Antiinflammatory and analgesic effects of somatostatin released from capsaicin-sensitive sensory nerve terminals in a Freund's adjuvant-induced chronic arthritis model in the rat.
OBJECTIVE
We previously demonstrated that somatostatin (SOM) released from the activated peripheral terminals of capsaicin-sensitive primary sensory neurons inhibits acute inflammation and nociception. This study was undertaken to examine this systemic "sensocrine" function of neuronally derived somatostatin in chronic inflammation in the Freund's complete adjuvant (CFA)-induced arthritis model.


METHODS
Arthritis of the tibiotarsal joint of Lewis rats was evoked by subcutaneous injection of CFA into the left hind paw and the tail root. For 3 weeks, the volume of the paws was measured by plethysmometry, and the mechanonociceptive thresholds were measured by esthesiometry. Plasma concentrations of SOM were determined by radioimmunoassay, and histologic studies of the joints were performed. To impair the function of capsaicin-sensitive afferents, the capsaicin receptor (VR1/TRPV1) agonist resiniferatoxin (RTX) was injected subcutaneously (30, 70, and 100 microg/kg on 3 subsequent days) 7 days before CFA administration. The SOM receptor antagonist cyclosomatostatin (c-SOM; 20 microg/kg) or, in another group, the synthetic heptapeptide agonist TT-232 (2 x 50-400 microg/kg) was administered intraperitoneally every day.


RESULTS
RTX pretreatment or c-SOM injection significantly increased edema and mechanical hyperalgesia of both CFA-treated and contralateral paws. The histologic score based on synovial thickening, cell infiltration, cartilage destruction, and bone erosion was also significantly higher both in the RTX- and the c-SOM-injected groups. These parameters were dose-dependently decreased by TT-232. Plasma SOM-like immunoreactivity increased 4-fold on the twenty-first day, and was inhibited by RTX pretreatment, as well as by daily administration of TT-232.


CONCLUSIONS
Our data suggest that SOM released into the circulation from capsaicin-sensitive afferents in response to prolonged activation exerts systemic antiinflammatory and analgesic effects. TT-232 can open new perspectives in the treatment of chronic arthritis.
Helyes
Zsuzsanna
Z
Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, H-7643 Pécs, Szigeti u.12, Hungary.
Szabó
Arpád
A
Németh
József
J
Jakab
Balázs
B
Pintér
Erika
E
Bánvölgyi
Agnes
A
Kereskai
László
L
Kéri
György
G
Szolcsányi
János
J
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D002908:Chronic Disease; D004195:Disease Models, Animal; D004224:Diterpenes / Q000494:pharmacology; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D005620:Freund's Adjuvant; D006614:Hindlimb; D008297:Male; D010456:Peptides, Cyclic / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D011955:Receptors, Drug / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism*; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000378:metabolism
D000700:Analgesics; D000893:Anti-Inflammatory Agents; D004224:Diterpenes; D010456:Peptides, Cyclic; D011955:Receptors, Drug; C067675:cyclosomatostatin; C094462:TT2-32; D013004:Somatostatin; D005620:Freund's Adjuvant; C024353:resiniferatoxin