Analgesic activity of a non-peptide imidazolidinedione somatostatin agonist: in vitro and in vivo studies in rat.
Several lines of evidence support an important role for somatostatin receptors (SSTRs) in pain modulation. The therapeutic use of established SSTR peptide agonists for this indication is limited by their broad range of effects, need for intrathecal delivery, and short half-life. Therefore, the goal of the present study was to investigate the analgesic effect of SCR007, a new, highly selective SSTR2 non-peptide agonist. Behavioral studies demonstrated that paw withdrawal latencies to heat were significantly increased following intraplantar SCR007. Furthermore, both intraperitoneal and intraplantar injection of SCR007 significantly reduced formalin- and capsaicin-induced flinching and lifting/licking nociceptive behaviors. Recordings from nociceptors using an in vitro glabrous skin-nerve preparation showed that SCR007 reduced heat responses in a dose-dependent fashion, bradykinin-induced excitation, heat sensitization and capsaicin-induced excitation. In both the behavioral and single fiber studies, the SCR007 effects were reversed by the SSTR antagonist cyclo-somatostatin, demonstrating receptor specificity. In the single fiber studies, the opioid antagonist naloxone did not reverse SCR007-induced anti-nociception suggesting that SCR007 did not exert its effects through activation of opioid receptors. Analysis of cAMP/protein kinase A (PKA) involvement demonstrated that SCR007 prevented forskolin- and Sp-8-Br-cAMPS (a PKA activator)-induced heat sensitization, supporting the hypothesis that SCR007-induced inhibition could involve a down-regulation of the cAMP/PKA pathway. These data provide several lines of evidence that the non-peptide imidazolidinedione SSTR2 agonist SCR007 is a promising anti-nociceptive and analgesic agent for the treatment of pain of peripheral and/or central origin.
Ji
G C
GC
Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX 77555-1069, USA.
Zhou
S T
ST
Shapiro
G
G
Reubi
J C
JC
Jurczyk
Simona
S
Carlton
S M
SM
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000528:radiation effects; D000700:Analgesics / Q000627:therapeutic use*; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D001920:Bradykinin / Q000494:pharmacology; D002211:Capsaicin / Q000009:adverse effects; D005576:Colforsin / Q000494:pharmacology; D004347:Drug Interactions; D005557:Formaldehyde / Q000009:adverse effects; D006358:Hot Temperature / Q000009:adverse effects; D048289:Imidazolidines / Q000627:therapeutic use; D066298:In Vitro Techniques; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy; D008297:Male; D009412:Nerve Fibers / Q000187:drug effects / Q000528:radiation effects; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D012867:Skin / Q000187:drug effects / Q000294:innervation; D013004:Somatostatin / Q000819:agonists*; D013873:Thionucleotides / Q000494:pharmacology
C105593:8-bromoadenosine-3',5'-cyclic monophosphorothioate; D000700:Analgesics; D048289:Imidazolidines; C513571:SCR007; D013873:Thionucleotides; D005576:Colforsin; D005557:Formaldehyde; D015124:8-Bromo Cyclic Adenosine Monophosphate; D013004:Somatostatin; D002211:Capsaicin; D001920:Bradykinin