The reaction of primary sensory neurons to peripheral nerve injury with particular emphasis on transganglionic changes

The Reaction of Primary Sensory Neurons to Peripheral Nerve Injury With Particular Emphasis on Transganglionic Changes HAKAN

ALDSKOGIUS.

JAN ARVIDSSON

and GUNNAR

GRANT

~e~t~rittletff ofAtzafotny, ~~rolinska lnsijrutef, Box- 61)40(1,S-104 01 Srockholtn (Swdtw) (Accepted E;q nor&:

April 23rd, lY85)

nerve injury - primary sensory neuron-central physi~~l~~icai alteration-plasticity

peripheral

process-structural

alteration

-

CONTENTS 27

.............................................................................................................................................

1. Introduction

2. Structural ohservatmns ................................................................................................................................ 7.1. Changes m terminal areas ...................................................................................................................... ........................................................................................................................ 2.1.1. Light microscopy .................................................................................................................... 2.1.2. Electron microscopy ........................................................................................... 2.7. Changes in axonsof primary afferent pathways ............................................................................................................................... 7.3. Changesinpanglia 2.4. Changes in primary sensory neurons of immature animals .............................................................................. 2-5. The reaction of primary sensory neurons of other types than spinal and trigeminal ones ......................................... 2.6. Effects ofvarioustypes of lesions of peripheral axons on primary sensory neurons ................................................ ........................................................................................... 2.7. The role of axonal transport and trophicfactors

28 28 2x 30 32 33 33 34 35 36

3. Ph~sj~lo~ic~il observations

37

4. Correlation

hetween

5. Transganglionic

...........................................................................................................................

transgnnglionicchanges

plasticity

and the response

of sensory ganglion cell bodies to peripheral

.................................................................................................

nerve injury

..........................

6. Sunim~lry ................................................................................................................................................. Acknowledgements References

... ...............................................................................................................................................

Interrupti~~n of a peripheral sensory axon results in a well characterized series of changes not only in the distal part of the injured axon but also in the proximal stump and in the perikaryon (for references see ref. 166). Generally. the portions of the primary sensory neuron central to the ganglion have been considered to be relatively unaffected. Yet, some early ohservations indicated that this might not be absolutely true. With methods available

at that time, some investiga-

C’~)m,.~~~?f~encc,~ H. Aldskogius,

Department

~)lh5-0172/X51$(13.3t) @ 1985 Elsevier

of Anatomy,

Science Publishers

Karolinska

tors were able roots of spinal glia and in the neurons after

37 39 JO II

........................................................................................................................................

INTRODUCTION

.....

31

to demonstrate changes in sensory and cranial nerves central to the gancentral pathways of primary afferent peripheral nerve lesions in mam-

m&2Y.%.I.?H.l4I

These methods, however, did not allow examination of changes in the central terminals of the affected sensory neurons. The absence of knowledge about the state of these terminals may be one of the main reasons why these early findings appear not to have been fully appreciated for a long time. More reInstitutet,

B.V. (Biomedical

Box tjo4t.k). S-104 01 Stockholm.

Division)

Sweden.

28 cently, studies with degeneration techniques, zyme histochemistry, immunohistochemistry electron

microscopy

have made possible

of peripherally

injured

significance

have been emphasized lesions to peripheral changes

territories

primary sensory neurons. of these morphological by physiological

synaptic

The

studies

findings

sensory nerves produce

in spinal cord or brainstem

served in the cuneate

Most of these changes apparently

the exami-

nation of changes in the central projection potential

enand

that

marked trans-

migjion53.88.174,

These findings provide ample evidence of peripheral

that lesions

sensory nerves induce

a series of com-

plex changes central to the ganglion

cell body. A de-

tailed analysis of these changes is likely to be relevant for the understanding of disturbances in sensory functions after peripheral nerve damage57,‘3” and how these might be prevented, compensated for or treated. In addition, an analysis of these changes may reveal features of interest for the understanding of the principal mechanisms involved in lesion-induced structural reorganization of the neuron. The purpose of this review is to summarize and present possible interpretations of current data on the structural alterations in the central processes and ganglion cell bodies of peripherally injured primary sensory neurons with emphasis on the somatosensory neurons in the spinal and trigeminal ganglia. A major aim of this review will be to describe and interpret a variety of changes commonly referred to as degenerative. To try to avoid confusion about the meaning of this term, it will be used according to the definition in general pathology, i.e. deterioration of the structure to a lower functional states*. Accordingly, degeneration is not in itself an irreversible condition. but a process from which the cell may recover, disintegrate or remain in a reduced functional, i.e. atrophic, state. As will be apparent, one of the most pressing problems in this field is the difficulty in determining which one of these outcomes will eventually follow the degenerative process. 2. STRUCTURAL

OBSERVATIONS

2.1. Changes in terminal areas 2.1.1. Light microscopy Following brachial plexotomy in the cat, marked alterations in various enzyme activities have been ob-

and external

cuneate involved

nucleilh. structures

in the neuropil, but could not be clearly related to primary afferent terminals. The presence of terminal changes

was clearly

indicated.

ments on the vestibular ter

the

branches,

transection silver

however,

in experi-

nerve in young rabbits’;. of

various

impregnated

vestibular

fiber-like

were seen in Nauta-stained

sections

ate regions of the vestibular

nuclei.

Af-

nerve

fragments

from appropriElectron

micro-

scopic sections from these regions showed electrondense terminals and axons. These findings led to the introduction of the term transganglionic degenerationT3. However, the results of these experiments may in some way have been related to the bipolar structure of the vestibular ganglion cells. Furthermore, the possibility of a direct partial injury to the vestibular ganglion itself could not be excluded. although the rather long postoperatrve survival times which were found necessary for eliciting the degeneration argued against this possibility. To exclude these possible sources of error. subsequent investigations were made on trigeminal and spinal primary afferent neurons. With the aid of suppressive silver stains, primarily the Fink-Heimer method. argyrophilic profiles were consistently demonstrated in the trigeminal nuclear complex of the rat and cat lx.7’. the rat thoracic-,I. cervical and lumbar spinal cord (Arvidsson et al.. unpublished), and the rat dorsal column nucleil~“. after peripheral nerve lesions. The argyrophilia in all these regions has been very similar-. iti appearance requires survival times in the order of one to sekcrai weeks. Thereafter. the amount ot argyrophilia gradually increases and remains at roughly the same level for many weeks. The staining pattern is dominated by argyrophilic granules of varying siLes especially evident at shorter postoperative survival times. lmpregnated fiher-like fragments increase in number at longer survival times but never predominate the degeneration picture. This transganghonic argyrophilia always appears in somatotopically appropriate areas in the trigeminal sensory nuclei and the spinal cord dorsal horn. A similar degeneration argyrophilia has been shown in certain parts of the cat trigeminal sensory nuclei following tooth extractions OJ toOth pu@XtOmies”.yF 17c.177. Kittens also show &generation arg!-

