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

Abstract

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 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 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-SOMinjected groups. These parameters were dosedependently 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 antiinflammatory and analgesic effects. TT-232 can open new perspectives in the treatment of chronic arthritis.Several studies have found that sensory innervation 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 released from these fibers into the surrounding tissues elicit neurogenic inflammation around the site of activation. Calcitonin gene-related peptide (CGRP) induces local vasodilation, and tachykinins, such as substance P (SP), evoke plasma protein extravasation in the innervated 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

Involvement of transient receptor potential vanilloid 1 in the vascular and hyperalgesic components of joint inflammation

“…A CGRP antagonist has recently been shown to have a favorable effect in the treatment of pain associated with migraine (50), and it is possible that CGRP is responsible for mediating some of the proinflammatory effects observed after TRPV1 activation. However, sensory nerve-mediated events are more complex in that activated sensory nerves also release antiinflammatory neuropeptides, in particular, somatostatin (51), in and around the joint. It should be noted that if the sum effect of TRPV1 activation is antiinflammatory, one would not expect the deletion of TRPV1 to act in the beneficial manner observed in the present study.…”

Transient Receptor Potential Vanilloid 1 Agonists as Candidates for Anti-inflammatory Agents

“…Some groups have demonstrated that TRPV1 plays a potential role in acute and chronic inflammation in the knee joint 4,36) . In contrast, other groups have shown that a TRPV1 agonist 37) and somatostatin 38) attenuate knee joint inflammation. However, there have been no reports using the collagen-induced arthritis model, one of the most important autoimmune models for human rheumatoid arthritis.…”

Role of peripheral μ‐opioid receptors in arthritis: Are they potential targets for therapy?

“…In this latter situation, more severe systemic signs develop, such as decreased appetite, body weight loss, fever, and diminished mobility (13). The mechanism of joint inflammation in these 2 models involves a T cell-mediated immunologic response, and the histologic picture is very similar to that observed in rheumatoid arthritis (12)(13)(14). Finally, CFA can be given by intraarticular injection, after which it induces a direct, destructive monarthritis localized to the affected joint, with onset within 4-6 hours and increasing intensity over 1-2 weeks (9,14).…”

“…This approach evokes acute subcutaneous inflammation at the site of injection within a few hours, while arthritis develops ipsilaterally, mainly in the tibiotarsal joint, by the seventh or eighth day after injection. On the contralateral side, much slighter arthritis symptoms develop, from the ninth day through the eleventh day (10)(11)(12). In contrast, CFA can be injected intradermally into the base of the tail to evoke polyarthritis with equal intensity on both sides but mainly in the tibiotarsal joints within 1 week, without soft tissue inflammation of the paws.…”

“…Throughout these experiments, inflammation remained confined to the soft tissue of the inoculated paw (19,21), and the contralateral side and the joints were not affected. Although intraplantar administration of the adjuvant causes inflammation of the unilateral tibiotarsal joint, a longer period of time (1-4 weeks) is required for the development of arthritis (12,14).…”