Acute pain serves a physiological purpose in preventing tissue damage, but chronic pain can linger as a complication of a wide range of illnesses due to maladaptive plasticity in the peripheral and central nervous systems. It is obvious that many patients treated as a homogeneous patient population fail to control their pain successfully, hence new treatment algorithms are urgently required. Early groundbreaking research showed that midbrain microstimulation resulted in a potent analgesia. Later research revealed that this modulation can be used to either augment or reduce spinal sensory transmission. These descending controls are balanced to optimize sensory acquisition when at rest, but they can quickly change based on the situation, the expectation, and the emotional state. Important examples are conditioned pain modulation, attentional analgesia, offset analgesia/onset hyperalgesia, and offset analgesia/onset hyperalgesia. All of these coexist inside the descending pain modulatory system (DPMS) and rely on signalling pathways and systems that partially overlap. For instance, conditioned pain modulation is mediated primarily by noradrenergic signalling and partially by opioidergic signaling, whereas attentional analgesia, stress-induced analgesia/hyperalgesia, and offset analgesia are linked to the periaqueductal grey-dorsal raphe axis and require descending opioidergic pathways, respectively.
