Fig. 1.

Schematic representation of the pain system and pathways for the influence of cytokines on brain function. Pain is a multidimensional sensation initiated at pain receptors in the periphery (nociceptors) by (potentially) harmful stimuli. The pain system consists of ascending and descending pathways which are highly interconnected at different processing stages up to the prefrontal cortex (PFC) as the highest station of nociceptive processing and a central hub of the cognitive dimension of pain. The most important transfer and “preprocessing” stations of nociceptive information are: the spinal cord (dorsal horn neurons), the brainstem including among others the medulla oblongata and peri-aqueductal grey (PAG), and the thalamus. From there and upwards one differentiates between two functionally overlapping but basically different subsystems. The lateral thalamus (LT) projects to the primary and secondary somatosensory cortices (SSC). These structures constitute the so-called lateral pain system responsible for the sensory-discriminative dimension of pain. The medial thalamus (MT) has tight connections to the anterior cingulate cortex (CC) and further to the PFC. These structures form the medial pain system considered to be in charge of the affective-motivational dimension of pain. Moreover, this system has extensive interconnections with the limbic system—entorhinal cortex, hippocampus (Hip), amygdala (Amy)—which is inseparably associated with emotions. The insular cortex has an intermediate position since it receives somatosensory input (posterior part, PIns), but has strong reciprocal connections to the amygdala (anterior part, AIns). Therefore, the insula can be ascribed to the medial pain system. As an “output” of pain processing, structures for immediate motor and autonomic responses and pain control are activated. Motor responses originate in the PFC, in higher order motor cortices and next in the primary motor cortex (MotC). They send downstream commands to the motor neurons in the spinal cord. The motor thalamus (MotT) and the motor basal ganglia dorsal striatum (DS) and cerebellum (Cer) take part in coordination of the motor responses. The other compartment of the basal ganglia, the ventral striatum (VS), belongs to an associative-limbic loop forming a link to the motor system influenced by motivational and emotional context. The hypothalamus (HT) orchestrates neuroendocrine and autonomic responses to pain. One of the most important elements of the descending inhibitory pain control acts via the PAG upon the dorsal horn neurons. Proinflammatory cytokines (IL-6, IL-1β, TNFα) reaching the brain exert powerful influence on the neurocircuits related to the affective-motivational dimension of pain and interfere with multiple physiologic processes relevant to mood regulation in the entire brain (see “Peripheral-to-central communication”). IL interleukin, TNF tumor necrosis factor