Pain in patients with chronic fatigue syndrome: does nitric oxide trigger central sensitisation?

Previous studies have provided evidence supportive of the clinical importance of widespread pain in patients with chronic fatigue syndrome (CFS): pain severity may account for 26-34% of the variability in the CFS patient's activity limitations and participation restrictions. The etiology of widespread pain in CFS remains to be elucidated, but sensitisation of the central nervous system has been suggested to take part of CFS pathophysiology. It is hypothesised that a nitric oxide (NO)-dependent reduction in inhibitory activity of the central nervous system and consequent central sensitisation accounts for chronic widespread pain in CFS patients. In CFS patients, deregulation of the 2',5'-oligoadenylate synthetase/RNase L pathway is accompanied by activation of the protein kinase R enzyme. Activation of the protein kinase R and subsequent nuclear factor-kappaB activation might account for the increased production of NO, while infectious agents frequently associated with CFS (Coxsackie B virus, Epstein-Barr Virus, Mycoplasma) might initiate or accelerate this process. In addition, the evidence addressing behavioural changes in CFS patients fits the central sensitisation-hypothesis: catastrophizing, avoidance behaviour, and somatization may result in, or are initiated by sensitisation of the central nervous system.