(1-s--2s)-4-amino-n-(1--carbamoyl-2--phenylethyl)-2-(4---methyl-1---naphthalenesulfonylamino)butanamide and Pain

Somatostatin (sst) is a cyclic neuropeptide known to have inhibitory roles in the central nervous system. It exerts its biological effects via the activation of the 5 sst receptor subtypes, which belong to the family of G-protein coupled receptors (GPCR). This peptide has analgesic properties, specifically via the activation of the sst4 receptor subtype. Although this is established, the precise molecular mechanisms causing this have not yet been fully elucidated. This research aimed to identify a possible anti-nociceptive mechanism, showing functional links to the transient receptor potential vanilloid type 1 (TRPV1) within the pain processing pathway. Calcium imaging and whole cell voltage clamp experiments were conducted on DRG neurons prepared from adult rats, utilizing capsaicin stimulations and the sst4 receptor specific agonist J-2156. The complete Freund's adjuvant (CFA) inflammatory pain model was used to examine if effects are augmented in pain conditions. The sst4 receptor agonist J-2156 was able significantly to inhibit capsaicin induced calcium and sodium influx, where the effect was more potent after CFA treatment. This inhibition identifies a contributory molecular mechanism to the analgesic properties of sst4 receptor activation.

Topics: Animals; Butanes; Calcium; Capsaicin; Cells, Cultured; Freund's Adjuvant; Ganglia, Spinal; Inflammation; Male; Naphthalenes; Neurons; Nociception; Pain; Pertussis Toxin; Rats; Receptors, Somatostatin; Sulfones; TRPV Cation Channels

Somatostatin released from capsaicin-sensitive afferents exerts systemic anti-nociceptive actions, presumably via somatostatin receptor subtype 4 (sst4). In the present study, the antinociceptive effects of a novel somatostatin sst4 receptor selective peptidomimetic compound, J-2156 (1-100 microg/kg i.p.), were examined. J-2156 inhibited nocifensive behaviour of mice in the second phase of the formalin test. Adjuvant-evoked chronic inflammatory mechanical allodynia was decreased in rats treated with J-2156 for 21 days. Sciatic nerve ligation-induced neuropathic mechanical hyperalgesia was inhibited by J-2156 on the seventh postoperative day. Results obtained using this highly selective agonist suggest that somatostatin sst4 receptors represent a promising target for new perspectives in analgesic therapy.

Topics: Acute Disease; Analgesics; Animals; Butanes; Chronic Disease; Hyperalgesia; Male; Membrane Proteins; Mice; Mice, Inbred BALB C; Naphthalenes; Pain; Pain Measurement; Pain Threshold; Physical Stimulation; Rats; Rats, Wistar; Receptors, Somatostatin; Sulfones; Touch