The Hypothermic Effect of Hydrogen Sulfide Is Mediated by the Transient Receptor Potential Ankyrin-1 Channel in Mice

This is the final version. Available from MDPI via the DOI in this record.Data is contained within the article and Supplementary Materials.Hydrogen sulfide (H2S) has been shown in previous studies to cause hypothermia and hypometabolism in mice, and its thermoregulatory effects were subsequently investigated. However, the molecular target through which H2S triggers its effects on deep body temperature has remained unknown. We investigated the thermoregulatory response to fast-(Na2S) and slow-releasing (GYY4137) H2S donors in C57BL/6 mice, and then tested whether their effects depend on the transient receptor potential ankyrin-1 (TRPA1) channel in Trpa1 knockout (Trpa1-/-) and wild-type (Trpa1+/+) mice. Intracerebroventricular administration of Na2S (0.5-1 mg/kg) caused hypothermia in C57BL/6 mice, which was mediated by cutaneous vasodilation and decreased thermogenesis. In contrast, intraperitoneal administration of Na2S (5 mg/kg) did not cause any thermoregulatory effect. Central administration of GYY4137 (3 mg/kg) also caused hypothermia and hypometabolism. The hypothermic response to both H2S donors was significantly (p < 0.001) attenuated in Trpa1-/- mice compared to their Trpa1+/+ littermates. Trpa1 mRNA transcripts could be detected with RNAscope in hypothalamic and other brain neurons within the autonomic thermoeffector pathways. In conclusion, slow- and fast-releasing H2S donors induce hypothermia through hypometabolism and cutaneous vasodilation in mice that is mediated by TRPA1 channels located in the brain, presumably in hypothalamic neurons within the autonomic thermoeffector pathways.National Research, Development and Innovation OfficeMedical School, University of PecsNew National Excellence Program of the Hungarian Ministry for Innovation and TechnologyNew National Excellence Program of the Hungarian Ministry for Innovation and TechnologyHigher Education Institutional Excellence Program of the Ministry of Human Capacities in HungaryEuropean UnionNational Research, Development and Innovation Fund of HungaryJanos Bolyai Scholarship of the Hungarian Academy of Science

Complex regional pain syndrome - phenotypic characteristics and potential biomarkers

Complex regional pain syndrome (CRPS) is a pain condition that usually affects a single limb, often following an injury. The underlying pathophysiology seems to be complex and probably varies between patients. Clinical diagnosis is based on internationally agreed-upon criteria, which consider the reported symptoms, presence of signs and exclusion of alternative causes. Research into CRPS biomarkers to support patient stratification and improve diagnostic certainty is an important scientific focus, and recent progress in this area provides an opportunity for an up-to-date topical review of measurable disease-predictive, diagnostic and prognostic parameters. Clinical and biochemical attributes of CRPS that may aid diagnosis and determination of appropriate treatment are delineated. Findings that predict the development of CRPS and support the diagnosis include trauma-related factors, neurocognitive peculiarities, psychological markers, and local and systemic changes that indicate activation of the immune system. Analysis of signatures of non-coding microRNAs that could predict the treatment response represents a new line of research. Results from the past 5 years of CRPS research indicate that a single marker for CRPS will probably never be found; however, a range of biomarkers might assist in clinical diagnosis and guide prognosis and treatment

Analgesic effects of the novel semicarbazide-sensitive amine oxidase inhibitor SZV 1287 in mouse pain models with neuropathic mechanisms: involvement of transient receptor potential vanilloid 1 and ankyrin 1 receptors.

Semicarbazide-sensitive amine oxidase (SSAO) produces tissue irritants by deamination of primary amines, which activate transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) receptors expressed predominantly on nociceptors. Since there are no data about its functions in pain, we studied the effects and mechanisms of action of our novel SSAO inhibitor and dual TRPA1/TRPV1 antagonist multi-target drug SZV 1287 in different pain models. Acute chemonociception was induced by TRPV1 and TRPA1 activation (resiniferatoxin and formalin, respectively), chronic arthritis by K/BxN serum transfer, traumatic mononeuropathy by sciatic nerve ligation. SZV 1287 (20mg/kg i.p.) was investigated in C57Bl/6J wildtype (WT), TRPA1- (TRPA1(-/-)) and TRPV1-deficient (TRPV1(-/-)) mice. Paw mechanonociception was measured by aesthesiometry, thermonociception by hot plate, nocifensive behavior by licking duration, volume by plethysmometry, myeloperoxidase activity by luminescence and plasma extravasation by fluorescence imaging, glia activation in pain-related brain regions by immunohistochemistry. SZV 1287 significantly inhibited both TRPA1 and TRPV1 activation-induced acute chemonociception and hyperalgesia. In K/BxN arthritis, daily SZV 1287 injections significantly decreased hyperalgesia, L4-L6 spinal dorsal horn microgliosis, edema and myeloperoxidase activity. SZV 1287-evoked antihyperalgesic and anti-edema effects were absent in TRPV1(-/-), and remarkably reduced in TRPA1(-/-) mice. In contrast, myeloperoxidase-inhibitory effect was absent in TRPA1(-/-,) but not in TRPV1(-/-) animals. Acute SZV 1287 administration resulted in approximately 50% significant reduction of neuropathic hyperalgesia 7days after nerve ligation, which was not observed in either TRPA1(-/-) or TRPV1(-/-) mice. SZV 1287 inhibits chronic inflammatory and neuropathic pain via TRPV1 and TRPA1/TRPV1 activation, respectively, highlighting its drug developmental potential

