1Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261; and 2Department of Physiology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599
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ABSTRACT |
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Koerber, H. Richard,
Karoly Mirnics,
Anahid M. Kavookjian, and
Alan R. Light.
Ultrastructural analysis of ectopic synaptic boutons arising from
peripherally regenerated primary afferent fibers. The central axons of peripherally regenerated A primary sensory neurons were impaled in the dorsal columns of
-chloralose-anesthetized cats 9-12
mo after axotomy. The adequate peripheral stimulus was determined, and
the afferent fibers intracellularly stimulated while simultaneously recording the resulting cord dorsum potentials (CDPs). Fibers that
successfully had reinnervated the skin responded to light tactile
stimulation, and evoked CDPs that suggested dorsally located boutons
were stained intracellularly with horseradish peroxidase (HRP). Two
HRP-stained regenerated A
afferent fibers were recovered that
supported large numbers of axon collaterals and swellings in laminae I,
IIo, and IIi. Sections containing the ectopic
collateral fibers and terminals in the superficial dorsal horn were
embedded in plastic. Analyses of serial ultrathin sections revealed
that ectopic projections from both regenerated fibers supported
numerous synaptic boutons filled with clear round vesicles, a few large dense core vesicles (LDCVs) and several mitochondria (>3). All profiles examined in serial sections (19) formed one to three asymmetric axo-dendritic contacts. Unmyelinated portions of ectopic fibers giving rise to en passant and terminal boutons often contained numerous clear round vesicles. Several boutons (47%) received asymmetric contacts from axon terminals containing pleomorphic vesicles. These results strongly suggest that regenerated A
fibers activated by light tactile stimuli support functional connections in
the superficial dorsal horn that have distinct ultrastructural features. In addition, the appearance of LDCVs suggests that primary sensory neurons are capable of changing their neurochemical phenotype.
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INTRODUCTION |
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Recent studies clearly have demonstrated
collateral sprouting of sensory neurons in the spinal dorsal horn in
response to peripheral injuries. Collateral sprouting can be induced by
a variety of lesions ranging from deafferentation and multiple lesion paradigms (e.g., LaMotte and Kapadia 1993;
LaMotte et al. 1989
; McMahon and Kett-White
1991
; Molander et al. 1988
) to simple axotomy with (Koerber et al. 1994
) and without (Shortland
and Woolf 1993
; Woolf et al. 1992
, 1995
)
peripheral regeneration. It is of obvious interest to examine these new
projections at the electron microscopic level to establish if they make
synaptic contacts with dorsal horn cells and if they exhibit modified ultrastructure.
In most instances, it is very difficult to determine which
individual synaptic boutons existed before sprouting and those that are
truly novel. Fortunately, one type of collateral sprouting does allow
for this determination. Large-diameter cutaneous fibers, with
projections usually confined to laminae III-V, have been shown to
sprout into the superficial dorsal horn (laminae I-II) in response to
peripheral lesions (Koerber et al. 1994;
Shortland and Woolf 1993
; Woolf et al.
1992
). Although many studies have relied on bulk labeling of
whole nerves to visualize these ectopic projections, some studies
employed intraaxonal injection of horseradish peroxidase (HRP), which
allowed detailed analysis of collateral sprouts and their terminations.
For example, ectopic collaterals extend longitudinally for several
hundred micrometers in the superficial dorsal horn and gave rise to
numerous axonal swellings throughout laminae I-IIi.
(Koerber et al. 1994
; Shortland and Woolf
1993
). In addition, ectopic projections have been shown to
remain in the superficial dorsal horn long after the fibers have
reinnervated the skin and are responsive to light tactile stimuli
(Koerber et al. 1994
).
In a recent study, Woolf et al. (1995) examined the
ultrastructure of synaptic boutons in lamina II labeled by injections of
-cholera toxin conjugated with HRP into sciatic nerves that previously were sectioned and ligated. They examined numerous stained
profiles that formed synaptic specializations with dendrites in lamina
II. Although it is difficult to determine whether any given stained
profile examined originated from collateral sprouts of A
fibers, the
authors provide compelling evidence that such fibers do make synaptic
contact with cells in lamina II. In addition, a recent preliminary
study has shown that after peripheral nerve transection, lamina II
cells respond to A
-fiber inputs that they would not in intact
preparations (Yoshimura et al. 1996
). Taken together,
the results from these studies (i.e., Koerber et al. 1994
; Shortland and Woolf 1993
; Woolf et
al. 1992
, 1995
; Yoshimura et al. 1996
) have led
many investigators to suggest that these ectopic sprouts may be an
anatomic substrate that could contribute to known postlesion pain
syndromes such as mechanical allodynia (e.g., Dellon
1981
; Lindbloom and Verillo 1979
).
