Analgesic effect of TT-232, a heptapeptide somatostatin analogue, in acute pain models of the rat and the mouse and in streptozotocin-induced diabetic mechanical allodynia.
Somatostatin released from capsaicin-sensitive sensory nerves exerts systemic anti-inflammatory and antinociceptive actions. TT-232 is a stable, peripherally acting heptapeptide (D-Phe-Cys-Tyr-D-Trp-Lys-Cys-Thr-NH2) somatostatin analogue with highest binding affinity for somatostatin sst4 receptors. It has been shown to inhibit acute and chronic inflammatory responses and sensory neuropeptide release from capsaicin-sensitive nociceptors. In the present study the antinociceptive effects of TT-232 were analysed using both acute and chronic models of nociception. Formalin-induced pain behaviour, noxious heat threshold and streptozotocin-induced diabetic neuropathic mechanical allodynia were examined in rats and phenylquinone-evoked abdominal constrictions were tested in mice. TT-232 (80 microg/kg i.p.) inhibited both early (0-5 min) and late phases (25-45 min) of formalin-induced nociception as revealed by determination of the composite pain score. The minimum effective dose to elevate the noxious heat threshold and diminish the heat threshold drop (heat allodynia) evoked by resiniferatoxin (0.05 nmol intraplantarly) was 20 and 10 microg/kg i.p., respectively, as measured by an increasing-temperature hot plate. TT-232 (10-200 microg/kg s.c.) significantly inhibited phenylquinone-evoked writhing movements in mice, but within this dose range no clear dose-response correlation was found. Five weeks after streptozotocin administration (50 mg/kg i.v.) the diabetes-induced decrease in the mechanonociceptive threshold was inhibited by 10-100 microg/kg i.p. TT-232. These findings show that TT-232 potently inhibits acute chemical somatic/visceral and thermal nociception and diminishes chronic mechanical allodynia associated with diabetic neuropathy, thereby it could open new perspectives in the treatment of various pain syndromes.
Szolcsányi
János
J
Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, H-7643, Pécs, Szigeti u. 12, Hungary. janos.szolcsanyi@aok.pte.hu
Bölcskei
Kata
K
Szabó
Arpád
A
Pintér
Erika
E
Petho
Gábor
G
Elekes
Krisztián
K
Börzsei
Rita
R
Almási
Róbert
R
Szuts
Tamás
T
Kéri
György
G
Helyes
Zsuzsanna
Z
D000208:Acute Disease; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D016227:Benzoquinones / Q000633:toxicity; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D004195:Disease Models, Animal; D004224:Diterpenes / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005260:Female; D005557:Formaldehyde / Q000633:toxicity; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010146:Pain / Q000139:chemically induced / Q000209:etiology / Q000517:prevention & control*; D010147:Pain Measurement / Q000379:methods; D010456:Peptides, Cyclic / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013004:Somatostatin / Q000031:analogs & derivatives
D000700:Analgesics; D016227:Benzoquinones; D004224:Diterpenes; D010456:Peptides, Cyclic; D005557:Formaldehyde; C029322:phenylbenzoquinone; C094462:TT2-32; D013004:Somatostatin; C024353:resiniferatoxin