29 rophilia in the same areas at the age of exfoliation the deciduous

teeth176. It is interesting

the degeneration argyrophilia been found also in the ventral

of

to note that

in these studies has parts of the spinal tri-

generation

the axon is immediately

deprived

port from the cell body. The simultaneous in the affected population

of neurons

distinct pattern of argyrophilia,

of supresponse

often leads to a

which varies with the

geminal nucleus, which are known to receive primary input from the ophthalmic divitrigeminal

survival time. For example, a heavy terminal degeneration of primary afferent fibers in the substantia

~~~~46.7?.YY.lO6.lll7.l~~l.lX~

gelatinosa

and maxillary thermore.

and

branches

not

from

innervating

the areas of degeneration

only partly with the projection

the

the teeth.

peroxidase

Fur-

seem to coincide

of tooth pulp fibers

observed in studies using transganglionic horseradish

mandibular

transport

of

(HRP)1’.‘78.179. The reason

for this discrepancy is not quite clear at present although lack of argyrophilia in some of the degenerating tooth pulp terminals

has been suggested

in a re-

cent electron microscopic studygh. Degeneration argyrophiha has also been observed in the contralateral trigeminal sensory nuclei in the cat following dental lesionsx.9s.175.177 and peripheral nerve transectionI”. This is at variance with HRP studies in the cat showing no contralateral trigeminal

can be observed

postoperative

only after a rather short

survival time79.

On the other hand, the perikaryal axon may cease gradually generation

support

to the

during transganglionic

as a result of the cell body response

axon injury.

The process

the central terminals

of degeneration

deto the

affecting

of primary sensory neurons

may

thus be initiated at different times in different neurons of the affected population. The limited argyrophilia in the substantia

gelatinosa

during transgang-

lionic degeneration may be related to these particular circumstances, resulting in a density of degenerating profiles below the level of detection. Alternative explanations are that transganglionic degenera-

primary afferent projections in the brainstem but only in the upper cervical spinal cord12.1*(‘.Although

tion in those primary sensory neurons, which project to the substantia gelatinosa is less or not argyrophilic, or that this group of ganglion cells do not react with

cells in the trigeminal sensory nuclei have been shown to respond to contralateral tooth pulp stimulationlil. other electrophysiological studies have failed to find evidence for a crossed projection from tooth

These explanations could also be true in view of the findings that transganglionic argyrophilia in other parts of the spinal cord dorsal horn have a more limit-

pulp afferents”?. In previous HRP studies it was claimed that some tooth pulp innervating neurons cross the midline in the periphery8. but these findings

transganglionic

degeneration

(see however

2.1.2.).

ed rostro-caudal extension than would be expected from other studies on the projection pattern of spinal primary sensory neurons (cf. refs. 25, 184). Without the examination of silver-impregnated

were not supported by other HRP studies”. More recent studies addressing this question have not confirmed the existence of a peripheral transmedian in-

sections at the ultrastructural level, it cannot be unequivocally determined whether the argyrophilic

nervation

properties

of the tooth pulp in the catjx, Furthermore.

since there is no evidence for degenerating fibers crossing the midline at brainstem levels following dental lesionsl77, the background for the occurrence of contralateral degeneration in the cat remains unclear. An intriguing feature regarding transganglionic degeneration is that in the spinal cord the substantia gelatinosa is apparently devoid of argyrophilia74 and in the corresponding region of the spinal trigeminaj nucleus only scanty impregnation has been foundlj. This staining picture is different from that observed after damage to the primary sensory axons centrally to the dorsal root ganglion. which induces a classical Wallerian degeneration. In the case of WaIlerian de-

reside in terminals

and axons of the prima-

ry sensory neurons or in glial cells and/or second-order neurons. It appears likely, however, that the argyrophilia indicates a marked alteration in the biochemical characteristics of many primary afferent terminals and axons and reflects a degenerative reaction in these structures (see Introduction). This notion is reinforced by the fact that suppressive silver methods have a high sensitivity for visualizing degenerating neuroplasml.‘.7X.171.17?. However, this tentative conclusion still leaves open the question of the final outcome of this process, After sectioning spinal or trigeminal peripheral sensory nerve branches in the rat. the species-specific fluoride-resistant acid phosphatase (FRAP) in the

substantia weeks or

gelatinosa

disappears

for

a period

~~~~~~3~.36.l~l,l~~.i5O,lS~,~SS, Trauma

of

to a pe_

cells, is increased

ripheral sensory nerve also results in a marked reduc-

has been reported

tion of substance

peripheral

P-like15.9~J2sJ~7, and somatostatin-

like’23 immunoreactivity,

and opiate-receptor

ing on primary afferent terminal&s4 cord dorsal horn. In autopsy where limb amputation in the ipsilateral

The disappearance tive transmitter terminals

material

from humans

had been performed,

stance P-like immunoreactivity reduced

bind-

in the rat spinal sub-

was also found to be

spinal cord dorsal hornst.

of FRAP substances

and depletion from

primary

return is mediated containing sensory

by a reduced number of FRAPganglion cells. The substance P-

like immunoreactivity shows a somewhat different pattern, since after peripheral nerve section substance P-like activity in affected primary sensory fibers in the dorsal horn does not return to normal lev~9~94.14s.This observation couId imply a permanent marked reduction in the density of substance P-containing primary afferent terminals due to a decrease in the number of substance P-containing ganglion cells or degeneration of their terminals following a delayed

or

FRAP-positive

deficient

peripheral

and substance

in the peripherally One particularly the clearcut

re-innervation

P-like immunoreactivc

cells appear to be largely separate subpopulations in spinal ganglia”sSslSl”(J. The differential long term alterations of these biochemical parameters suggest that all types of ganglion cells do not respond identically to peripheral nerve section. Within a few days after peripheral nerve lesion. a striking increase in the number of glial cells occurs in the dorsal hornhs. The localization in the dorsal horn of this glial response is cIosely related to the projection area of the injured peripheral nerve branch. indicating that this response is specifically related to changes in the affected terminals and preterminal axons. Although the precise identification of these glial cells is still somewhat uncertain, most of them seem to have the characteristics of microglial cellsfiX. In addition, however, immunohistochemical staining of glial fibrillary acidic protein. typical for astroglial

findings reviewed

injured intriguing

alterations

primary afferent

above tell

in the substantia

for substance show

neurons.

aspect of these studies is

shown with FRAP-histochemistry ver methods

turn of FRAP when re-innervation occurs is compatible with this notion, although it is possible that this

to sci-

activity in glia

in cat spinal cord dorsal horn after

The light microscopic

afferent

the metabotism in the reacting ganglion cells in favor of the synthesis of structural proteins at the expense of transmitter-related enzymes (cf. ref. 70). The re-

enzyme

us little about the actual processes going on centrally

chemistry

of

Increased

nerve sectionI’.

of puta-

could be the result of a reorganization

in the dorsal horn ipsilateral

atic nerve injuryQ.

