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

To determine whether deficient activity of the hypothalamic corticotropin-releasing hormone (CRH) neuron, which stimulates the hypothalamic-pituitary-adrenal (HPA) axis and the central control nuclei of the sympathetic nervous system and inhibits ascending pain pathways, may be pathogenic in patients with fibromyalgia (FM).We administered interleukin-6 (IL-6; 3 microg/kg of body weight subcutaneously), a cytokine capable of stimulating hypothalamic CRH release, and measured plasma levels of adrenocorticotropic hormone (ACTH), cortisol, and catecholamines and their metabolites and precursors. Thirteen female FM patients and 8 age- and body mass index-matched female controls were studied. The diagnosis of FM was made according to American College of Rheumatology criteria. Tender points were quantitated by pressure algometry. All subjects had HPA axis studies. Seven FM patients and 7 controls also had catecholamine measurements.After IL-6 injection, delayed ACTH release was evident in the FM patients, with peak levels at 96.9 +/- 6.0 minutes (mean +/- SEM; control peak 68.6 +/- 10.3 minutes; P = 0.02). Plasma cortisol responses to IL-6 did not differ significantly between patients and controls. Basal norepinephrine (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 injection in the controls, NE levels dramatically increased over basal levels in the FM patients between 60 and 180 minutes after IL-6 injection. Both peak 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 patients than in controls. Heart rate was increased by IL-6 injection in FM patients and controls, but rose to significantly higher levels in the FM patients from 30 minutes to 180 minutes after IL-6 injection (P < 0.03).Exaggerated NE responses and heart rate increases, as well as delayed ACTH release, were observed among female FM patients compared with age-matched female controls. Delayed ACTH release after IL-6 administration in FM is consistent with a defect in hypothalamic CRH neuronal function. Exaggerated NE release may reflect abnormal regulation of the sympathetic nervous system, perhaps secondary to chronically deficient hypothalamic CRH. The 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 sensitivity of cardiac beta-adrenoceptors to NE. These responses to a physiologic stressor support the notion that FM may represent a primary disorder of the stress system.