NGF‐dependent and NGF‐independent recovery of sympathetic function after chemical sympathectomy with 6‐hydroxydopamine

Abstract

To help clarify the distinction between the nerve growth factor (NGF)-dependent collateral sprouting of sympathetic nerves and their NGF-independent regeneration after crush, we used 6-hydroxydopamine (OHDA) to destroy the sympathetic terminals in adult rats; this leaves the axons damage-free. Would recovery occur by regeneration and/or collateral sprouting? A single 6-OHDA injection abolished the sympathetic pilomotor field revealed by electrical stimulation of a cutaneous nerve. Recovery began within 2 days, and by 20 days the field was reestablished. If the field was "isolated" by adjacent denervations at the time of 6-OHDA treatment, the recovering pilomotor field expanded extensively into the surrounding territory. In the presence of anti-NGF, however, the pilomotor field expansion ceased at about 60% of its former size; if anti-NGF treatment was discontinued, expansion recommended and extended into the surrounding skin. We suggest that the latter, NGF-dependent, growth phase corresponds to collateral sprouting, and the initial NGF-independent one to regeneration. After simple nerve crush, however, such regeneration can triple the normal sympathetic field size. This difference between crush- and 6-OHDA-induced regeneration might relate to the "cell body reaction" (CBR); the CBR is reduced with increasing distance of the lesion and is undetectable after a 6-OHDA lesion. Since the CBR and the vigor of regeneration are both increased by repeated axonal injury, we tested the effects of multiple 6-OHDA treatments; this significantly increased the initial NGF-independent expansion. We hypothesize that regeneration is regulated largely by mechanisms associated with the CBR, and that neurotrophin-dependent collateral sprouting occurs independently of these.

gp130 cytokines are positive signals triggering changes in gene expression and axon outgrowth in peripheral neurons following injury

“…For example, following transection of the sciatic nerve it has been shown that the neurotrophin receptor p75 and the neurotrophin nerve growth factor (NGF) are up-regulated by non-neuronal cells, and it was originally proposed that NGF binding to these receptors played an important role in sensory and sympathetic nerve regeneration (Taniuchi et al, 1986; Heumann et al, 1987; Taniuchi et al, 1988). However, evidence from Diamond and colleagues and others demonstrated that sensory and sympathetic regeneration is not affected by blockade of endogenous NGF, although under the same conditions collateral sprouting is blocked (Rich et al, 1984; Diamond et al, 1987, 1992; Gloster and Diamond, 1992, 1995; Doubleday and Robinson, 1995). …”

Sympathetic sprouting and changes in nociceptive sensory innervation in the glabrous skin of the rat hind paw following partial peripheral nerve injury

“…Collateral sprouting is from undamaged, intact axons of neighbouring regions while regenerative sprouting is from damaged axons of the injured nerve. Additionally, collateral sprouting was found to be dependent on growth factors derived from the target tissue, namely NGF, while regenerative sprouting was NGF-independent (Gloster and Diamond, 1995;Ro et al, 1998). The source of sympathetic sprouting into the upper dermis in this model is unknown as sympathetic fibres in the rat hindlimb travel in both the sciatic nerve as well as along blood vessels.…”

The density of nociceptive SP- and CGRP-immunopositive nerve fibers in the dura mater lumbalis of rats is enhanced after laminectomy, even after application of autologous fat grafts

“…This peptide is not only an important component of wound healing and tissue repair [31] but also an inductor of sprouting of sensory afferent nerve fibers [9,54]. Diamond and his group [13,14,22,23] stated that NGF mediates collateral sprouting in rats, but that regenerative sprouting is NGF independent. In fact, the sprouting of cutaneous nerves and an increase of NGF at the same time has been shown by Leslie et al [41] in inflamed rat paws.…”