Collateral Sprouting of Uninjured Primary Afferent A-Fibers into the Superficial Dorsal Horn of the Adult Rat Spinal Cord after Topical Capsaicin Treatment to the Sciatic Nerve

Abstract

That terminals of uninjured primary sensory neurons terminating in the dorsal horn of the spinal cord can collaterally sprout was first suggested by Liu and Chambers (1958), but this has since been disputed. Recently, horseradish peroxidase conjugated to the B subunit of cholera toxin (B-HRP) and intracellular HRP injections have shown that sciatic nerve section or crush produces a long-lasting rearrangement in the organization of primary afferent central terminals, with A-fibers sprouting into lamina II, a region that normally receives only C-fiber input (Woolf et al., 1992). The mechanism of this A-fiber sprouting has been thought to involve injury-induced C-fiber transganglionic degeneration combined with myelinated A-fibers being conditioned into a regenerative growth state.In this study, we ask whether C-fiber degeneration and A-fiber conditioning are both necessary for the sprouting of A-fibers into lamina II. Local application of the C-fiber-specific neurotoxin capsaicin to the sciatic nerve has previously been shown to result in C-fiber damage and degenerative atrophy in lamina II. We have used B-HRP to transganglionically label A-fiber central terminals and have shown that 2 weeks after topical capsaicin treatment to the sciatic nerve, the pattern of B-HRP staining in the dorsal horn is indistinguishable from that seen after axotomy, with lamina II displaying novel staining in the identical region containing capsaicin-treated C-fiber central terminals.These results suggest that after C-fiber injury,uninjuredA-fiber central terminals can collaterally sprout into lamina II of the dorsal horn. This phenomenon may help to explain the pain associated with C-fiber neuropathy.

Stereological and somatotopic analysis of the spinal microglial response to peripheral nerve injury

“…Within nucleus caudalis microglial activation was more exaggerated in superficial laminae, corresponding to C-fibre input -similar to the pattern seen in this study. It is an intriguing possibility that the microglial activation is driven by altered C-fibre input as a consequence of peripheral nerve injury as has been previously proposed (Mannion et al, 1996(Mannion et al, , 1998. Unmyelinated C-fibres have been shown to be more susceptible to peripheral nerve injury, with a large percentage of unmyelinated cells dying following peripheral nerve injury (Coggeshall et al, 1997) and further studies will be required to ascertain whether the microglial response is indicative of the first stage of degeneration of unmyelinated primary afferents following peripheral nerve injury.…”

Capsaicin-induced activation and chemical injury of nociceptive primary sensory neurons

“…In the 1990s Woolf and co-workers reported that crush or section of a peripheral nerve cause a long-lasting morphological reorganization of the central terminals of primary afferent neurons (Coggeshall et al, 1997;Lekan et al, 1996;Mannion et al, 1996;Woolf et al, 1992;Woolf et al, 1995). This observation has mainly been based on the utilization of the retrograde and transganglionic neuronal tracer CTB-HRP.…”

“…Based on these findings Mannion and his colleagues studied whether C-fibre degeneration and A-fibre conditioning are both necessary for the sprouting of A-fibres into lamina II (Mannion et al, 1996). They took advantage of the perineural capsaicin treatment of the sciatic nerve which causes transganglionic degeneration exclusively within the C-fibre population of primary afferents (Jancsó, 1992;Jancsó and Lawson, 1990), without affecting the integrity of sciatic A-fibres.…”

“…Based on earlier studies, this time interval seemed to be very short for such significant anatomic rearrangements of the neuronal circuits of the spinal cord dorsal horn (Nagy and Hunt, 1983). Besides, regarding the observation of Mannion et al (Mannion et al, 1996) it seems less probable that the extent of the sprouting response is independent of the presence or absence of the injury of the peripheral axons of Aß-fibres. Axotomy indeed, influences the regenerative capacity of these neurons therefore it was plausible to assume its importance in the proposed central sprouting, which was finally not supported by their later observations.…”

“…Moreover, this hypothesis has raised some problems e.g. the supposed sprouting response of myelinated afferents is a fast process, since the first signs of it occur 1 week after the injury and reaches its maximum in 2 weeks (Mannion et al, 1996;Woolf et al, 1992;Woolf et al, 1995). Based on earlier studies, this time interval seemed to be very short for such significant anatomic rearrangements of the neuronal circuits of the spinal cord dorsal horn (Nagy and Hunt, 1983).…”