What is this thing called pain?

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. Classifying painWhat exactly, from a neurobiological perspective, is pain?Pain is actually three quite different things, although we and many of our physicians commonly fail to make the distinction.First, there is the pain that is an early-warning physiological protective system, essential to detect and minimize contact with damaging or noxious stimuli.This is the pain we feel when touching something too hot, cold, or sharp.Because this pain is concerned with the sensing of noxious stimuli, it is called nociceptive pain (Figure 1A), a highthreshold pain only activated in the presence of intense stimuli (1).The neurobiological apparatus that generates nociceptive pain evolved from the capacity of even the most primitive of nervous systems to signal impending or actual tissue damage from environmental stimuli.Its protective role demands immediate attention and action, which occur by virtue of the withdrawal reflex it activates, the intrinsic unpleasantness of the sensation elicited, and the emotional anguish it engages.Nociceptive pain presents itself as something to avoid now, and when engaged, the system overrules most other neural functions.The second kind of pain is also adaptive and protective.By heightening sensory sensitivity after unavoidable tissue damage, this pain assists in the healing of the injured body part by creating a situation that discourages physical contact and movement.Pain hypersensitivity, or tenderness, reduces further risk of damage and promotes recovery, as after a surgical wound or in an inflamed joint, where normally innocuous stimuli now elicit pain.This pain is caused by activation of the immune system by tissue injury or infection, and is therefore called inflammatory pain (Figure 1B); indeed, pain is one of the cardinal features of inflammation.While this pain is adaptive, it still needs to be reduced in patients with ongoing inflammation, as with rheumatoid arthritis or in cases of severe or extensive injury.Finally, there is the pain that is not protective, but maladaptive, resulting from abnormal functioning of the nervous system.This pathological pain (Figure 1C), which is not a symptom of some disorder but rather a disease state of the nervous system, can occur after damage to the nervous system (neuropathic pain), but also in conditions in which there is no such damage or inflammation (dysfunctional pain).Conditions that evoke dysfunctional pain include fibromyalgia, irritable bowel syndrome, tension type headache, temporomandibular joint disease, interstitial cystitis,