The possible contribution of the ectopic projections to postlesion pain syndromes magnifies the need for a more thorough examination of these projections. Therefore, the following experiments were undertaken to examine the fine structure of ectopic projections supported by identified regenerated fibers that responded to light tactile stimulation, specifically to determine if ectopic boutons formed synaptic specializations in the superficial dorsal horn and to provide detailed examination of the ultrastructure of identified ectopic synapses. Subsequently the ultrastructure of the ectopic boutons could be compared with the known synaptic ultrastucture of nociceptors in the superficial dorsal horn and low-threshold mechanoreceptors in deeper laminae.
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METHODS |
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Axotomy
Adult cats, unselected as to sex, were anesthetized with an intramuscular injection of a mixture of ketamine (Ketoset) 30 mg/kg and xylazine (Rompun) 1.5 mg/kg. While the animal was maintained in an areflexive state of anesthesia, the tibial and sural nerves were exposed in the popliteal fossa. The tibial nerve was cut 5-8 mm distal to its origin, and the sural nerve was cut at roughly the same position in the fossa. The proximal and distal stumps of each sectioned nerve were sutured back together using epineural sutures (8-0 silk). The wound was cleared of any debris, and the skin incision closed. The wound was coated with an antibacterial powder (furazolidone), and an intramuscular injection of antibiotics (Ampicillin, 60 mg) was administered. Animals were monitored continuously until they recovered the ability to right themselves and to maintain a normal core body temperature. Animals remained under daily supervision for 1 wk, and the sutures were removed 5-7 days after the surgery. All the procedures used in this study were reviewed and approved by the Institutional Animal Care and Use Committee at the University of Pittsburgh School of Medicine.
Recording and iontophoresis
Surgical preparation and animal maintenance have been described
previously in detail (Koerber et al. 1990) and are
described briefly here. Intact animals and those allowed to survive
9-12 mo after axotomy were anesthetized initially with an mixture of ketamine (20 mg/kg) and xylazine (0.5 mg/kg). A carotid artery, a
jugular vein, and the trachea were cannulated. While the blood pressure
was monitored, the short-acting anesthetic was replaced by intravenous
injection of
-chloralose (70 mg/kg). Animals were placed in a rigid
frame, and the left hindlimb stabilized using a bone pin. The animals
were paralyzed with gallamine triethiodide and artificially ventilated
to maintain end tidal CO2 levels between 3.5 and 4.5%.
Rectal temperature was monitored and maintained between 37.5 and
38.5°C, and an indwelling catheter was used to avoid urine
stagnation. A dorsal laminectomy was performed to expose the lumbar
enlargement. A small plexiglas platform was placed beneath the cord and
lifted slightly to stabilize the cord and four surface electrodes were
placed at 5- to 7-mm intervals along the lumbar enlargement.
The regenerated tibial and sural nerves were placed on a pair of
bipolar stimulating electrodes and the intact peroneal nerve on a
second set. In intact animals, the sciatic nerve was isolated and
placed on stimulating electrodes. The peripheral nerves were stimulated
electrically proximal to the lesion site while the dorsal funiculus was
explored with a microelectrode containing 12-15% HRP in 0.05 M Tris
buffer (pH 7.6) and 0.2 M KCl. When a responding fiber was impaled
adequately, its adequate stimulus was determined and its receptive
field location recorded. The fiber was stimulated via the
microelectrode, and the resulting cord dorsum potentials (CDPs) were
averaged and recorded. This stimulation consisted of two different
paradigms; first, single-action potentials were elicited in the fiber
at 18 Hz (n = 512) and second, pairs of action
potentials were elicited at 50-ms intervals and repeated once every
2 s (n = 32). Previous studies have shown that
these two stimulus paradigms are sufficient for characterization of the
afferent as having originally been a cutaneous or proprioceptive fiber
and are a good indicator of the adaptive properties of the receptors
originally innervated by the fiber (Koerber et al. 1989, 1994
).