gelatinosa

and immunohisto-

P. while the suppressive

very

little

or no evidence

silof

changes going on in this area. Ultrastructural studies. however. have thrown some light on this issue. as well as providing additional relevant information about transganglionic

changes

2.12. Electron microscop_t Fine structural changes after peripheral sions have been described in the trigeminal

nerve lemain sen-

sorvl[J , and spinal~~~~~.175nuclei, in the substantia gelatinosa of the spinal cordfis.hQ.1~”and in the cuneate nucleusr2fi. These changes involve terminals, axons and glial cells, and are generally reported to occur from about one week after nerve injury and during a period of at least several weeks. The most commonly described changes in the terminals include a darkening of the axoplasm, distortion of the shape of the terminal, loss of axoplasmic matrix, accumulation of neurofilaments~ as well as swelling and disintegration of mitochondria. Similar changes have also been described in myelinated axons, where in addition collapse of the myelin sheath has been reportedl”. Terminals with varying degree of increased electron density appear to predominate in the substantia gelatinosa of the spinal trigeminal nucleus (ref. 66 and Arvidsson, unpublished) and spinal cordbs8.hY.t(11. Organelle-rich, greatly enlarged terminals appear to be common in the cuneate nucIeusIJf%. This type of alteration has also been observed in the gracile nucleus (Aldskogius et al., unpublished). Neurofilamentous hyperplasia is commonly observed in the trigeminal main sensory nucleus at shorter survivalsI”. At later stages, neurofilamentous terminals are outnumbered by various types of darkened terminals. but no intermediate forms between neurof~lamentous and dark terminals were encounteredl~~. In many respects these changes observed during

31 transganghonic of alterations

degeneration

resemble

during anterograde

the spectrum

terminal

degenera-

nerve*h’. Although

some terminals

displayed

these were considered

changes,

tion (for review see ref. 127). Since in this situation

minor event compared

electron-dense

completely

terminals

impregnated with odsr.2.78.171.17?,it seems darkened

terminals

transganglionic

and axons are usually well silver methsuppressive reasonable

and

axons

argyrophilia.

tion is not readily applicable

to assume contribute

However,

that

to the

this assump-

to the substantia

gelati-

nosa, where numerous darkened terminals are present. but argyrophilia is absent or sparse. At present, this discrepancy

cannot

be adequately

explained.

different

has been described

to the dendritic

gelatinosa

cell bodies

neuronsro”.

by

A

reaction

in the monkey spinal cord follow-

terminals

viz. darkened.

shrun-

and axons of substantia

These changes were reported

to occur in second-order tacted

to be a

alterations.

type of transsynaptic

ing sciatic nerve transection. ken dendrites,

and axons also

neurons undergoing

changes It is somewhat mysterious

synaptically

con-

transganglionic

why peripheral

nerve le-

Some possible factors of relevance in this context have been discussed above (see 2.1.1.). Whether the other types of ultrastructural changes appearing dur-

sions would produce transsynaptic changes. while the much more extensive deafferentation following tri-

ing transganglionic degeneration show argyrophilia is not clear at present. Neurofilamentous terminals,

Two features distinguish these two types of lesions. First, after peripheral nerve injury. many sensory ax-

which appear during transganglionic degeneration’“, are usually not argyrophilic when suppressive silver methods are used during Wallerian degenerationr7’.

ons undergo changes in their electrophysiological propertieszl.r’J. Second, the injury induces altera-

In the electron microscopic study of tooth pulp neurons during transganglionic degeneration, electrondense terminals were observed in those areas of the spinal trigeminal nucleus where light microscopic argyrophilia was foundyh. Neurofilamentous terminals, as well as flocculent terminals and terminals with glycogen accumulation, were also observed in that

geminal

(cf. ref. 65) or dorsal137 root lesions do not.

tions in anterogradely transported proteins in the central processesrq.1”“. However. it appears unlikely that the latter would involve depletion of trophic substance+, since root lesions. which do not cause transsynaptic changes, should cause a rapid and probably more extensive decrease in the trophic support of the integrity of postsynaptic cells. It is also intriguing why any of these two mechanisms would in-

areas outside the field of degeneraSimilar findings have been made in the time of primary tooth exfoliadirect observations in the electron

duce primarily transsynaptic effects and essentially spare the terminals and axons of the injured sensory

microscope on silver-impregnated sections are needed to clarify definitely the correlation between

changes in the majority of hitherto published studies could be related to species and/or regional differ-

light and electron microscopic findings. The ultrastructural alterations described above most probably occur within the central processes of the primary sensory neurons, and certainly within

ences. However, further studies on this issue are necessary before this explanation can be accepted. Furthermore. because of the nature of the transsynaptic changes described so far, forthcoming studies will have to pay particular attention to the preparative procedures used. After peripheral nerve lesions. the glial cell changes involve engulfment of profiles resembling

study. but only in tion argyrophilia. the kitten during tionrs”. However,

presynaptic elements. The possible occurrence of postsynaptic (transsynaptic) changes is not mentioned in these studies~~‘.“7.“Y.1(11.1~‘~. In a few other studies, however. transsynaptic changes have been reported. In laminae I and II in the spinal trigeminal nucleus of the cat, dendrites of postsynaptic neurons develop extensive cavitations following tooth-pulpectomiesfis. These dendrites are reported to eventually disappear65. Similar changes have been described in laminae I-V of the cat cervical spinal cord dorsal horn following transection of the radial

ganglion cells. As yet, the absence

of reports

on transsynaptic

axonal debris, degenerating terminals and collapsed myelinio. Microglial cells and astrocytes participate in this process in the trigeminal main sensory nucleusIO. Complex, flattened multiple layers of astrocytic, and possibly also neuronal. processes surrounding altered terminals have been observed in the substantia gelatinosa in addition to glial cells involved in engulfmentror.

.33 .

The electron vide further terminals

microscopic

observations

evidence

for a degenerative

of peripherally

axotomized

ry neurons.

These findings,

of questions.

For instance,

however.

thus proprocess

primary

in

senso-

raise a number

are all terminals

affected

in some way and what does the great variety of alterations mean in terms of the final outcome generative

process?

process occurring

Is the presumed

throughout

changes more or less restricted of the injured

of the de-

degenerative

the neuron,

or are the

to the terminal

parts

neurons?

number

of such fibers observed

The circumscribed

analysis of axonal numbers jury. Ranson’

Several

early

investigators

noticed

that

Marchi-

positive structures occurred along the central processes of the injured neurons following lesions to peripheral nerves or limb arnputations~Y~~6.~~~.~~0.These observations chi positivity

have since been confirmedb. The Martakes a few weeks to develop and even

of axons in dorsal

subject

for quantitative

after peripheral

noted a 17% decrease

nerve in-

in myelinated

axons in the rat C2 dorsal root after sectioning corresponding

dorsal

ramus.

Ibis

figure.

should be viewed with some caution. ber of myelinated be similar.

afferentpathways

population

roots is a fairly convenient

the number

the

however.

