d-phenylalanyl-cysteinyl-tyrosyl-tryptophyl-lysyl-cysteinyl-threoninamide and Edema

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.. 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.. 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.. 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.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Arthritis, Experimental; Chronic Disease; Disease Models, Animal; Diterpenes; Edema; Freund's Adjuvant; Hindlimb; Male; Peptides, Cyclic; Rats; Rats, Inbred Lew; Receptors, Drug; Sensory Receptor Cells; Somatostatin

The putative anti-inflammatory and anti-nociceptive activity of the heptapeptide somatostatin analogue TT-232 ( D-Phe-Cys-Tyr- D-Thr-Lys-Cys-Thr-NH(2)) was investigated in the rat and mouse, as well as its effect on neuropathic hyperalgesia, gastric ulceration and the release of sensory neuropeptides. In the rat, carrageenin-induced paw oedema was inhibited dose dependently by TT-232 (3x2.5-20 microg/kg i.v.). Evans blue accumulation induced by intraarticular bradykinin injection (0.5 nmol in 0.1 ml) was slightly, but significantly inhibited by a single TT-232 dose (5-20 microg/kg). Cutaneous neutrophil accumulation over a 3-h period after intradermal (i.d.) injection of carrageenin (1 mg/site) or interleukin 1beta (IL-1beta, 3 pmol/site) was inhibited significantly by TT-232 (3x80 microg/kg i.v.), while diclofenac (3x10 mg/kg i.v.) elicited significant inhibition only in the IL-1beta test. In the mouse, TT-232 potently decreased oedema formation induced by 2.5% capsaicin applied topically to the ear. Mechano-nociception in the rat hind-paw during neuropathic pain induced by partial sciatic nerve injury (model of Seltzer) was measured using the Randall-Selitto test. TT-232 (5-20 microg/kg i.p. on the 7th day after the operation) dose-dependently inhibited the mechano-nociceptive hyperalgesia. In vitro release of substance P (SP), calcitonin gene-related peptide (CGRP) and somatostatin from the isolated rat trachea in response to electrical field stimulation (40 V, 0.1 ms, 10 Hz, 120 s) of its nervous elements was inhibited significantly by 500 nM TT-232. The role of G protein-coupled receptors in the effect of TT-232 was indicated by the prevention of its inhibitory action on the release of sensory neuropeptides by incubation the tissue for 1 or 6 h with pertussis toxin (100 ng/ml). The release of sensory neuropeptides to in response to electrical nerve stimulation was not inhibited by a potent tyrosine kinase inhibitor, genistein (50 microM). TT-232 (up to 5 mg/kg i.p.) did not induce mucosal lesions in either the stomach or the duodenum. These data suggest that TT-232, a somatostatin analogue devoid of endocrine effects, is a promising lead molecule in the search for novel, broad-spectrum anti-inflammatory and analgesic agents.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Carrageenan; Dose-Response Relationship, Drug; Edema; Genistein; Hyperalgesia; Indomethacin; Inflammation; Interleukin-1; Male; Mice; Mice, Inbred BALB C; Neuropeptides; Neutrophils; Nociceptors; Peptides, Cyclic; Pertussis Toxin; Rats; Rats, Sprague-Dawley; Rats, Wistar; Sciatic Nerve; Somatostatin; Stomach Ulcer