Distribution and axonal relations of macrophages in a neuroma

After axotomy in the peripheral nervous system, most axons regrow and re-establish contact with their targets. Depending on the type of lesion, a varying number of nerve fibers fail to regenerate and terminate far from the target, forming a neuroma. Sensory axons trapped in a neuroma show abnormal sensitivity to various stimuli, and often fire spontaneously. In this study we have examined the distribution and axonal relations of macrophages in rat sciatic neuromas three days to one year after cutting and ligating the nerve. ED1-immunoreactive macrophages migrated into the neuroma in large numbers within the two first weeks after the injury. Most cells were at that time located 0.5-1 mm proximal to the ligature. From three weeks on, a majority of the ED1-immunoreactive cells contained numerous large vacuoles filled with myelin fragments. At sites of focal demyelination, macrophages often had direct contact with axonal membranes. At later survival stages (three months to one year) ED1-immunoreactive cells were seen not only in the area just proximal to the ligature, but also several millimeters proximal to this. Macrophages persisted in considerable numbers in the neuroma for at least one year. These data suggest that neuroma macrophages may participate in the genesis of electrophysiological abnormalities thought to underly chronic pain after neuroma formation, possibly by creating demyelinated axonal regions susceptible to external stimuli from e.g. neighboring nerve fibers, by releasing substances which influence regeneration and remodelling of axonal growth cones, or by direct actions on the denuded axonal membranes.