First, the num-

axons on both sides was assumed to

a situation

(cf. ref. 183). Second, 2.2. Changes in axons ofprimary

in each single experi-

ment appears to be small.

which may not be quite true a certain

underestimation

of the smallest myelinated

of

axons, which

may be relatively numerous ipsilateral to the operation’“” . is possible because of the difficulties with the methods available at the time to examine these axons. Recent studies in the cat employing plastic-embedded semithin sections for quantitation and taking the possibility of right-left asymmetries into account have not been able to demonstrate any significant

at its maximal extent it affects only a small number of axons. In the sensory roots it appears to be signifi-

change in the number of dorsal root myelinated ons after sciatic nerve resectionl’h. or hindlimb

cantly more marked central to the transitional region than peripherally4.l28. This finding may be related to the slower removal in the CNS of the degeneration

putation?“. This discrepancy compared to Ranson’\ studies could also be due to species differences.

products, products,

leading to a gradual accumulation of these or to a more extensive disintegration of the

axam-

Quantitative electron microscopic studies in the cat periferally to the transitional region have also failed to demonstrate

any significant

change in the number

CNS myelin, which has a markedly different molecular composition (for review see ref. 132) and struc-

of dorsal root unmyelinated glionlJ8. However, dorsal

ture (for review see ref. Xl) than its PNS counterpart (for review see ref. 109). Further studies are necessary to determine whether the Marchi-positive profiles appearing centrally to sensory ganglia after peripheral nerve injury are products of primary demyelination, arise secondarily to axonal fragmentation or

nerve lesion were found to contain some so-called regenerating units, i.e. a group of thin myelinated axons and a group of unmyelinated axon profiles within one and the same basement membraneldx. This find-

both. There is a marked atrophy of large and medium-sized myelinated dorsal root axons after peripheral nerve injuryzx.148. A scattered demyelination could possibly occur as a result of this atrophy. Degeneration-like argyrophilic profiles have been observed after infraorbital nerve transection in silver-stained sections from the spinal trigeminal root and tract’“. Electron-dense myelinated axons have been found ultrastructurally in the same type of experiments1° and in the gracile fasciculus after sciatic nerve transectionl~)~. These observations indicate that degeneration of primary afferent myelinated axons does occur after peripheral nerve lesions. but the

axons central to the ganroots ipsilateral to the

ing suggests that regenerating axons, the source of which is presently unknown, are present in the dorsal root. Obviously, this observation implies that the number of remaining unmyelinated axons after a peripheral nerve lesion may have been significantly overestimated. This has in fact been found to be the case after similar peripheral nerve lesions in young kittens-. The evidence summarized above supports the notion that at least some myelinated axons undergo dcgeneration centrally to sensory ganglia after peripheral nerve lesions. The effect on the original popuiation of unmyelinated axons is still unclear. Circumstantial evidence to be discussed below suggests. however. that this population tnay in fact be significantly

reduced.

33 2.3, Changes

refs. 3, 182). This conclusion

in ganglia

is supported

from a recent study where the number

by results

of HRP-label-

Peripheral nerve injuries can result in total or partial recovery of the nerve cell body or in its degenera-

ed dorsal root ganglion cells projecting into the transected sural nerve of the cat was found to be reduced

tion and death (for review see ref. 113). Obviously.

by about 50% compared

the presence of significant

ganglion

cell degeneration

and death would be an immediate

explanation

for

many, maybe most. of the changes described above. Some early investigators concluded that a substantial number

of ganglion

section.

This conclusion

impression

of

a

cells died after peripheral

nerve

was based on a subjective

reduced

number

cellsh’~.l~“.on the actual observation

of

ganglion

of morphological

signs interpreted as cellular disintegrationhCJ~llx.l~y. as well as on ganglion cell count+Y”.l~x. The presence of degenerating sensory ganglion cells has been reported more recently in ultrastructural studies of the trigeminal ganglion of the adult rat after infraorbital nerve transection3.l’. Degenerating ganglion cells have usually been found to be relatively srnall’.ll~l~Y. a finding, however. which does not necessarily imply that these cells were small in their original, normal state. In the rat, trigeminal ganglion neuronal numbers on right and left sides are quite similar normally’. After unilateral infraorbital nerve transection, there is a reduction in ganglion cell number by about lo- 17% on the operated side’ (see also ref. 59). At the spinal level. the existence of large individual differences in the number of neurons in a certain ganglion, as well as the large differences which may exist between right and left sides for a certain ganglion cell pair in an individuall83. creates difficulties in determining whether or not transection leads to a ganglion cell loss. These difficulties are inherent in the earlier studies claiming that a very extensive cell loss did oc-

The findings

to the normal situationy’.

that peripheral

lead to a significant

nerve

loss of sensory

section

does

ganglion

cells,

have been challenged by observations in some other studieslCll.lh?, However. these contradictory findings have not been obtained cells. Therefore,

by counting

the evidence

the number

accumulated

seems to support the notion that a substantial of axotomized

dorsal root and trigeminal

cells in adult rats and cats disappear

of

so far fraction ganglion

following periph-

eral nerve transection. This cell loss could in some way predominate

in a

certain population(s) of ganglion cells. Some information on this issue might be obtained through ganglion cell size measurements in the surviving population. Such studies have sometimes demonstrated a marked shift in perikaryal size spectra towards smaller sizes’x,Y3.ljx. This change has been suggested to arise from atrophy

of surviving

large and medium-

sized ganglion cells, rather than a selective loss of large ganglion cellsl~x. In other studies no change in ganglion cell size spectrum has been observed ipsilatera1 to the nerve lesionlti’. Thus. there seems to be no direct support for the view that ganglion cells of a certain size are affected more than other ones. It should be emphasized. however. that a selective loss of ganglion cells sharing some other feature than perikaryal size could have taken place. 2.4. Changes

in primary

.sensory

neurons

of imma-

ture animuls

cur. However, in more recent studies where this important source of error has been considered, loss of ganglion cells has been found in the cat L7 ganglion after hindlimb amputatio+, or sciatic nerve resectionh.lJX.lh7.lh8, and in rat thoraciclx* and lumbar (Ar-

Immature animals frequently respond with rapid and extensive retrograde degeneration and nerve cell death after axon injuryll(‘,ll”. Therefore. the analysis of the characteristics of the degenerative process in primary sensory neurons after peripheral nerve injury in immature animals might aid in eluci-

vidsson et al.. unpublished) ganglia after intercostal and sciatic nerve transection, respectively. The percentage of lost neurons varies from about 15% to 3W. However, at the trigeminal as well as the spinal level a proportion of cells in the examined ganglia were never included in the axotomy. Therefore, the quoted figures are likely to be underestimates (see

dating principal features of transganglionic phenomena. However, the immaturity of the animals introduces the potential complication that the changes observed might be merely or largely due to interference with very specific developmental processes and not with an ‘exaggeration’ of a similar degenerative response in the mature animal. The observations made

34 so far on immature illustrate

primary

this problem.

tens have demonstrated argyrophilia dorsal

horn

weeks.

after

respectively,

in one-week-old

kittens

ganglion

compared

scopic studies have demonstrated

to adult

true with regard to

rats as we1123. Quantitative

tion in the number

within the first

when the nerve lesion is

cats5J4sJ53. The same is probably neonatal

trigeminal

On the other hand,

cell loss is more extensive made

nuclei72 and spinal cord

unpublished)

and sciatic nerve injury, few postnatal

seem to

studies in kit-

at the most very moderate

in the trigeminal (Grant,

sensory neurons

Thus, extensive

arises

Measurements myelinated

whether

there

present

the most likely explanation

appears to be a marked since there

is a relative

sized fibers ipsilateral

atrophy

nerve

injury

in

a marked

ascending

for thih finding

to nerve inluryiJh.

show a marked growth retardation

to peripheral

selectivity.

of the larger fibers.

