Papers of the Week

Since the conventional and adjuvant analgesics have limited effectiveness frequently accompanied by serious side effects, development of novel, potent pain killers for chronic neuropathic and inflammatory pain conditions is a big challenge. Somatostatin (SS) regulates endocrine, vascular, immune and neuronal functions, cell proliferation through 5 G protein-coupled receptors (SST-SST). SS released from the capsaicin-sensitive peptidergic sensory nerves mediates anti-inflammatory and antinociceptive effects without endocrine actions via SST. The therapeutic use of the native SS is limited by its diverse biological actions and short plasma elimination half-life. Therefore, SST selective SS analogues could be promising analgesic and anti-inflammatory drug candidates with new mode of action. TT-232 is a cyclic heptapeptide showing great affinity to SST and SST. Here, we report the in silico SST receptor binding mechanism, in vitro binding (competition assay) and cAMP- decreasing effect of TT-232 in SST-expressing CHO cells, as well as its analgesic and anti-inflammatory actions in chronic neuropathic pain and arthritis models using wildtype and SST-deficient mice. TT-232 binds to SST with similar interaction energy (-11.03kcal/mol) to the superagonist J-2156, displaces somatostatin from SST binding (10nM to 30µM) and inhibits forskolin-stimulated cAMP accumulation (EC: 371.6±58.03nmol; E: 78.63±2.636%). Its i.p. injection (100, 200µg/kg) results in significant, 35.7% and 50.4%, analgesic effects upon single administration in chronic neuropathic pain and repeated injection in arthritis models in wildtype, but not in SST-deficient mice. These results provide evidence that the analgesic effect of TT-232 is mediated by SST activation, which might open novel drug developmental potentials. Chemical compounds Chemical compounds studied in this article TT-232 (PubChem CID: 74053735).