To maximize the probability of injecting a fiber giving rise to ectopic
boutons, impaled fibers had to meet certain criteria before injection.
The criteria used to select such afferents included: peripheral
conduction velocity in the A range, activation by light tactile
cutaneous stimulation, and CDPs suggesting that the fiber originally
innervated a cutaneous low-threshold mechanoreceptor (e.g., hair
follicle, rapidly adapting pad, or slowly adapting type 1 or 2). The
last criteria ensures that the fiber in question is not a proprioceptor
that had reinnervated the skin (Koerber et al. 1994
).
Once the fiber was injected adequately, the stimulus trials were
repeated to verify that the electrode had remained in the single fiber
during the course of the iontophoresis. The HRP electrode was removed,
and the preparation was maintained for 6-9 h to allow for adequate
diffusion. A single fiber was injected in each animal to ensure that
all labeled terminals originated from the characterized fiber. On
termination of the experiment, animals were perfused with
phosphate-buffered saline (0.1 M PBS, at 37°C) followed by a fixative
solution containing 2% paraformaldehyde, 2% glutaraldehyde, and 4%
sucrose in phosphate buffer (0.1 M PB, pH 7.4 at 4°C). A block of
spinal cord containing the stained fiber was removed and stored
overnight in the same fixative.
Histological procedures
The next day, the block of spinal cord was sectioned in the
parasagittal plane (100 µm) on a vibratome. Serial sections were collected in phosphate buffer and processed using diaminobenzidine as
the chromogen. The sections were mounted on slides in phosphate buffer
and examined microscopically to determine if the fiber supported
collateral sprouts in the superficial laminae. Sections containing
collateral sprouts then were placed in a solution of osmium (2%
OsO4) and 4% sucrose in 0.1 M PB (pH 7.4) for
45-60 min. After osmication, the sections were dehydrated and
infiltrated in a mixture of Epon and Araldite and embedded in thin
wafers (Réthelyi et al. 1982). Selected
collaterals were reconstructed using a camera lucida and/or
photographed. The sections then were recut, collecting ultrathin serial
sections and placing them on formvar-coated grids.
HRP-labeled material is often too darkly stained, making it difficult to examine internal ultrastructure. To examine relatively lightly stained profiles, uncounterstained sections were scanned to locate appropriately HRP-stained profiles (Fig. 1A). Once a stained profile was located, the adjacent sections were contrasted by treatment with uranyl acetate and lead citrate (see Fig. 3 for an example).
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RESULTS |
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These experiments resulted in the recovery of two regenerated
afferent fibers from different animals that supported numerous collaterals and axonal swellings in the superficial laminae
(I-IIi) of the dorsal horn (Fig. 1, A and
B). Both afferent fibers had conduction velocities in the
A range and successfully had reinnervated the skin (fiber 1, 64 m/s,
9 mo postaxotomy; fiber 2, 78 m/s, 12 mo postaxotomy). Although each
afferent fiber had reinnervated glabrous skin and responded to light
tactile stimulation, one responded in a slowly adapting manner (fiber
1) and the second (fiber 2) was characterized as rapidly adapting (Fig.
1C). Although this is apparently a small sample size, it
should be noted that such material is very difficult to obtain. In an
earlier study, we estimated that roughly only 30% of A
-cutaneous
fibers maintained ectopic projections 9-12 mo after peripheral
axotomy. In addition, the recovery of adequately stained material at
the electron microscopic level further reduces the probability of
successfully obtaining suitable material for ultrastructural analysis.
CDPs
Intracellular electrical stimulation of both fibers resulted in
CDPs that indicated that both fibers had retained their original adaptation properties. For example, in response to 18-Hz stimulation, fiber 1 evoked relatively large monosynaptic CDPs (peak amplitude = 4.9 µV), and in response to conditioning-testing pairs of shocks, the ratio of the response [(amplitude of testing response/amplitude of
conditioning response) 1 =
0.33] was similar to that seen for slowly adapting low-threshold mechanoreceptors before axotomy (Koerber and Mendell 1988
) (Fig.
2). Similarly, intracellular electrical
stimulation of fiber 2 evoked CDPs indicative of intact rapidly
adapting mechanoreceptors (monosynaptic CDP = 1.9 µV and a
conditioning/testing ratio of
0.73).