predominance

reduc-

viously, ultrastructural studies of primary afferent pathways and terminal territories at various times after peripheral nerve lesions are necessary to clarif)

the

of surviving

dorsal root axons demonstrate

a significant

of

axons.

shift towards smaller sizes after sciatic nerve injury at one day:‘, one week146 or seven weeks’)? of age. At

linated

in the column

ih any

of the size distribution

micro-

of synapses

responses

question

to the loss of myelinated

electron

Clarke following neonatal sciatic nerve crush in ratsz4. However, the structural changes preceding this loss of terminals have not been examined. Ob-

the central

With regard

collaterals

of medium‘I‘he my+

in the gracile fasciculus of the sciatic nerve

is injured early postnatally (ref. 11tOand Grant, unpublished), and some fiber degeneration has been rc:ported with the Marchi technique and suppressive silver method+?. From these findings and from current views ahout the relationship between ganglion cell body size and fiber diameter~~~~l~‘, a preferentiai loss of small gan-

pears after peripheral nerve lesion in one-week-old kitten+(J and in neonatal rat@. After transection of the sciatic nerve in kittens, this dorsal root axon loss was found to be roughly similar for myelinated and

glion cells would be expected. l’hc available evidence does not support this assumption. however. Ganglion cell size measurements in aaotomized immature animals show a relative decrease. a relative increase and no clearcut change irl the proportiorl of large. medium-sized and small neurons. respcctive1~5, which is very similar to finding\ in adultsl’h. Intfi-

unmyelinated axons tively. This operative

rectly, these data support recent observationa that the correlation between ganglion ~11 body siLe and

immature animals. A significant fraction

of dorsal root axons disap-

about 2-6 months postoperaprocedure results in the forma-

is not always very goodlJ ::.I i ’

tion of a neuroma in the proximal stump. If kittens subjected to sciatic nerve resection are re-operated

fiber diameter

several weeks later with excision of this neuroma and the dorsal root analyzed one to two weeks later. the

2.5. The reuctlon cfprimury .svnzsor\~neurons c?fothtlt types than spinul and trigeminal cm’\

number of unmyelinated - but not myelinated -dorsal root axons decreased further, whereas the number of dorsal root ganglion cells was unchanged’. These findings demonstrate that large numbers of sprouting unmyelinated axons from the neuroma grow retrogradely into the ipsilateral dorsal root. When these ‘foreign’ axons are removed. and a more accurate estimation of the effect of peripheral nerve transection on the original population of dorsal root axons is possible, it was found that the ratio unmyelinated/myelinated axons was significantly reduced compared to normal roots. These experiments therefore provide evidence for the conclusion that C-fiber dorsal root afferents are more affected than myelinated afferents after peripheral neurectomy in kittens’.

As mentioned in the Introductmn. degenerative changes in central projection territories were first demonstrated in the vestibular system of young rabbits7J. Although there is the possibility that this drgeneration may have been caused by a direct effect on the vestibular ganglion. the time course of the appearance of the argyrophilia speaks against this as the principal explanation. However, the peculiar structure of the vestibular ganglion cells may be an important factor. The developmentally and morphologically closely related spiral ganglion cells react with extensive degeneration and death after lesions of their peripheral processes’6”. Interestingly, this retrograde nerve cell death appears to affect primarily the perikarya surrounded by a myclin sheath. This

anatomical vestibular

arrangement ganglion

is a regular

feature

in the

as wel114YJ59J87.

One of the earliest findings

dicates,

however,

that transganglionic

certainly not restricted

demonstrating

the oc-

currence of changes centrally to sensory ganglia after peripheral nerve lesions is the observation of Marchi-

and structural

organization

may contribute

positive reaction products along the course and in the termination area of the sensory fibers of the intermediate nerve in manr*s. Although have been done on this particular

injury.

to transganglionic

degeneration,

suggests that gustatory act principally

primary

this afferent

of sensory ganglion cells to peripheral

in the nerve

2.6. Effects of various types of lesions of peripheral

neurons

axons on primary sensory neurons

re-

nerve in-

ganglion cells.

The mesencephalic trigeminal nucleus appears to respond even more intensely than most other primary afferent systems studied so far. Section of the mandibular nerve results in a massive loss of neurons in the nucleusY2 and the course of degenerating fibers apparently corresponding to the central processes of these unipolar neurons can be readily visualized with the Marchi method or suppressive silver stains after transection of individual jaw muscle nerve branche+. After transection of the vagus nerve in the neck, a significant fraction of neurons in the nodose ganglion of the cat disappear+. FRAP-positivity in a small but well defined region in the nucleus of the solitary tract disappears following a similar lesion in the ratI’ll. Argyrophilic profiles appear in regions associated with the glossopharyngeal and vagal nerves after transection of the carotid sinus nerve in cats”“. Clearcut terminal changes have not been observed, however8’J.lrY. This may be another reflection of the factors discussed previously

reaction

to an in-

phenomena

observation

in a similar way to peripheral

jury as do somatosensory

are

soma-

tosensory primary sensory neurons. Further studies comparing sensory systems with different modalities sight into what might be general

no further studies system with regard

changes

to spinal and trigeminal

with regard to the lack of

or scanty argyrophilia in the substantia gelatinosa of the spinal cord and the spinal trigeminal nucleus, respectively. However, ultrastructural changes similar to some of those observed in the trigeminal nuclei were found in the nucleus of the solitary tract after combined vagal and glossopharyngeal nerve transectionl”. These findings provide additional support for the notion that suppressive silver stains reveal only part of the entire spectrum of transganglionic changes. The information available so far on the response of the intermediate, glossopharyngeal and vagal nerves to peripheral nerve injury is incomplete and needs to be extended. Even the present scanty information in-

It is well known that neurons ly different

to peripheral

respond quantitative-

nerve lesions of varying in-

tensity (cf. ref. 113). This appears to be also the case for the centrally occurring changes in primary sensory neurons, providing further evidence for a key role of the cell body in the production of these changes. Thus, argyrophilia similar to that seen after transection of a peripheral nerve is also observed after nerve crush, but to a lesser extent (Arvidsson, unpublished). Even a very distal lesion, such as removal

of

facial skin, which in essence causes a very distal axoresults in transganglionic argyrophilial4. tomy, FRAP-activity in the substantia gelatinosa disappears temporarily after peripheral nerve crushto* and physiological alterations such as a decrease in primary afferent

depolarization,

also occur

after

nerve

crush, but to a smaller extent and for a much shorter time than after nerve sectionxs,l74. However, substance P-like and somatostatin-like immunoreactivity in the dorsal horn is reported to be unaffected by nerve crush, in contrast to the marked depletion

after

nerve sectionls.12-l. Likewise. the decrease in dorsal root potentials and alterations in receptive field properties observed after nerve section have not been observed after crush injurys’J.l*7,lTJ. A significant proportion of dorsal root ganglion cells appear to be lost following peripheral nerve crush in adult guinea pigslJ1 and in one-week-old kittensrJ7. Ganglion cell death and the extent of myelinated fiber atrophy is significantly less pronounced in the kitten L7 dorsal root ganglion and dorsal root after crushing the sciatic nerve than after resecting it’.14h.1J7.These differences appear to be established prior to reconnection with the peripheral target, Thus, the responding ganglion cells seem to be capable of distinguishing between various types of lesions

before peripheral

contacts are re-established

88). The rapid access to trophic substances tal stump143 following

crush injury

(cf. ref. in the dis-.

may be a crucial’

factor in this situation.

axonal transport

Nerve growth factor (NGF) IS a trophic substance for dorsal root ganglion

2.7. The role of axonal transport and trophic factors of the axon by surgical means results

in disruption

of the communication

port between

the perikaryon

the injured

via axonal trans-

and periphery.

