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.