Normal and precocious sprouting of heat nociceptors in the skin of adult rats

The ability of intact cutaneous thermonociceptive C fibers to sprout into adjacent denervated skin, and the effects of this of electrical activity in the axons, were studied in adult rats. The presence of heat-sensitive endings in the back skin was assessed physiologically by the ability of a hot probe to elicit the reflex contraction of the underlying cutaneous trunci muscle; sensory C fibers were detected both by the Evans Blue technique, in which antidromic excitation of the C fibers causes a visible extravasation of dye in the skin it supplied, and by direct electron microscope (EM) examination of skin. The field of an identified branch of a selected dorsal cutaneous nerve (DCN) was "isolated" by eliminating all the nerves supplying the surrounding skin. The heat-sensitive area began to expand between 10 and 14 days after its isolation and reached a maximum (approximately doubling the initial value) by about 24 days. When the isolated nerve was antidromically excited, the borders within which dye extravasation now occurred had extended; the area of discoloration correlated well with that of the (enlarged) heat field, showing that its expansion was indeed attributable to C fiber sprouting. Electron microscopic examination showed that some of the "empty" Schwann tubes, routinely observed in the subepidermal horizontal fiber system of insensitive skin following denervation, had acquired unmyelinated axons when heat sensitivity had returned. A precocious expansion of the heat field, which was obvious by 10 days after its isolation, was produced if the heat stimulus was applied randomly throughout the field at the time of the adjacent denervations; this expansion too was shown to be due to sprouting of C fibers. Precocious sprouting of heat-nociceptive fibers also occurred if, immediately following the field isolation, the C fibers in the spared DCN were electrically excited, and also if pinches were applied through its field, i.e., the C fibers involved seemed to be polymodal, responding both to heat and to noxious mechanical stimulation. Precocious sprouting did not occur when tetrodotoxin was used to block central conduction of the "conditioning" impulses in the isolated DCN. Peripheral nerve damage often occurs in a situation likely to cause activation of nociceptive nerves; we suggest that the accelerated sprouting of spared axons could be important in reducing the period during which atrophic changes might occur in denervated target regions, in addition to hastening the provision of a nociceptive innervation. The various experimental approaches now available for producing differential innervation of selected regions of back skin are summarized.