In addi-

at the lesion site may be taken up by

axons and transported

retrogradely

to the

soma. Finally, the formation of axonal sprouts is induced. By using pharmacological blockade of the axoplasmic transport, the first of these events could be separated from the others. Interestingly, after local application of microtubule inhibitors, the decrease in FRAP activity39,4(‘, substance P-like and somatostat112in the spinal cord dorsal in-like immunoreactivity horn as well as the ultrastructural

changes

in termi-

nals”‘,N) in the substantia gelatinosa appear to be essentially identical to those following nerve lesion. All these results were obtained using doses of vinblastine which were reported not to cause conduction failure or morphological signs of fiber degeneration4O,lO2 On the basis of these findings it has been proposed that interruption of the normal retrograde flow of trophic substances from the receptor area to the perikaryon is the critical event in producing transganglionic alterations”l.r~‘?. However, more recent findings indicate that even lower doses of vinblastine

transport

fore, another tionship

tion, substances

cells exerting at least some of

its effects on perikaryal retrograde

Interruption

per se.

line of investigation

between

perturbations

and transganglionic their possible

metabolism

changes

dependence

the axotomized

ganglion

NGF

or delays

prevents

root ganglion

after uptake and

from the peripheryrfi’J. Thereregarding in axonal would

the relatransport

be to examine

on the access of NGF to cell pertkarya.

Exogenous

axotomy-induced

cell loss in immature

dorsal

ratsrx5.ls6. These

observations strongly suggest that transported NGF is of vital importance

retrogradely for the struc-

tural integrity of a large population of sensory ganglion cells in immature animals. Exposing the proximal stump of the transected sciatic nerve to NGF in adult rats is reported to counteract the depletion of FRAP and substance P-like immunoreactivity from the substantia gelatinosa’j. However, the doses of NGF needed to obtain this effect were in the milligramme range. which appears to exceed the physiological levels sLlbstantially”‘3.*“‘. raising the question of an unspecific ble basis for these findings.

effect as a possi-

An alternative way of analyzing the possible role of NGF in the normal maintenance of primary sensory neurons is by immunological deprivation. This procedure results in some reduction in the number of dorsal root ganglion cells in immature rats186 and a marked decrease in substance P lcveis in dorsal root

cause extensive degeneration, particularly of unmyelinated peripheral sensory axonsi5. Furthermore. the

ganglion cells of adult rat and guinea pig’y(l. AntiNGF also produces a moderate reduction in the

use of low doses of agents blocking rapid anterograde

mean size of this type of cell in guinea pigl4r. However. treatment with anti-NGF following peripheral nerve crush did not reduce the number of dorsal root ganglion cells, nor did it have an! adverse effect on their capability to regenerate the ,Ixons following pe-

axonal transport may induce degenerative changes in the terminal portions of the axor+l.J?. Under these circumstances, the structural continuity between pcripheral sensory axon terminals and the peripheral target will be disrupted in a similar way as after a very distal axotomy. Indeed, doses of vinblastine which do not affect nerve conduction or axon morphology. do interfere with the normal function of peripheral sensory C-fiber terminaW. FRAP activity in the spinal cord dorsal horn is temporarily depleted at these dose levels but substance P-like immunoreactivity is not clearly affectedsi. Thus. it is not quite clear whether transganglionic changes in the substantia gelatinosa are produced by blocking the retrograde

ripheral nerve crushlJ1. In conclusion. these findings suggest that retrograde transport of NGF may be necessary for optimal function of dorsal root ganglion cells in adult mammals, but its precise role in this respect as well as the possible role of other trophic factclrc in the periphery (cf. ref. 145) with respect to transganglionic changes remains to be clarified.

3. PHYSIOLOGICAL

the periphery

OBSERVATIONS

synaptic The electrophysiological

changes

in spinal

cord

or notaX. Likewise,

excitatory

quire restoration Several

potentials

recovery

of full sensory activ,ityh’.

studies

have

presented

data

synaptic transmission following peripheral nerve injury have been discussed in detail recentlyt?T. Since

marked

changes

these changes

neurons

in the spinal cord de-afferented

are obviously

relation

to the

changes

reviewed

physiological Peripheral decrease myelinated posterior

of great significance

morphological here,

and

in

histochemical

a brief summary

of recent

data is presented. nerve lesion is followed by a significant

in the conduction

velocity

axonsJJJ4 and ascending funiculusx’.xb.

The dorsal

of dorsal collaterals

root in the

root compound

action potential is substantially reduced if the peripheral nerve is sectioned”J.r7J. These changes probably at least partially correlate to the reduction in the diameter of the large myelinated dorsal root fibe$i.l4X,

In addition

to these changes,

there are numerous

of mono-

does not seem to re-

in the receptive

suggesting

field properties

al nerve sectionJX-‘(l,t7J. Manv of these neurons seemed

to be activated

by stimulation

regions far outside the normally ~50.IIS.Ilh.l7l.l~~,

found

Somewhat

in the spinal

nou

of body

effective territories+

similar

trigeminal

pulp removal’-3.xY. Under

of

by peripher-

changes

nucleus

were

after tooth

these experimental

condi-

tions there was also a marked increase in the incidence of spontaneous firing by de-afferented neurons?l)J3.NY.Similar changes have also been described in the dorsal column nuclei after peripheral nerve transection in kittens’x. but not in adult rats”‘. However. in more recent studies on the physiological effects in the spinal cord of peripheral nerve injury

reports on alterations in primary afferent synaptic transmission in the spinal cord. Thus, A-fiber-mediated inhibition of C-fiber input is reducedtXr and the dorsal root potential evoked in the affected dorsal roots by stimulation of the cut ipsilateral or intact contralateral nervel7J. as well as primary afferent depolarizatiotFrT’.r7”. are decreased. Primary afferent depolarization shows a clearcut tendency towards normalization as peripheral regeneration proceeds

whether neurons in the spinal cord dorsal horn of adult mammals display the functional plasticity suggested by the earlier studies. A change in dorsal horn somatotopy is observed after a transected sensory nerve has regenerated to

but does not become completely normal for a long time. even when the nerve has been crushed rather

the periphery. Under such circumstances. ;I distortion of the central sensory projection map is most

than sectionedsx. The mean amplitudes of monosynaptic excitatory potentials in cat lumbar motoneurons decrease after transection of the corresponding muscle nerve. and gradually return towards normal levels after re-innervationh7. The decrease in the dorsal root potential does not occur when the nerve has been crushed”d. These changes in synaptic efficacy appear to be compatible with a restricted terminal degeneration of primary afferent terminals. followed by their gradual, but frequently incomplete, re-appearance as the injured peripheral axons regenerate (cf. refs. X-38). However. these changes appear equally compatible with the permanent disappearance of some primary afferent terminals due to sensory ganglion cell loss. An intriguing observation is that the absence or presence of primary afferent depolarization seems independent of whether the regenerated axons had formed functional contacts in

likely due to misdirection in the periphery of the regenerating fibers with a maintenance of the original central projection fieldsL7.75.87. I Ih.Ihh,

where a somewhat different methodology plied and a rigorous control of the recording

was apsites was

performed. these changes in receptiv,e fields have not been reproduced’“.l.3i. Therefore, it is doubtful

