Responses of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis to interleukin-6 - A pilot study in fibromyalgia

Objective. To determine whether deficient activity of the hypothalamic cort icotropin-releasing hormone (CRH) neuron, which stimulates the hypothalamic -pituitary-adrenal (HPA) axis and the central control nuclei of the sympath etic nervous system and inhibits ascending pain pathways, may be pathogenic in patients with fibromyalgia (FM). Methods. We administered interleukin-6 (IL-6; 3 mu g/kg of body weight subc utaneously), a cytokine capable of stimulating hypothalamic CRH release, an d measured plasma levels of adrenocorticotropic hormone (ACTH), cortisol, a nd catecholamines and their metabolites and precursors. Thirteen female FM patients and 8 age- and body mass index-matched female controls were studie d. The diagnosis of FM was made according to American College of Rheumatolo gy criteria. Tender points were quantitated by pressure algometry. All subj ects had HPA axis studies. Seven FM patients and 7 controls also had catech olamine measurements. Results. After IL-6 injection, delayed ACTH release was evident in the FM p atients, with peak levels at 96.9 +/- 6.0 minutes (mean +/- SEM; control pe ak 68.6 +/- 10.3 minutes; P = 0.02). Plasma cortisol responses to IL-6 did not differ significantly between patients and controls, Basal norepinephrin e (NE) levels were higher in the FM patients than in the controls, While a small, although not significant, rise in NE levels occurred after IL-6 inje ction in the controls, NE levels dramatically increased over basal levels i n the FM patients between 60 and 180 minutes after IL-6 injection. Both pea k NE levels (mean +/- SEM 537.6 +/- 82.3 versus 254.3 +/- 41.6 pg/ml; P = 0 .0001) and time-integrated NE responses (93.2 +/- 16.6 pg/ml x minutes(-3) versus 52.2 +/- 5.7 pg/ml x minutes(-3); P = 0.038) were greater in FM pati ents than in controls. Heart rate was increased by IL-6 injection in FM pat ients and controls, but rose to significantly higher levels in the FM patie nts from 30 minutes to 180 minutes after IL-6 injection (P < 0.03). Conclusion. Exaggerated NE responses and heart rate increases, as well as d elayed ACTH release, were observed among female FM patients compared with a ge-matched female controls. Delayed ACTH release after IL-6 administration in FM is consistent with a defect in hypothalamic CRH neuronal function. Ex aggerated NE release may reflect abnormal regulation of the sympathetic ner vous system, perhaps secondary to chronically deficient hypothalamic CRH. T he excessive heart rate response after IL-6 injection in FM patients may be unrelated to the increase in NE, or it may reflect an alteration in the se nsitivity of cardiac beta-adrenoceptors to NE. These responses to a physiol ogic stressor support the notion that FM may represent a primary disorder o f the stress system.