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To confirm that the electrode had remained within the same fiber throughout the staining procedure, a second series of CDPs were recorded after iontophoretic injection. In both cases, the evoked CDPs were very similar to those recorded before staining (Fig. 2). The only obvious differences between the traces were changes in the stimulus artifact that was most likely the result of changes in the electrode resistance after iontophoresis.
Light microscopic observations
At the light microscopic level, the central projections of
both regenerated fibers were very similar in appearance to each other
and those previously reported (Koerber et al. 1994). The central projections consisted of relatively dense projections in
laminae III-IV with significant collaterals and axonal swellings in
the superficial laminae (I-IIi) (Fig. 1A).
Collaterals in laminae III-IV were oriented dorsoventrally, whereas
those in the superficial laminae were oriented longitudinally. It is
important to point out that the collaterals in the superficial lamina
were not simply limited extensions of existing deep collaterals into
adjacent dorsal neuropil. Sprouted collaterals were often branches from large myelinated fibers that entered the superficial laminae and extended over several hundred microns dropping off smaller collaterals at several different rostrocaudal locations. Although axonal swellings in the superficial laminae ranged greatly in size, they were comparable on average with those found in deeper laminae.
Ultrastructure of ectopic projections
A total of 19 boutons (1-5 µm) was examined from both
regenerated fibers. Profiles from both fibers had very similar
ultrastructure. All profiles arose from unmyelinated fibers, contained
numerous clear round vesicles (45 nm in diameter), a few dense core
vesicles, and several mitochondria. All boutons examined in serial
sections formed one to three asymmetric axodendritic synapses within
lamina I and II. In addition, half of the profiles also received
presynaptic contacts with terminals containing clear pleomorphic
vesicles that are characteristics of profiles shown previously to
contain GABA (e.g., Alvarez et al. 1993). On the basis
of the ultrastructural features observed in serial sections, terminals
forming presynaptic terminals were assumed to be axonic in origin.
However, it should be noted that individual terminals were not followed
back to myelinated fibers raising the possibility that they also might
arise from dendrites. Although many profiles were glomerular-like in
appearance, other profiles had a less complex structure. Examples of
the general morphology for boutons from both fibers can be seen in
Figs. 3, A-C, and
4.
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In addition to these general features, ectopic profiles also exhibited some novel ultrastructure. First, the putative axoaxonic synaptic specializations were asymmetrical with the stained ectopic bouton postsynaptic to profiles containing clear pleomorphic vesicles (Figs. 3C and 5, A-C). This finding was consistent for all presynaptic contacts on labeled terminals observed in this study. This result clearly differs from the symmetrical appearance of these specializations in the intact neuropil. Interestingly, one such contact synapsed on the unmyelinated portion of the stained fiber just before the terminal swelling (Fig. 5C). A second novel feature was the presence of light LDCV in addition to the usually observed dark LDCV. These two types of LDCV were observed within the same boutons (Fig. 6B). Similar light and dark LDCVs also were observed in unstained terminals (Fig. 6B). The third novel feature was observed within the unmyelinated portion of the stained fibers. The fibers were filled with clear vesicles (40-50 nm in diameter) identical to those observed within the terminal. Like the other ultrastructural features described this was observed for both fibers studied (Figs. 6, B and C, and 7, A and B).
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DISCUSSION |
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The findings presented here confirm the earlier report
showing that regenerated A fibers reinnervating low-threshold
cutaneous mechanorectors sprout and maintain collaterals in the
superficial laminae (I-II) of the cat up to a year after transection
(Koerber et al. 1994
). At the light microscopic level,
these fibers were indistinguishable from those reported previously. For
example, some collateral sprouts originated from laminae III and
extended up into laminae I-II, whereas others originated from apparent myelinated collaterals as they coursed through the superficial laminae.
Regardless of their origins, collateral sprouts adopted a longitudinal
orientation in laminae I-II that differed from the transversely
oriented projections in laminae III-IV. The finding that collateral
sprouts can originate from myelinated collateral branches demonstrates
that afferent fibers are not limited to simple extensions of existing
terminal branches. This suggests that given the appropriate stimulus
they are capable of supporting collateral sprouts at many locations
along their projections in the gray matter.
