Modulation of nociception and
inflammation by
sulfide in
rheumatoid arthritis and activation of transient receptor potential
ankyrin 1 (TRPA1)
ion channels by
sulfide compounds are well documented. The present study aims to investigate TRPA1-mediated effects of
sulfide donor
GYY4137 in K/BxN serum-transfer
arthritis, a rodent model of
rheumatoid arthritis. TRPA1 and
somatostatin sst4 receptor wild-type (WT) and knockout mice underwent K/BxN serum transfer and were treated daily with
GYY4137. Functional and biochemical signs of
inflammation were recorded, together with histological characterization. These included detection of hind paw
mechanical hyperalgesia by dynamic plantar esthesiometry, hind paw volume by plethysmometry, and upside-down hanging time to failure. Hind paw
erythema,
edema, and passive movement range of tibiotarsal joints were scored.
Somatostatin release from sensory nerve endings of TRPA1 wild-type and knockout mice in response to
polysulfide was detected by radioimmunoassay.
Polysulfide formation from
GYY4137 was uncovered by cold cyanolysis.
GYY4137 aggravated
mechanical hyperalgesia in TRPA1 knockout mice but ameliorated it in wild-type ones.
Arthritis score was lowered by
GYY4137 in TRPA1 wild-type animals. Increased
myeloperoxidase activity, plasma extravasation, and subcutaneous MIP-2 levels of hind paws were detected in TRPA1 knockout mice upon
GYY4137 treatment. Genetic lack of sst4 receptors did not alter
mechanical hyperalgesia,
edema formation, hanging performance,
arthritis score, plasma extravasation, or
myeloperoxidase activity. TRPA1 WT animals exhibited smaller cartilage destruction upon
GYY4137 administration.
Sodium polysulfide caused TRPA1-dependent
somatostatin release from murine nerve endings.
Sulfide released from
GYY4137 is readily converted into
polysulfide by
hypochlorite.
Polysulfide potently activates human TRPA1 receptors expressed in Chinese hamster ovary (CHO) cells. According to our data, the protective effect of
GYY4137 is mediated by TRPA1, while detrimental actions are independent of the
ion channel in the K/BxN serum-transfer
arthritis model in mice. At acidic pH in inflamed tissue
sulfide is released from
GYY4137 and reacts with neutrophil-derived
hypochlorite. Resulting
polysulfide might be responsible for TRPA1-mediated antinociceptive and anti-inflammatory as well as TRPA1-independent pro-inflammatory effects.