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Noxious stimuli usually cause pain and pain usually arises from noxious stimuli, but exceptions to these apparent truisms are the basis for clinically important problems and provide valuable insight into the neural code for pain. In this Review, we discuss how painful sensations arise. We argue that, although primary somatosensory afferents are tuned to specific stimulus features, natural stimuli often activate more than one type of afferent. Manipulating coactivation patterns can alter perception in ways that argue against each type of afferent acting independently (as expected for strictly labeled lines), suggesting instead that signals conveyed by different types of afferents interact. Deciphering the central circuits that mediate those interactions is critical for explaining the generation and modulation of neural signals that ultimately elicit pain. The advent of genetic and optical dissection techniques promise to dramatically accelerate progress toward this goal, which will facilitate the rational design of future pain therapeutics.

Normal and abnormal coding of somatosensory stimuli causing pain