Functional connections
Intracellular stimulation of the two regenerated fibers
evoked relatively large and characteristic CDPs. As stated in
RESULTS, these evoked potentials were indistinguishable
from those elicited by intact fibers. However, CDPs elicited by
paired-pulse stimulation of the two afferent fibers in the present
study did differ from those presented in the earlier study
(Koerber et al. 1994). Previously, fibers supporting
ectopic sprouts exhibited different amounts of facilitation in response
to conditioning-testing pairs of pulses. Here, both fibers activated
central networks that exhibited different levels of depression. Taken
together, the results of this study and previous studies in the cat
(Koerber et al. 1989
, 1994
) strongly suggest that both
rapidly adapting and slowly adapting low-threshold mechanoreceptors are
capable of supporting ectopic sprouts in laminae I-IIo.
This differs somewhat from the results of single fiber studies in rat
where only fibers with flame-shaped central arbors, characteristic of
hair follicle afferents, were observed to support ectopic superficial
projections (Shortland and Woolf 1993
; Woolf et
al. 1992
). Although it is possible that this could be a species
difference, the fibers in rat studies were chronically axotomized,
raising the possibility that some of those fibers may have been slowly
adapting before axotomy.
Ultrastructural features
The results of this study show conclusively that the ectopic
boutons supported by regenerated A fibers, form synaptic
specializations, confirming the previous work by Woolf et al.
(1995)
. Many of the ultrastructural features of the ectopic
boutons were similar to those of intact primary afferent terminals
(e.g., asymmetric axodendritc synapses, numerous clear round vesicles).
However, ectopic synaptic profiles differed from the normal
ultrastructure of uninjured A
fiber terminals in deeper dorsal horn
laminae. Most notably, ectopic terminal swellings contained LDCVs that
are not present in intact A
-fiber terminals in laminae III-IV
(e.g., Maxwell et al. 1982
, 1984
; Semba et al.
1983
-1985
). The frequent axoaxonic synaptic specializations
and small numbers of LDCVs also distinguish them from those of C-fiber
nociceptors (Alvarez et al. 1993
). In general, the
ultrastructure of ectopic boutons arising from regenerated
low-threshold mechanorectors is most similar to that of myelinated
nociceptors (Réthelyi et al. 1982
). For example, they both exhibit multiple axodendritc synaptic specializations and
frequent axoaxonic contacts with terminals containing clear pleomorphic vesicles.
Previous studies have shown that similar terminals containing LDCVs in
intact preparations also stain positively for neuropeptides including
calcitonin gene related peptide (CGRP) and/or substance P (e.g.,
Alvarez et al. 1993; De Biasi and Rustioni
1988
; Merighi et al. 1989
, 1991
). This suggests
that in addition to sprouting into the superficial laminae, regenerated
A
fibers may be capable of altering their neurochemical phenotype.
This apparent phenotypic change is in agreement with the results of
Noguchi et al. (1995)
, who demonstrated that injured
medium and large sensory neurons projecting to the gracilis nucleus
expressed preprotachykinin message de novo. In addition, they reported
an increase in substance P immunoreactivity in the gracilis nucleus and
the appearance of immunoreactivity in large myelinated fibers after
sciatic nerve transection. Interestingly a similar increase in
substance P staining in sensory neurons also was observed after
experimental inflammation in rats (Neumann et al. 1996
).
Together these results suggest the possibility that sensory neurons
supporting ectopic projections in the superficial dorsal horn are
adjusting their phenotype possibly to match their new environment.
Although numerous studies have shown that sensory neurons can alter the
levels of their production of neurochemicals after axotomy (reviewed in
Hokfelt et al. 1994
), the present findings suggest that
sensory neurons supporting ectopic terminals transport them centrally
where they could modulate synaptic activity.
It should be pointed out that these findings differ from those reported
by Woolf et al. (1995). In that study, the authors concluded that the ultrastructure of ectopic boutons visualized using
bulk labeling of axotomized nerves with a
-cholera toxin-HRP conjugate most closely resembles terminals of low-threshold
mechanoreceptors observed in laminae III-IV (e.g., no LDCVs). The
reason for this discrepancy is not clear. One possible explanation
would be species differences. Another possibility is that they may have
missed LDCVs given the fact that they did not follow the boutons in
serial sections. However, it is interesting to note that in some of the figures in that study (Figs. 6-8 in Woolf et al. 1994
),
it appears that some LDCVs are present.
