Brain sites involved in endogenous analgesia

Pain modulation is a fundamental survival mechanism that prioritises, shapes, and suppresses nociceptive inputs to optimise behaviour. Although acute pain signals potential or actual tissue damage, sustained pain can impair essential behaviours, necessitating modulatory circuits that dynamically regulate nociception according to context and motivational state. These systems are deeply conserved, embedded within primitive spinal and brainstem structures, and capable of powerful modulation independent of cortical input, although higher regions such as the prefrontal cortex can influence their function. Decades of work have sought to identify these core modulatory circuits to advance basic understanding and develop strategies for clinically meaningful hypoalgesia. More recently, dysfunction within these circuits has been implicated in chronic pain, driving efforts to characterise how their organisation and function change during persistent pain states. Although most mechanistic insights come from animal studies, human neuroimaging, particularly since the advent of functional magnetic resonance imaging, has begun to map their location and engagement during pain modulation. Early work focused on forebrain regions due to the limited spatial resolution of standard MRI, but ultra-high-field functional magnetic resonance imaging now enables mm3-scale investigation of brainstem nuclei. This review synthesises evidence from animal and human studies to outline the best-characterised modulatory pathway, consisting of projections from the midbrain periaqueductal gray to the rostral ventromedial medulla and onward to the dorsal horn/spinal trigeminal nucleus, and highlights recent work detailing its organization.