4, CORRELATION

BETWEEN

CHANGES

AND

THE

GANGLION

CELL

BODIES

TRANSGANGLIONI(‘

RESPONSE

OF

TO PERIPHERAL

SENSOR\ NER\‘E

INJURY

The normal maintenance of neuronal processes is dependent on a functioning perikaryon. Therefore, it is reasonable to assume that at least certain alterations in the central processes of primary sensory neurons after peripheral nerve injury result from changes in perikaryal metabolism and/or routing of material via axonal transport, forming an integrated part of the metabolic ‘program’ for survival of the neuron and support of the regenerating peripheral

3x axon. ‘Signals’ induced

ripheral

nerve

and mediated

by the peripheral nerve lesion via retrograde axonal transport reach

generally

thought

the celt body prior to any possible further

processes.

peripheral

axons leads to immediate

transmission

However,

transport to interruption of the

the central

of nerve impulses

changes

in the

to second-order

neu-

transection

nerve injuryL4s. Thereby, unmyelinated

and an initial preferential

very early structural

responses

can be partially

nals, which in turn may affect the characteristics the retrogradely tral terminals alterations ripheral

transported

material

to the sensory ganglion

of

from the cencell bodies. The

in the cell body induced directly by the peaxotomy

could

then

be significantly

mod-

ified by how the central terminals respond to the prompt cessation of impulses from the receptor region. When trying to correlate

current

observations

on

transganglionic changes with those of axotomy-induced changes in sensory ganglia, no clear distincti(~n between the significance of the two mechanisms described above can be made with respect to changes occurring within the first few weeks. However, the presence of degenerating ganglion cells in the trigeminal ganglion from about 1-R weeks postlesion survival time” and the time-course of ganglion cell loss in thoracic spinal ganglia’s? support the notion of a close relationship between ganglion cell death and transCentral processes asganglionic argyrophilia 11.7?.14. sociated with the lost neurons ly, a process called indirect

must degenerate

which would be closely related Wallerian

degeneration

rapidto so-

observed

in

peripheral efferent neurons and neurons intrinsic the CNS61.7’. The subsequent substantial reduction

to in

the density of primary afferent terminals is likely to have profound consequences for the surviving terminals. A most important

question

elucidate the characteristics destined to degenerate and vestigators have suggested be found primarily within

in this connection

is to

of the neurons which are die. Several previous inthat these neurons are to the population of small

ganglion cells, which are presumed to have unmyelinated C-fibers. The evidence for this notion is indirect, however, and includes the following observations. In trigeminal’-I1 and C2 spinal’“’ ganglia, degenerating gangiion cells appear to be small. Substance P-like immunoreactivity in dorsal horn primary afferents shows a permanent reduction after pe-

dorsal root ganglion

of new

in the dorsal root axons

as has been shown to bc

animals’.

A substantial

loss of

cells has been observed

in com-

with an unchanged

axons proximal

number

loss of unmyelinated

concealed.

the case in immature bination

a significant

axons could appear

could play a rote in initiating termi-

This peptide is in C-fiber afferents.

Some regenerating, presumably largely unmyelinated axons. are present in dorsal roots ipsilateral 10

rons. These changes

in the central

15.94. lh,

to be present

number

of myelinated

to a sensory nerve neuroma”‘.

Mlc-

tin sheath degeneration as observed in one autopsy case with the Marchi technique was absent in the PNS portion of the intermediate nerve root”“. After spinal nerve lesion it was sparse in the PNS portion of spinal dorsal root+. No significant decrease in the number of dorsal root myelinatcd axons has been found2s.l”. These latter two findings indicate that degeneration of ganglion cells with myelinated axons is limited. Seemingly in contradiction to the conclusion that ganglion cells with C-fiber affercnts arc involved more than other ganglion cells in axotomy-inciuce~~ ganglion cell loss are the findings that perikaryal size spectra show no evidence of a selective decrease of small ganglion cellslJ*.1sl. As indicated above, however. perikaryal size may not be very strictly r&ted to fiber diameter alone. thus comp~ic~~ting the grncral view that small ganglion cells are associated with unmyelinated axons (cf. refs. 12, 3. 111). Degeneration in the substantia gelatinosa is readily observed at the ulstrastructural level following peripheral neur(~ton~y~~s.~Y,“)i, although very little of this degencration is revealed by suppressive zilver methods’-‘,? FRAP-activity seems to be at least partially restored even if peripheral nerve regeneration is impededa’. This restoration does not exclude the possibility that a significant fraction of the original primary afferent terminals in this area is permanently lost since surviving terminals could increase their level of FRAP and/or give rise to new collaterals. which would also contain FRAP. However, the issue of what kind of ganglion cells degenerate and die subsequent to a PCripheral nerve tesion needs further analysis. A small amount of myelin shearh degeneration has been observed in dorsal roots” and posterior columns2Y and a limited number of electron-dense mye-

39 hnated axons can be observed ripheral

in those areas after pe-

neurotomvhY.l~rt. The terminals

bers probably

undergo

tribute to the argyrophilia

degeneration in projection

ceiving myelinated

primary

the dorsal horn.

myelinated

afferents. primary

of these fiand may conterritories

re-

sort of alteration pending

or is there a selectivity,

on functional

changes in termination

afferents

mized primary referred

perhaps de-

and/or

characteristics of the neurons? In the initial studies where attention

As shown for fre-

properties

structural

was drawn to

areas of peripherally

sensory neurons.

to as transganglionic

axoto-

these changes were degeneration

(TGD).

quently branch extensively within their projection territory”. Therefore. even the death of a small num-

This term has since been used in a number

of light-

ber of ganglion

and electron

changes

cells with myelinated

give rise to rather structural

prominent

axons could

argyrophilia.

Ultra-

studies in the main sensory trigeminal

nu-

following

microscopic

peripheral

the Introduction,

studies on central

nerve lesions.

As indicated

the term degeneration

in

implies

process of deterioration,

alterations. which are unlikely to display argyrophilial’).‘Jh.Although it is possible that all these terminal

to disintegration, atrophy or recovery of the cell or cellular element. The term TGD therefore appears to cover the entire spectrum of regressive processes

changes may occur as a result of ganglion cell degeneration, it is also possible that certain changes are restricted to the central axon terminals of surviving ganglion cells. The axon terminals appear to be particularly sensitive to interference with rapid axoplasmic transporF and changes do occur in the composition of rapidly transported proteins in the central processes of peripherally injured ganglion cellslY.133. Peculiarly. these changes mimic those in the peripheral regenerating axons which could indicate that also the central processes present a state of growth as a result of injury section 5).

to their peripheral

processes

(cf.

