The aim of the present study was to investigate changes in the plasma calcitonin gene-related peptide (CGRP) concentration and platelet serotonin (5-hydroxytriptamine, 5-HT) content during the immediate headache and the delayed genuine migraine attack provoked by nitroglycerin. Fifteen female migraineurs (without aura) and eight controls participated in the study. Sublingual nitroglycerin (0.5 mg) was administered. Blood was collected from the antecubital vein four times: 60 min before and after the nitroglycerin application, and 60 and 120 min after the beginning of the migraine attack (mean 344 and 404 min; 12 subjects). In those subjects who had no migraine attack (11 subjects) a similar time schedule was used. Plasma CGRP concentration increased significantly (P<0.01) during the migraine attack and returned to baseline after the cessation of the migraine. In addition, both change and peak, showed significant positive correlations with migraine headache intensity (P<0.001). However, plasma CGRP concentrations failed to change during immediate headache and in the subjects with no migraine attack. Basal CGRP concentration was significantly higher and platelet 5-HT content tended to be lower in subjects who experienced a migraine attack. Platelet serotonin content decreased significantly (P<0.01) after nitroglycerin in subjects with no migraine attack but no consistent change was observed in patients with migraine attack. In conclusion, the fact that plasma CGRP concentration correlates with the timing and severity of a migraine headache suggests a direct relationship between CGRP and migraine. In contrast, serotonin release from platelets does not provoke migraine, it may even counteract the headache and the concomitant CGRP release in this model.

Sumatriptan-induced changes in plasma calcitonin gene-related peptide (CGRP) concentration and headache intensity were investigated in 19 female migraineurs during nitroglycerin-induced migraine attack. Sumatriptan nasal spray was administered 120 min after the onset of the attack. Blood samples were obtained immediately before and 60 min after sumatriptan administration. In those subjects whose migraine attack improved considerably 60 min after the treatment the plasma CGRP concentration decreased significantly (P<0.05). In contrast, plasma CGRP concentration failed to change in patients whose headache did not improve. In addition, plasma CGRP concentrations showed significant positive correlations with the headache scores both 60 and 120 min after sumatriptan administration (P<0.05). According to our results plasma CGRP concentration decreases parallel to headache intensity during sumatriptan treatment and this decrease in CGRP predicts effectiveness of antimigraine drug therapy. This supports that one of the main effects of triptans is to decrease CGRP release.

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