Angiotensin type 2 receptor antagonism as a new target to manage gout.

BACKGROUND: There is a growing search for therapeutic targets in the treatment of gout. The present study aimed to evaluate the analgesic and anti-inflammatory potential of angiotensin type 2 receptor (AT2R) antagonism in an acute gout attack mouse model. METHODS: Male wild-type (WT) C57BL/6 mice either with the AT2R antagonist, PD123319 (10 pmol/joint), or with vehicle injections, or AT2R KO mice, received intra-articular (IA) injection of monosodium urate (MSU) crystals (100 µg/joint), that induce the acute gout attack, and were tested for mechanical allodynia, thermal hyperalgesia, spontaneous nociception and ankle edema development at several times after the injections. To test an involvement of AT2R in joint pain, mice received an IA administration of angiotensin II (0.05-5 nmol/joint) with or without PD123319, and were also evaluated for pain and edema development. Ankle joint tissue samples from mice undergoing the above treatments were assessed for myeloperoxidase activity, IL-1ß release, mRNA expression analyses and nitrite/nitrate levels, 4 h after injections. RESULTS: AT2R antagonism has robust antinociceptive effects on mechanical allodynia (44% reduction) and spontaneous nociception (56%), as well as anti-inflammatory effects preventing edema formation (45%), reducing myeloperoxidase activity (54%) and IL-1ß levels (32%). Additionally, Agtr2tm1a mutant mice have largely reduced painful signs of gout. Angiotensin II administration causes pain and inflammation, which was prevented by AT2R antagonism, as observed in mechanical allodynia 4 h (100%), spontaneous nociception (46%), cold nociceptive response (54%), edema formation (83%), myeloperoxidase activity (48%), and IL-1ß levels (89%). PD123319 treatment also reduces NO concentrations (74%) and AT2R mRNA levels in comparison with MSU untreated mice. CONCLUSION: Our findings show that AT2R activation contributes to acute pain in experimental mouse models of gout. Therefore, the antagonism of AT2R may be a potential therapeutic option to manage gout arthritis.

The Role of Cold-Sensitive Ion Channels in Peripheral Thermosensation.

The detection of ambient cold is critical for mammals, who use this information to avoid tissue damage by cold and to maintain stable body temperature. The transduction of information about the environmental cold is mediated by cold-sensitive ion channels expressed in peripheral sensory nerve endings in the skin. Most transduction mechanisms for detecting temperature changes identified to date depend on transient receptor potential (TRP) ion channels. Mild cooling is detected by the menthol-sensitive TRPM8 ion channel, but how painful cold is detected remains unclear. The TRPA1 ion channel, which is activated by cold in expression systems, seemed to provide an answer to this question, but whether TRPA1 is activated by cold in neurons and contributes to the sensation of cold pain continues to be a matter of debate. Recent advances have been made in this area of investigation with the identification of several potential cold-sensitive ion channels in thermosensory neurons, including two-pore domain potassium channels (K2P), GluK2 glutamate receptors, and CNGA3 cyclic nucleotide-gated ion channels. This mini-review gives a brief overview of the way by which ion channels contribute to cold sensation, discusses the controversy around the cold-sensitivity of TRPA1, and provides an assessment of some recently-proposed novel cold-transduction mechanisms. Evidence for another unidentified cold-transduction mechanism is also presented.

Sensitisation of TRPV1 in rat sensory neurones by activation of SNSRs.

The novel sensory neurone specific receptor (SNSR) family of G-protein coupled receptors are activated by non-opiate fragments of opioid precursor peptides. SNSRs are expressed in nociceptors, and SNSR agonists have been found to cause sensitisation to painful stimuli in vivo. We explored the basis of sensitisation caused by SNSR agonists in sensory neurones by investigating the effect of the SNSR-selective agonist bovine adrenal medulla peptide 8-22 (BAM (8-22)) on gating of the heat and capsaicin-sensitive ion channel TRPV1. Using calcium imaging we found that BAM (8-22) caused sensitisation of the TRPV1 response in approximately 13% of DRG neurones. Sensitisation of TRPV1 in a similar proportion of neurones was observed using whole-cell patch clamping. The PKC-specific inhibitor Ro-31-8220 reduced but did not completely abolish sensitisation, while the protein kinase A inhibitor H-89 was without significant effect. No translocation of the PKC delta, epsilon and zeta isoforms to the cell membrane was observed in response to BAM (8-22). These observations implicate PKC in the sensitisation of TRPV1, but suggest that other pathways are also involved.