Neuropeptides CRH, SP, HK-1, and Inflammatory Cytokines IL-6 and TNF Are Increased in Serum of Patients with Fibromyalgia Syndrome, Implicating Mast Cells

Abstract

Fibromyalgia syndrome (FMS) is a chronic, idiopathic condition of widespread musculoskeletal pain affecting more women than men. Even though clinical studies have provided evidence of altered central pain pathways, the lack of definitive pathogenesis or reliable objective markers has hampered development of effective treatments. Here we report that the neuropeptides corticotropin-releasing hormone (CRH), substance P (SP), and SP-structurally-related hemokinin-1 (HK-1) were significantly (P = 0.026, P < 0.0001, and P = 0.002, respectively) elevated (0.82 ± 0.57 ng/ml, 0.39 ± 0.18 ng/ml, and 7.98 ± 3.12 ng/ml, respectively) in the serum of patients with FMS compared with healthy controls (0.49 ± 0.26 ng/ml, 0.12 ± 0.1 ng/ml, and 5.71 ± 1.08 ng/ml, respectively). Moreover, SP and HK-1 levels were positively correlated (Pearson r = 0.45, P = 0.002) in FMS. The serum concentrations of the inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF) were also significantly (P = 0.029 and P = 0.006, respectively) higher (2.97 ± 2.35 pg/ml and 0.92 ± 0.31 pg/ml, respectively) in the FMS group compared with healthy subjects (1.79 ± 0.62 pg/ml and 0.69 ± 0.16 pg/ml, respectively). In contrast, serum IL-31 and IL-33 levels were significantly lower (P = 0.0001 and P = 0.044, respectively) in the FMS patients (849.5 ± 1005 pg/ml and 923.2 ± 1284 pg/ml, respectively) in comparison with healthy controls (1281 ± 806.4 pg/ml and 3149 ± 4073 pg/ml, respectively). FMS serum levels of neurotensin were not different from controls. We had previously shown that CRH and SP stimulate IL-6 and TNF release from mast cells (MCs). Our current results indicate that neuropeptides could stimulate MCs to secrete inflammatory cytokines that contribute importantly to the symptoms of FMS. Treatment directed at preventing the secretion or antagonizing these elevated neuroimmune markers, both centrally and peripherally, may prove to be useful in the management of FMS.

Fig. 1.

(A, B) Comparison of serum CRH and SP levels in healthy controls and FMS patients. Symbols represent individual data points, and the horizontal line represents the mean for each group.

Fig. 2.

(A) Comparison of serum HK-1 levels in healthy controls and FMS patients. Symbols represent individual data points, and the horizontal line represents the mean for each group. (B) Correlation between serum HK-1 and SP levels.

Fig. 3.

(A, B) Comparison of serum IL-6 and TNF levels in healthy controls and FMS patients. Symbols represent individual data points, and the horizontal line represents the mean for each group.

Fig. 4.

(A, B) Comparison of serum IL-33 and IL-31 levels in healthy controls and FMS patients. Symbols represent individual data points, and the horizontal line represents the mean for each group.

Fig. 5.

Diagrammatic representation of the proposed interactions among neuropeptides, mast cells, inflammatory cytokines, neurons, and FMS pathogenesis. Environmental, immune, and infectious triggers activate MCs leading to secretion of inflammatory mediators such as IL-6 and TNF, which could further stimulate nerves to release CRH, HK-1, and SP, further stimulating MCs. Luteolin and quercetin could be of help by blocking MC stimulation and/or release of inflammatory mediators.