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Nociception is an afferent neural activity which carries sensory information about harmful stimuli. It often leads to a feeling of pain, but the two are not synonyms. Pain is defined as a conscious experience that can occur in the absence of nociception. There are several theories about the nature of pain. One of them is Descartes’ Specificity Theory, according to which there are specific pain receptors that transmit signals via the PNS to the spinothalamic tract of the spinal cord, and hence the thalamus in which the brain produces a sense of pain. Another theory is Nafe’s Model Theory of Pattern. It describes pain as a product of enhanced stimulation on nonspecific receptors. In 1965, Melzac and Wall presented their vision of nociception, also known as Gate Theory. It was followed by Melzac’s concept of central brain pain modulation with a network of structures, also called neuromatrix. This concept was most commonly used to explain clinical situations. Later, Plughaus and Boly developed a more specific term: the “pain matrix”.The connection between pain matrix, emotions, attention, placebo effect, pain expectations, and anxiety was further explored and discussed. Some adaptive changes in the CNS in pain have also been found, such as that repetitive harmful stimulation can alter not only the function but also the structure of the brain. When pain is present, the amount of gray matter also varies.Changes in patients’ neural and brain activity could be observed in the presence of various chronic pain disorders, as in analgesia, meditation, acupuncture, and hypnosis. There is also a relationship between the neuromatrix and pain insensitivity, as well as between the pain matrix and neuropathic pain.Only the systematic research focused on the integrated brain function and structure could lead to a better understanding, and hence to a better management of pain.