The transmission of a pain signal from the periphery to the central nervous system is complex and only partially understood. Tissue damage results in peripheral release of endogenous chemicals that can directly activate nociceptive afferent fibers, sensitize nociceptors, or cause increased local extravasation and vasodilatation. These algesiogenic substances may be found in local tissues, plasma, and nerve terminals. Release of these substances may be caused by mechanical injury, radiation, or heat, or release may be stimulated by the by-products of tissue injury (ie, catecholamines or collagen). Peripheral nociceptors may be further sensitized by repeated noxious stimuli. Nociceptive afferents have their neurons in the dorsal root ganglion and contact second-order neurons in the dorsal horn or, less often, in the medulla. Modulation of the pain signal in the dorsal horn involves local inhibitory and facilitatory interneurons as well as diverse excitatory and inhibitory neurotransmitters. The neuronal circuitry in the dorsal horn can change and modulate with time so that pain signals sometimes long outlast the original peripheral tissue injury. This central sensitization is thought to be mediated largely through the NMDA receptor complex.