Non-Peptide Somatostatin Agonist Analgesics

The overall goal of this proposal is to determine that peripheral somatostatin (SST) receptor activation by NISAs (Non-peptide Imidazolidindione Somatostatin Agonists) can control nociceptor excitability, reducing peripheral sensitization and promoting analgesia. Peripheral sensitization of nociceptors is a key element that not only underlies primary hyperalgesia in the periphery but also contributes to central sensitization of dorsal horn neurons. This proposal explores the use of NISAs in the periphery to reduce peripheral sensitization in inflammatory pain. The specific aims will support the hypothesis that peripheral administration of NISAs will reduce nociceptor sensitization in normal and inflamed skin. The aims are to show that 1) the individual enantiomers of a potent, highly SST2 selective NISA agonist model compound can be readily synthesized 2) activation of SST2 receptors on peripheral terminals with NISAs can inhibit nociceptor activation in normal and prevent nociceptor sensitization that underlies inflammatory pain using an in vitro preparation; 3) activation of SST2 receptors following systemic administration of NISAs can inhibit nociceptive behavioral responses in normal animals and animals with hindpaw injections of formalin and also that NISAs act through non-opioid mechanisms. Our preliminary data indicates that SST2 receptors are localized on nociceptors in the skin and that activation of these receptors with a moderately selective SST2 agonist Octreotide attenuates bradykinin-induced sensitization of the nociceptors and intraplantar injection of Octreotide attenuates formalin-induced pain behaviors. These findings support the hypothesis that activation of peripheral SST2 receptors with NISAs will reduce peripheral sensitization and inflammatory nociceptive behaviors. If true, NISAs may offer a novel, non-opioid drug therapy for reducing the pain and long-term deleterious changes that can accompany inflammation.