While the acute sensation of pain is protective, signaling the presence of actual or potential bodily harm, its persistence is unpleasant. When pain becomes chronic, it has limited evolutionarily advantage. Despite the differing nature of acute and chronic pain, a common theme is that sufferers seek pain relief. The possibility to medicate pain types as varied as a toothache or postsurgical pain reflects the diverse range of mechanism(s) by which pain-relieving “analgesic” therapies may reduce, eliminate, or prevent pain. Systemic application of an analgesic able to cross the blood–brain barrier can result in pain modulation via interaction with targets at different sites in the central nervous system. A so-called supraspinal mechanism of action indicates manipulation of a brain-defined circuitry. Pre-clinical studies demonstrate that, according to the brain circuitry targeted, varying therapeutic pain-relieving effects may be observed that relate to an impact on, for example, sensory and/or affective qualities of pain. In many cases, this translates to the clinic. Regardless of the brain circuitry manipulated, modulation of brain processing often directly impacts multiple aspects of nociceptive transmission, including spinal neuronal signaling. Consideration of supraspinal mechanisms of analgesia and ensuing pain relief must take into account nonbrain-mediated effects; therefore, in this review, the supraspinally mediated analgesic actions of opioidergic, anti-convulsant, and anti-depressant drugs are discussed. The persistence of poor treatment outcomes and/or side effect profiles of currently used analgesics highlight the need for the development of novel therapeutics or more precise use of available agents. Fully uncovering the complex biology of nociception, as well as currently used analgesic mechanism(s) and site(s) of action, will expedite this process.

虽然剧烈的疼痛感具有保护作用，表明存在实际或潜在的身体伤害，但其持续存在却令人不快。当疼痛变成慢性时，它的进化优势就有限了。尽管急性和慢性疼痛的性质不同，但一个共同的主题是患者寻求疼痛缓解。治疗牙痛或术后疼痛等各种疼痛类型的可能性反映了缓解疼痛的“镇痛”疗法可以减轻、消除或预防疼痛的多种机制。全身应用能够穿过血脑屏障的镇痛剂可以通过与中枢神经系统不同部位的靶标相互作用来调节疼痛。所谓的脊髓上作用机制表明对大脑定义的电路进行操纵。临床前研究表明，根据目标大脑回路，可以观察到不同的疼痛缓解治疗效果，这些效果与例如疼痛的感觉和/或情感质量的影响有关。在许多情况下，这也适用于诊所。无论大脑回路如何操纵，大脑处理的调节通常会直接影响伤害性传递的多个方面，包括脊髓神经元信号传导。考虑椎上镇痛机制和随后的疼痛缓解必须考虑非脑介导的作用；因此，在本综述中，讨论了阿片类药物、抗惊厥药物和抗抑郁药物的脊髓上介导的镇痛作用。目前使用的镇痛药治疗效果不佳和/或副作用的持续存在突出表明需要开发新的治疗方法或更精确地使用现有药物。 充分揭示伤害感受的复杂生物学，以及目前使用的镇痛机制和作用位点，将加速这一过程。