Physiology Of Pain Generation In The Periphery

This review addresses our current knowledge on the mechanisms of pain generation in the joint. It focuses on the process of nociception in nociceptive nerve fibres of the joint and describes how disease processes in the joint act on nociceptors. While nociceptors of the normal joint have a high threshold for excitation and are activated only by stimuli of high intensity, disease processes in the joint often sensitise these nerve fibres such that they respond to stimuli of low intensity (movements, palpation) and, after processing in the central nervous system, elicit pain sensation. Sensitisation is frequently elicited by inflammatory mediators for which nociceptors express receptors. If nerve fibres are damaged during the disease process, neuropathic pain mechanisms may be triggered as well. Chronic joint diseases are characterised by inflammatory and destructive processes. In primary arthritis as well as osteoarthritis, inflammatory processes are responsible for the sensitisation of nociceptors. This process has been attributed to prostaglandins as well as, more recently, to proinflammatory cytokines and the nerve growth factor (NGF). For all of these mediators, receptors are expressed in nociceptors. Accordingly, these molecules are targets of innovative therapies, e. g. the application of antibodies to NGF to treat osteoarthritis pain. In particular, the neutralisation of TNF has been shown to elicit a direct rapid pain-reducing effect resulting from the interruption of nociceptive processes at the nociceptor. The direct pro-nociceptive effect of cytokines and the expression of binding sites for Fc fragments of antibodies in nociceptors show that immune mechanisms are important for the generation of pain. Pain can also be elicited by destructive joint processes. The activity of osteoclasts may elicit pain at the preclinical stage of arthritis, and after the outbreak of manifest arthritis, destructive processes contribute to pain. The extent to which the inhibition of osteoclast activity might alleviate pain is currently being investigated. This review also presents other novel approaches, peripherally acting opioids, cannabinoids and ion channel blockers. Finally, it addresses the importance of general/systemic factors which influence disease processes in the joint and pain generation. In particular, the importance of diabetes mellitus is addressed. This metabolic disease is a risk factor for the development of osteoarthritis and it contributes to pain aggravation, possibly by the involvement of more intense inflammatory processes as well as neuropathic pain components.