Nocebo and the contribution of psychosocial factors to the generation of pain.

The biopsychosocial model claims that illness is generated by biological, psychological, and social factors. The nocebo response, particularly nocebo hyperalgesia, is an excellent model and approach to understand these effects and their psychophysiological underpinnings, as nocebos are made of negative psychological and social factors, such as negative expectations and social interactions. There is today experimental evidence that nocebos can create symptoms and illness from nothing, in particular pain, whereby a combination of biological, psychological and social factors interact with each other in the generation of the global painful experience. Several biochemical pathways have been identified, e.g. cholecystokinin and cyclooxygenase, and the activation of these mechanisms has been specifically investigated in the field of pain, analgesia and hyperalgesia. The study of placebo and nocebo oxygen at high-altitude has been crucial to unravel these mechanisms, as reduction of oxygen pressure (hypoxia) leads to headache pain. Indeed, the investigation of oxygen-related conditions, such as hypoxia, represents today an excellent approach to understand how nocebos can contribute to generate illness and pain. In this review we discuss old and new findings that help us better understand the interplay between biology and psychology.