There appear to be several principally different ways in which the terminal could regress. One is the existence of an overt degenerative process, which

which will eventually

a

clear complex have shown a variety of axon terminal

which might occur in the central

branch

tive atrophy (TDA) has been used for a variety of histochemical and ultrastructural changes in the substantia gelatinosa after peripheral nerve injury37.tot.t’J?. These changes have been claimed to be unassociated with ganglion cell loss and followed by complete restitution of the central terminals in the event of successful peripheral nerve regeneration. In our opinion, the initial stages in this series of events could very well fall within the framework of TGD as defined above. In addition, the fact that ganglion cell loss does occur after peripheral section 2.3). renders the notion

nerve lesions (see of TDA as princi-

pally distinct from TDG questionable.

traction,

5. TRANSGANGLIONIC PLASTICITY

which could occur without any conspicuous

otomized sympathetic ganglion cellsl3h, and certain de-afferentation-induced changes in synaptic organization in the hippocampu+x3. The retraction of dendritic arbors of axotomized motoneuronsIhr.Ihs may also occur in a morphologically inconspicuous manner. Extensive studies will be necessary to clarify this and several important related issues. For instance, do terminals of all the injured neurons undergo some

of primary

sensory neurons after peripheral nerve injury. In some other studies, transganglionic degenera-

could render the terminal portion of the axon argyrophilic. In contrast. other terminals may undergo restructural changes. This particular way of elimination of nerve terminals would resemble several other situations where apparently non-functional or superfluous terminals are eliminated, such as the polyneuronal innervation of skeletal muscle during early developmentl”J,IJJ. the reduction in synaptic coverage on developing33 and axotomized motoneurons?I.ihd. ax-

lead

The issues discussed in the preceding section lead to the question of the possibility of a structural reorganization of the primary sensory input as one of the processes underlying functional recovery after peripheral nerve injury. Such a reorganization could include several different mechanisms. The presynaptic contacts previously made by sensory ganglion cells which have died after nerve injury may be partially or entirely occupied by collateral sprouts of surviving ganglion cells. If that is the case, it appears likely that this synaptic replacement is brought about primarily by neurons of similar modality and overlapping receptive fields to those which have died. Collateral sprouting could also take place at the interneuronal

40 level. The reported increase in vasoactive intestinal polypeptide (VIP)123 and recovery of substance PI@

these instances

in the spinal cord dorsal horn ipsilateral

minalsrss.

nerve injury Sprouting

to peripheral

could be the result of such a process.

from

interneurons

may

not

necessarily

take place at the axonal but also at the dendritic (cf. refs. 18, 76, 134). Another for synaptic reorganization titution

of axon terminals

which the nerve injury restricted

possible

level

mechanism

could be based on the resof sensory ganglion has been followed

effect on the terminal.

then be the result of regenerative

ceils in

by only a

been observed in normal adult mammals152J~s, but in interpreted

as regression

of axon ter-

although

the changes

which have

Thus,

been described compatible

after peripheral

with axonal growth,

they could also rep-

resent late forms of a degenerative studies are needed

files, as well as their origin, nate from injured

process.

Further

to clarify the nature of these proi.e. whether

or uninjured

glion cells or from interneurons.

This process would

use of sensitive markers,

sprouting

proper electron

at the ter-

nerve injury may be

primary

they origisensory gan-

This will require the

which can be combined

microscopic

preparation

with

technique\.

minal level. There are observations

indicating

that a structural

reorganization may take place in the projection territories of peripherally injured primary afferents. Primary afferent depolarization is substantially reduced after peripheral nerve lesion, but at Ieast partially reversibie even if functional reconnection is not made in the periphery”*. The hypoxic hyperventitatory response caused by stimulating the carotid sinus nerve or body disappears completely for some time after cutting the nerve or removing the carotid body. However, a similar refiex response is subsequently induced after stimulation of the aortic body. which is not the case normallyls’. FRAP in the substantia gelatinosa, which disappears after peripheral nerve injury, appears to be completely restored after nerve crush-‘6 and at least partially restored even if nerve regeneration does not take placeJ7. The reappearance of this enzyme is not necessarily related to collateral or regenerative sprouting, however, but may merely reflect a resumption of the anterograde transport of the enzyme from the ganglion cell body to its central terminals. ~ltrastructural studies have described the presence of neuronai processes filled with profiles resembling smooth endoplasmic reticulum, microtubules and small vesicles in projection areas of peripherally injured primary afferentsx*rtY. These processes may reflect axonal growth3s,ll~, although their appearance is not identical with growth cones during development, regeneration or in tissue culturel()s. An interesting finding which may be relevant in this context is that regenerative growth of ascending central sensory ganglion cell processes into peripheral nerve grafts can occur, provided the periphera1 processes of the same neurons are injuredr42. On the other hand profiles similar to those described above have

6. SUMMARY

This paper reviews light- and electron microscopic. histochemical and physiological evidence which demonstrate that peripheral nerve injury in mammals is followed by profound structural and functj(~nal changes in the central terminals of the affected primary sensory neurons. Available evidence indicates that at least some of these so-called transganglionic changes are the result of ganglion cell degeneration and death, although other mechanisms are probably in effect as well. Existing data suggest that this ganglion cell death does not effect all types of ganglion cells equally, but do not permit a clearcut answer to the question of which kinds of ganglion cells are at’fected more than others. Results from studies with microtubule inhibitors and antibodies to nerve growth factor are compatible with the notion that depletion of retrogradely transported trophic factors is involved in the production of certain transganglionic changes. This issue needs further examination: however. Physiological studies indicate marked alterations in certain primary afferent synaptic connections after peripheral nerve lesions. So far, these changes have not been satisfactorily correlated with the structural changes induced by similar &ions. Further studies on the structural and functional response of primary sensory neurons to peripheral nerve injury are likely to contribute to the understanding of the frequent failure to regain normal sensory functions after peripheral nerve lesions in man. as well as of the basic aspects of lesion-induced changes in general in the peripheral and central nervous system.

41

ACKNOWLEDGEMENTS

The excellent Marianne

assistance

by Miss My Kjall and Ms.

Rapp in typing the manuscript

guistic revision

by Dr. Zsuzsanna

are gratefully

acknowledged.

The

and the lin-

Wiesefeld-Hallin authors

quoted in the article were supported

by the Swedish

Medical

nos. 553, 5420

Research

Council,

project

and 6540, and by grants from the Karolinska tet, Loo and Hans Ostermans

stiftelse

institu-

and Ake Wi-

bergs stiftelse.

works

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Note added in proof

Nerve Growth Factor administered via an osmotic minipump to the proximal stump of the transected rat sciatic nerve hay been found to prevent axotomy-induced loss of FRAP and also to some extent substance P-like immunoreactivity in the dorsal horn as well as certain physiological effects which follow peripheral nerve transection (Fitzgerald. M. et al.. Nerve Growth Factor counteracts the neurophysiologi~al and neurochemicat effects of chronic sciatic nerve section, Brain Rrs.. 332(19%) 131-l-1I ) These observa~~[)ns support the view that deficiency in the supply of retrogradely transported NGF is a critical factor for the manifes~a~j~~nof certain transganglionic changes (cf. section 2.7).