ARTHRITIS & RHEUMATISM Vol. 50, No. 5, May 2004, pp 1677–1685 DOI 10.1002/art.20184 © 2004, American College of Rheumatology 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 Zsuzsanna Helyes, 1 A ´ rpa ´d Szabo ´, 1 Jo ´zsef Ne ´meth, 3 Bala ´zs Jakab, 1 Erika Pinte ´r, 1 A ´ gnes Ba ´nvo ¨lgyi, 1 La ´szlo ´ Kereskai, 1 Gyo ¨rgy Ke ´ri, 4 and Ja ´nos Szolcsa ´nyi 2 Objective. We previously demonstrated that so- matostatin (SOM) released from the activated peri- pheral 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 somatosta- tin 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 stud- ies of the joints were performed. To impair the function of capsaicin-sensitive afferents, the capsaicin receptor (VR1/TRPV1) agonist resiniferatoxin (RTX) was in- jected subcutaneously (30, 70, and 100 g/kg on 3 subsequent days) 7 days before CFA administration. The SOM receptor antagonist cyclosomatostatin (c- SOM; 20 g/kg) or, in another group, the synthetic heptapeptide agonist TT-232 (2  50–400 g/kg) was administered intraperitoneally every day. Results. RTX pretreatment or c-SOM injection significantly increased edema and mechanical hyperal- gesia of both CFA-treated and contralateral paws. The histologic score based on synovial thickening, cell infil- tration, 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. Conclusion. Our data suggest that SOM released into the circulation from capsaicin-sensitive afferents in response to prolonged activation exerts systemic anti- inflammatory and analgesic effects. TT-232 can open new perspectives in the treatment of chronic arthritis. Several studies have found that sensory innerva- tion of the joint by capsaicin-sensitive primary afferent neurons is not only involved in sensory input for stretch and pain, but these nerve fibers also exert local and systemic effector functions (1,2). Neuropeptides re- leased from these fibers into the surrounding tissues elicit neurogenic inflammation around the site of acti- vation. Calcitonin gene-related peptide (CGRP) induces local vasodilation, and tachykinins, such as substance P (SP), evoke plasma protein extravasation in the inner- vated area (1–3). Furthermore, they have a trophic role and cooperate with the immune system (4,5). SP releases inflammatory mediators from mast cells, induces the secretion of prostaglandin E 2 and collagenase from synoviocytes and interleukin-1 (IL-1) from macrophages Supported by Hungarian grants OTKA T-034911, T-043467, TS 040753, NRDP 1A/0021/2002, ETT-03543/2003, ETT-03597/2003, and ETT-05598/2003, the Wellcome Trust, and by the Hungarian Academy of Sciences. Drs. Helyes and Pinte ´r’s work was supported by Ja ´nos Bolyai Postdoctoral Fellowships. Dr. Ne ´meth’s work was sup- ported by an Istva ´n Sze ´chenyi Research Fellowship. 1 Zsuzsanna Helyes, MD, PhD, A ´ rpa ´d Szabo ´, MD, Bala ´zs Jakab, MSc, Erika Pinte ´r, MD, PhD, A ´ gnes Ba ´nvo ¨lgyi, MSc, La ´szlo ´ Kereskai, MD: University of Pe ´cs, Pe ´cs, Hungary; 2 Ja ´nos Szolcsa ´nyi, MD, PhD, DSc: Neuropharmacological Research Group of the Hun- garian Academy of Sciences and University of Pe ´cs, Pe ´cs, Hungary; 3 Jo ´zsef Ne ´meth, PhD: Neuropharmacological Research Group of the Hungarian Academy of Sciences, Pe ´cs, Hungary; 4 Gyo ¨rgy Ke ´ri, PhD, DSc: Semmelweis University, Budapest, Hungary. Address correspondence and reprint requests to Ja ´nos Szolcsa ´nyi, MD, PhD, DSc, Department of Pharmacology and Phar- macotherapy, University of Pe ´cs, Faculty of Medicine, H-7643, Pe ´cs, Szigeti u. 12, Hungary. E-mail: janos.szolcsanyi@aok.pte.hu. Submitted for publication July 31, 2003; accepted in revised form January 16, 2004. 1677