When we describe pain as burning, stabbing, or aching, do we really know what those sensations are? The reviews in this series describe the neurobiological basis of pain, including how signals are transmitted, received, and modulated, and how modern technology allows this process to be visualized. These articles also discuss what goes wrong in chronic pain syndromes, and how our understanding of the biology of pain can help direct the development of new analgesics.
To paraphrase Cole Porter’s famous 1926 song, “What is this thing called pain? This funny thing called pain, just who can solve its mystery?” Pain, like love, is all consuming: when you have it, not much else matters, and there is nothing you can do about it. Unlike love, however, we are actually beginning to tease apart the mystery of pain. The substantial progress made over the last decade in revealing the genes, molecules, cells, and circuits that determine the sensation of pain offers new opportunities to manage it, as revealed in this Review series by some of the foremost experts in the field.
Clifford J. Woolf
Mendelian heritable pain disorders have provided insights into human pain mechanisms and suggested new analgesic drug targets. Interestingly, many of the heritable monogenic pain disorders have been mapped to mutations in genes encoding ion channels. Studies in transgenic mice have also implicated many ion channels in damage sensing and pain modulation. It seems likely that aberrant peripheral or central ion channel activity underlies or initiates many pathological pain conditions. Understanding the mechanistic basis of ion channel malfunction in terms of trafficking, localization, biophysics, and consequences for neurotransmission is a potential route to new pain therapies.
Ramin Raouf, Kathryn Quick, John N. Wood
Despite intensive research into pain mechanisms and significant investment in research and development, the majority of analgesics available to prescribers and patients are based on mechanistic classes of compounds that have been known for many years. With considerable ingenuity and innovation, researchers continue to make the best of the mechanistic approaches available, with novel formulations, routes of administration, and combination products. Here we review some of the mechanisms and modalities of analgesics that have recently entered into clinical development, which, coupled with advances in the understanding of the pathophysiology of chronic pain, will hopefully bring the promise of new therapeutics that have the potential to provide improved pain relief for those many patients whose needs remain poorly met.
Gillian Burgess, Dic Williams
Specialized peripheral sensory neurons known as nociceptors alert us to potentially damaging stimuli at the skin by detecting extremes in temperature and pressure and injury-related chemicals, and transducing these stimuli into long-ranging electrical signals that are relayed to higher brain centers. The activation of functionally distinct cutaneous nociceptor populations and the processing of information they convey provide a rich diversity of pain qualities. Current work in this field is providing researchers with a more thorough understanding of nociceptor cell biology at molecular and systems levels and insight that will allow the targeted design of novel pain therapeutics.
Adrienne E. Dubin, Ardem Patapoutian
The somatic sensory system responds to stimuli of distinct modalities, including touch, pain, itch, and temperature sensitivity. In the past century, great progress has been made in understanding the coding of these sensory modalities. From this work, two major features have emerged. First, there are specific neuronal circuits or labeled lines transmitting specific sensory information from the skin to the brain. Second, the generation of specific sensations often involves crosstalk among distinct labeled lines. These features suggest that population coding is the mechanism underlying somatic sensation.
It has long been appreciated that the experience of pain is highly variable between individuals. Pain results from activation of sensory receptors specialized to detect actual or impending tissue damage (i.e., nociceptors). However, a direct correlation between activation of nociceptors and the sensory experience of pain is not always apparent. Even in cases in which the severity of injury appears similar, individual pain experiences may vary dramatically. Emotional state, degree of anxiety, attention and distraction, past experiences, memories, and many other factors can either enhance or diminish the pain experience. Here, we review evidence for “top-down” modulatory circuits that profoundly change the sensory experience of pain.
Michael H. Ossipov, Gregory O. Dussor, Frank Porreca
Since modern brain imaging of pain began 20 years ago, networks in the brain related to pain processing and those related to different types of pain modulation, including placebo, have been identified. Functional and anatomical connectivity of these circuits has begun to be analyzed. Imaging in patients suggests that chronic pain is associated with altered function and structural abnormalities in pain modulatory circuits. Moreover, biochemical alterations associated with chronic pain are being identified that provide information on cellular correlates as well as potential mechanisms of structural changes. Data from these brain imaging studies reinforce the idea that chronic pain leads to brain changes that could have functional significance.
Petra Schweinhardt, M. Catherine Bushnell