Role of nitric oxide in the physiopathology of pain.

Many painful disorders, including joint dysfunctions such as rheumatoid arthritis (RA) or temporomandibular joint disorders (TMD), are associated with hyperthermia of the overlying skin. The same is true of certain intractable chronic pain conditions, such as chronic orofacial pain, which may be associated with TMD. We suggest that this skin hyperthermia, caused by regional vasodilation, is induced by extravascular nitric oxide (NO). Extravascular NO can be produced in the affected joint by osteoblasts, chondrocytes, and macrophages, by mechanical stimulation of endothelial cells, or by stimulated neurons. In view of a strong correlation between pain and skin hyperthermia in these disorders, and the evidence that NO enhances the sensitivity of peripheral nociceptors, we also suggest that at least this kind of pain is associated with excessive local level of NO. This hypothesis can be verified by dynamic area telethermometry, assessing the effect of NO on the sympathetic nervous function. This mechanism, which is in line with the general role of NO as a mediator between different organ systems, also may be relevant to any pain associated with enhanced immune response. Clinical implications of the proposed mechanism are discussed.