There is good evidence showing that placebo and nocebo responses do not only reflect a psychological reappraisal of an unchanged nociceptive activity. There are several scientific evidences indicating that placebo or nocebo responses trigger changes in the brain that activate descending modulatory mechanisms, affecting the nociceptive signal early in the CNS. Among the psychological factors that trigger a placebo or nocebo response, conditioning and expectation have been demonstrated to greatly affect the outcomes of pain perception, but also the response to treatment. Placebo or nocebo responses can be triggered without the administration of an inert substance in several therapeutic contexts and will affect the treatment outcome. In this article, we will describe different experimental situations where psychological factors produce physiological changes of the nociceptive signal in the brain, and how these changes are reflected in the spinal cord. Finally, we will discuss the importance of better understanding placebo and nocebo mechanisms in clinical contexts for pain treatment.