Clinical pain is a serious public health issue. Treatment of pain-related suffering requires knowledge of how pain signals are initially interpreted and subsequently transmitted and perpetuated. This review article is one of three reviews in this issue of Neuron that address our understanding of the pain process and possible solutions to the problem from both cellular- and systems-level viewpoints. Our understanding of the neural correlates of pain perception in humans has increased significantly since the advent of neuroimaging. Relating neural activity changes to the varied pain experiences has led to an increased awareness of how factors (e.g., cognition, emotion, context, injury) can separately influence pain perception. Tying this body of knowledge in humans to work in animal models of pain provides an opportunity to determine common features that reliably contribute to pain perception and its modulation. One key system that underpins the ability to change pain intensity is the brainstem's descending modulatory network with its pro- and antinociceptive components. We discuss not only the latest data describing the cerebral signature of pain and its modulation in humans, but also suggest that the brainstem plays a pivotal role in gating the degree of nociceptive transmission so that the resultant pain experienced is appropriate for the particular situation of the individual.
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