Hemokinin-1 mediates anxiolytic and anti-depressant-like actions in mice

The tachykinin NK1 receptor was suggested to be involved in psychiatric disorders, but its antagonists have failed to be effective as antidepressants in clinical trials. Hemokinin-1 (HK-1), the newest tachykinin, is present in several brain regions and activates the NK1 receptor similarly to substance P (SP), but acts also through other mechanisms. Therefore, we investigated the roles of the Tac4 gene-derived HK-1 in comparison with SP and neurokinin A (NKA) encoded by the Tac1 gene, as well as the NK1 receptor in anxiety and depression-like behaviors in mice. Mice lacking SP/NKA, HK-1 or the NK1 receptor (Tac1(-/-), Tac4(-/-), Tacr1(-/-), respectively) compared to C57Bl/6 wildtypes (WT), and treatment with the NK1 antagonist CP99994 were used in the experiments. Anxiety was evaluated in the light-dark box (LDB) and the elevated plus maze (EPM), locomotor activity in the open field (OFT) tests. Hedonic behavior was assessed in the sucrose preference test (SPT), depression-like behavior in the tail suspension (TST) and forced swim (FST) tests. FST-induced neuronal responsiveness was evaluated with Fos immunohistochemistry in several stress-related brain regions. In the LDB, Tac4(-/-) mice spent significantly less, while Tacr1(-/-) and CP99994-treated mice spent significantly more time in the lit compartment. In the EPM only Tac4(-/-) showed reduced time in the open arms, but no difference was observed in any other groups. In the OFT Tac4(-/-) mice showed significantly reduced, while Tac1(-/-) and Tacr1(-/-) animals increased motility than the WTs, but CP99994 had no effect. NK1(-/-) consumed markedly more, while Tac4(-/-) less sucrose solution compared to WTs. In the TST and FST, Tac4(-/-) mice showed significantly increased immobility. However, depression-like behavior was decreased both in cases of genetic deletion and pharmacological blockade of the NK1 receptor. FST-induced neuronal activation in different nuclei involved in behavioral and neuroendocrine stress responses was significantly reduced in the brain of Tac4(-/-) mice. Our results provide the first evidence for an anxiolytic and anti-depressant-like actions of HR-1 through a presently unknown target-mediated mechanism. Identification of its receptor and/or signaling pathways might open new perspectives for anxiolytic and anti-depressant therapies. 2016 Elsevier Inc. All rights reserved

The hypothermic effect of hydrogen sulfide is mediated by the transient receptor potential ankyrin-1 channel in mice

Hydrogen sulfide (H(2)S) has been shown in previous studies to cause hypothermia and hypometabolism in mice, and its thermoregulatory effects were subsequently investigated. However, the molecular target through which H(2)S triggers its effects on deep body temperature has remained unknown. We investigated the thermoregulatory response to fast-(Na(2)S) and slow-releasing (GYY4137) H(2)S donors in C57BL/6 mice, and then tested whether their effects depend on the transient receptor potential ankyrin-1 (TRPA1) channel in Trpa1 knockout (Trpa1(−/−)) and wild-type (Trpa1(+/+)) mice. Intracerebroventricular administration of Na(2)S (0.5–1 mg/kg) caused hypothermia in C57BL/6 mice, which was mediated by cutaneous vasodilation and decreased thermogenesis. In contrast, intraperitoneal administration of Na(2)S (5 mg/kg) did not cause any thermoregulatory effect. Central administration of GYY4137 (3 mg/kg) also caused hypothermia and hypometabolism. The hypothermic response to both H(2)S donors was significantly (p < 0.001) attenuated in Trpa1(−/−) mice compared to their Trpa1(+/+) littermates. Trpa1 mRNA transcripts could be detected with RNAscope in hypothalamic and other brain neurons within the autonomic thermoeffector pathways. In conclusion, slow- and fast-releasing H(2)S donors induce hypothermia through hypometabolism and cutaneous vasodilation in mice that is mediated by TRPA1 channels located in the brain, presumably in hypothalamic neurons within the autonomic thermoeffector pathways