The stimulus for the sprouting of A fibers and the putative
phenotypic change is not known. In a series of inventive studies, Woolf
and colleagues (Doubell et al. 1997
; Mannion et
al. 1996
, 1998
) have attempted to clarify the underlying
mechanism. They have shown that both injured and intact A
fibers are
capable of sprouting but only after peripheral injury to C fibers. They suggested that peripherally injured C fibers transport a signal back to
the cell body that elicits an upregulation and the central transport of
a novel chemotropic factor. Once released centrally, this factor would
induce collateral sprouting. Results from the present study and that of
Noguchi et al. (1995)
would suggest further that the
novel chemotropic factor also may stimulate a transcriptional change in
A
fibers resulting in the de novo production and central transport
of neuropeptides.
In addition to the normal ultrastructure, novel features also were observed. Stained and unstained terminals in the surrounding neuropil contained both light and dark LDCVs. Numerous clear round vesicles were located in the unmyelinated portions of the fiber. Putative axoaxonic synaptic specializations with pleomorphic vesicles containing terminals were clearly asymmetric. Although these novel features were observed consistently for ectopic boutons from both fibers, there is no apparent functional significance that can be ascribed to them. However, they may be useful for the identification of novel synapses in other areas of the dorsal horn or in the identification of unstained ectopic boutons.
Functional implications
It is well known that peripheral nerve transection and
regeneration can result in a variety of sensory deficits including impaired localization of peripheral stimuli, diminished two-point discrimination, hyposensitivity (increases in peripheral thresholds), and hypersensitivity (e.g., Dellon 1981; Ford and
Woodhall 1938
; Hallin et al. 1981
;
Hawkins 1948
; Head 1920
; Lindbloom
and Verillo 1979
; Moberg 1962
; Onne
1962
; Poppen 1980
), the latter ranging from
relatively innocuous hyperesthesia to allodynia or causalgia in which
debilitating painful sensations are elicited by innocuous cutaneous
stimuli. Although ectopic projections do not address all postaxotomy
deficits, the existence of large numbers of synaptic terminals in the
superficial dorsal horn activated by light tactile stimulation would
result in obvious perceptual abnormalities (i.e., mechanical
allodynia). Interestingly, although nociceptive thresholds were not
directly measured in these animals or those in previous studies, they
did not show overt signs of hyperalgesia or mechanical allodynia. For
example, the animals moved freely around the enclosure and used the
effected limb without hesitation. In addition, they did not respond
adversely to manual inspection of the reinnervated skin nor were there
any signs of peripheral inflammation or hair loss.
The fact that these animals do not openly exhibit behavioral responses
that would indicate that light tactile stimuli were eliciting painful
sensations suggests that either these projections are nonfunctional or
they are actively inhibited. As noted earlier, a recent preliminary
study has suggested that these inputs are functional (Yoshimura
et al. 1996), suggesting that active inhibition made be playing
a significant role in controlling the effectiveness of these ectopic
projections. The axoaxonic contacts observed here could be a substrate
for this inhibition. This also suggests that collateral sprouting may
be the normal response to peripheral injury, possibly replacing
nonfunctional C-fiber inputs and possibly serving a postlesion
neuroprotective role. It is also important to note that although this
collateral sprouting always occurs after peripheral injury in animal
models (e.g., Doubell et al. 1997
; Koerber et al.
1994
; Mannion et al. 1996
; Woolf et al.
1992
, 1995
), peripheral nerve injury in humans doesn't always
result in chronic pain (e.g., Dellon 1981
; Hallin
et al. 1981
). This in turn suggests that chronic pain syndromes
observed in some individuals are not simply the result of the sprouting
of myelinated fibers into the superficial dorsal horn but also the
inability of the inhibitory systems to adequately control the ectopic inputs.
In summary, results from this study substantiate the results of previous studies showing that peripheral nerve injury results in abundant growth and synaptogenesis in the adult spinal cord. In addition to making novel synapses with cells in the superficial dorsal horn, they also receive inputs from putative inhibitory interneurons. Finally, the existence of large dense core vesicles in the ectopic terminals suggests that the sensory neurons supporting these projections have altered their neurochemical phenotype.
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FOOTNOTES |
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Address for reprint requests: H. R. Koerber, Dept. of Neurobiology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15261.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 18 September 1998; accepted in final form 20 December 1998.
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REFERENCES |
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