Based Complementary and Alternative Medicine

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“…We have reported lately antinociceptive properties of DMTS against mechanical hyperalgesia evoked by heat injury in mice. Transient receptor potential ankyrin 1 (TRPA1) ion channels and somatostatin (SOM) sst4 receptors contribute pivotally to these effects ( 9 ). Chemically, alkyl trisulfides (such as DMTS) produce tri/disulfide metabolites with the thiol groups of cysteine amino acids (unlike inorganic POLYs leading to protein persulfidation).…”

Section: Introductionmentioning

confidence: 99%

Role of Transient Receptor Potential Ankyrin 1 Ion Channel and Somatostatin sst4 Receptor in the Antinociceptive and Anti-inflammatory Effects of Sodium Polysulfide and Dimethyl Trisulfide

et al. 2018

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Transient receptor potential ankyrin 1 (TRPA1) non-selective ligand-gated cation channels are mostly expressed in primary sensory neurons. Polysulfides (POLYs) are Janus-faced substances interacting with numerous target proteins and associated with both protective and detrimental processes. Activation of TRPA1 in sensory neurons, consequent somatostatin (SOM) liberation and action on sst4 receptors have recently emerged as mediators of the antinociceptive effect of organic trisulfide dimethyl trisulfide (DMTS). In the frame of the present study, we set out to compare the participation of this mechanism in antinociceptive and anti-inflammatory effects of inorganic sodium POLY and DMTS in carrageenan-evoked hind-paw inflammation. Inflammation of murine hind paws was induced by intraplantar injection of carrageenan (3% in 30 µL saline). Animals were treated intraperitoneally with POLY (17 µmol/kg) or DMTS (250 µmol/kg) or their respective vehicles 30 min prior paw challenge and six times afterward every 60 min. Mechanical pain threshold and swelling of the paws were measured by dynamic plantar aesthesiometry and plethysmometry at 2, 4, and 6 h after initiation of inflammation. Myeloperoxidase (MPO) activity in the hind paws were detected 6 h after challenge by luminescent imaging. Mice genetically lacking TRPA1 ion channels, sst4 receptors and their wild-type counterparts were used to examine the participation of these proteins in POLY and DMTS effects. POLY counteracted carrageenan-evoked mechanical hyperalgesia in a TRPA1 and sst4 receptor-dependent manner. POLY did not influence paw swelling and MPO activity. DMTS ameliorated all examined inflammatory parameters. Mitigation of mechanical hyperalgesia and paw swelling by DMTS were mediated through sst4 receptors. These effects were present in TRPA1 knockout animals, too. DMTS inhibited MPO activity with no participation of the sensory neuron–SOM axis. While antinociceptive effects of POLY are transmitted by activation of peptidergic nerves via TRPA1, release of SOM and its effect on sst4 receptors, those of DMTS partially rely on SOM release triggered by other routes. SOM is responsible for the inhibition of paw swelling by DMTS, but TRPA1 does not contribute to its release. Modulation of MPO activity by DMTS is independent of TRPA1 and sst4.

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“…This could explain why activation of TRPA1 channels in wild‐type mouse diminishes mild heat injury‐induced thermal hyperalgesia; nevertheless, it cannot be observed in TRPA1 receptor knock out animals. Alkylated polysulfide compounds, such as dimethyl trisulfide (DMTS), activate TRPA1 channels of primary sensory neurons inducing release of the neuropeptide somatostatin that might elicit analgesic effect in animal models of nociception via sst4 receptors (Pozsgai et al ., ).…”

Section: Neuronal and Non‐neuronal Trpa1 Channelsmentioning

confidence: 97%

“…administration of DMTS inhibited nociception, oedema formation and myeloperoxidase activity in murine carrageenan‐evoked paw inflammation. These inhibitory effects were still present in TRPA1 knockout mice, indicating actions independent of TRPA1 channels (Bautista et al ., ; Koizumi et al ., ; Yassaka et al ., ; Shokoohinia et al ., ; Pozsgai et al ., ; Bátai et al ., ) (Table ).…”

Section: Effects Of Sulfur Species Mediated By Trpa1 Channelsmentioning

confidence: 98%

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Effects of sulfide and polysulfides transmitted by direct or signal transduction‐mediated activation of TRPA1 channels

Pozsgai

Bátai

Pintér

2018

British J Pharmacology

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Hydrogen sulfide (H2S) is a gaseous mediator in various physiological and pathological processes, including neuroimmune modulation, metabolic pathways, cardiovascular system, tumour growth, inflammation and pain. Now the hydrogen polysulfides (H2Sn) have been recognised as signalling molecules modulating ion channels, transcription factors and protein kinases. Transient receptor potential (TRP) cation channels can be activated by mechanical, thermal or chemical triggers. Here, we review the current literature regarding the biological actions of sulfide and polysulfide compounds mediated by TRP channels with special emphasis on the role of TRPA1, best known as ion channels in nociceptors. However, the non‐neuronal TRPA1 channels should also be considered to play regulatory roles. Although sulfide and polysulfide effects in different pathological circumstances and TRPA1‐mediated processes have been investigated intensively, our review attempts to present the first comprehensive overview of the potential crosstalk between TRPA1 channels and sulfide‐activated signalling pathways.Linked ArticlesThis article is part of a themed section on Chemical Biology of Reactive Sulfur Species. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.4/issuetoc

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Analgesic effect of dimethyl trisulfide in mice is mediated by TRPA1 and sst 4 receptors

Cited by 31 publications

References 66 publications

Investigation of Lake Hévíz Mineral Water Balneotherapy and Hévíz Mud Treatment in Murine Osteoarthritis and Rheumatoid Arthritis Models

Investigation of Lake Hévíz Mineral Water Balneotherapy and Hévíz Mud Treatment in Murine Osteoarthritis and Rheumatoid Arthritis Models

Role of Transient Receptor Potential Ankyrin 1 Ion Channel and Somatostatin sst4 Receptor in the Antinociceptive and Anti-inflammatory Effects of Sodium Polysulfide and Dimethyl Trisulfide

Effects of sulfide and polysulfides transmitted by direct or signal transduction‐mediated activation of TRPA1 channels

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