Neurogenic and tissue-mediated components of formalin-induced edema: evidence for supraspinal regulation

Injection of formalin into a hind paw of rats produces localized inflammation and pain. The nociceptive effect of formalin, recorded as flinching/shaking of the injected paw, is biphasic. The present study shows that formalin-induced inflammation and edema (assessed by measurement of paw volume up to 24 h post-injection) is also biphasic, an early neurogenic component being followed by a later tissue-mediated response. Rapid initiation of edema is closely related to early phase nociception and is dependent on activity in primary afferent neurons and axon reflexes, but not on transmission of the noxious stimulus and the perception of pain itself. The major site responsible for down-regulating the inflammatory response, particularly in the later stages when tissue-mediated components are most heavily involved, appears to be located supraspinally. Down-regulation occurs principally by means of descending neuronal pathways but may also involve a secondary humoral component. The perhaps surprising dependence on neuronal mechanisms which this study demonstrates promotes spinal and peripheral sites as potential therapeutic targets in certain inflammatory conditions.