Peripheral nitric oxide signaling directly blocks inflammatory pain

Pain is a classical sign of inflammation, and sensitization of primary sensory neurons (PSN) is the most important mediating mechanism. This mechanism involves direct action of inflammatory mediators such as prostaglandins and sympathetic amines. Pharmacologic control of inflammatory pain is based on two principal strategies: (i) non-steroidal anti-inflammatory drugs targeting inhibition of prostaglandin production by cyclooxygenases and preventing nociceptor sensitization in humans and animals; (ii) opioids and dipyrone that directly block nociceptor sensitization via activation of the NO signaling pathway. This review summarizes basic concepts of inflammatory pain that are necessary to understand the mechanisms of peripheral NO signaling that promote peripheral analgesia; we also discuss therapeutic perspectives based on the modulation of the NO pathway.