Brain Research, 588 (1992) 335-340 © 1992 Elsevier Science Publishers B.V. All rights reserved 0006-8993/92/$05.00

335

BRES 25314

Time course of serotonergic afferent plasticity within rat spinal trigeminal nucleus following infraorbital nerve transection B r a d l e y G. K l e i n

a,

W i l l i a m D. B l a k e r b, Carl F. W h i t e

a

a n d B i b h u R. M i s r a

a

a Department of Biomedical Sciences, Virginia-MarylandRegional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061 (USA) and b Department of Biology, Furman University, Greem,iile, SC 29613 (USA) (Accepted 19 May 1992)

Key words: High-performance liquid chromatography with electrochemical detection; lmmunocytochemistry; Serotonin; 5-Hydroxyindoleacetic acid; Brainstem; Monoamine; Plasticity; Sprouting

High-performance liquid chromatography with electrochemical detection (HPLC-ED) and immunocytochemistry were used to examine the time course of serotonergic afferent plasticity within trigeminal subnucleus interpolaris (SpVi) following infraorbital nerve (ION) transection in adult rats. Biochemical analysis was also performed in trigeminal subnucleus caudalis (SpVc) to examine the possibility of transient lesion-induced changes in this region. No significant changes in serotonin (5-HT) or 5-hydroxTindoleacetic acid (5-HIAA) concentration, or in density of 5HT-immunoreactive (5-HTIR) axonal varicosities were observed in either subnucleus on the lesioned side, up to 51 days following ION cut. However, at 76-79 days post-lesion, a significant increase in 5-HT concentration was again demonstrated within SpVi.

We have previously demonstrated that non-peripheral serotonergic afferents to rat spinal trigeminal subnucleus interpolaris exhibit an increased concentration of serotonin and an increased density of serotonin-immunoreactive varicosities between 76 and 187 days following infraorbital nerve transection in adults 2°. Electrical stimulation of serotonergic afferents to spinal cord and trigeminal brainstem nuclear complex (TBNC) of normal animals7's't2a6'ts, as well as iontophoretic administration of serotonin 5'~7'29 have been shown to modulate the responses of spinal and TBNC neurons to peripheral stimulation. One of the more notable effects of activating serotonergic systems is analgesia, related to supression of noxious inputs from the periphery. Such effects may result from a complex interaction between monoaminergic, opioid and other neuronal types 4. Nevertheless, heterotypic plasticity of serotonergic afferents to SpVi, following ION transection, is a viable substrate for alterations in somatosensory function which we have described in this subnucleus at comparable post-lesion survival times ~9. Although alterations of somatosensory function and serotonergic afferent plasticity within adult rat SpVi

are both observed at fairly long post-lesion survival times, the time course of these changes is not known. Correlating the development of these modifications could provide a better understanding of the possible role of serotonergic afferent plasticity in the somatosensory sequelae observed following ION damage. To begin to address this issue, we used high-performance liquid chromatography with electrochemical detection and immunocytochemistry to examine the time course of serotonergic afferent plasticity within SpVi following ION transection in adult rats. Although chronic alterations in serotonergic afferents to spinal trigeminal subnucleus caudalis were not previously observed following ION transection, this subnucleus was examined for transient alterations of the serotonergic afferent system in the present experirnent. Non-monotonic changes in neurochemically characterized projections to spinal cord and acute modifications of 5-HT metabolism have been reported following peripheral deafferentation ~!,32. For the biochemical analysis, 85 adult male Sprague-Dawley rats were used. Forty-eight of these animals had the left ION transected (see ref. 28).

Correspondence: B.G. Klein, Dept. of Biomedical Sciences, College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24061, USA. Fax. (1) (703) 231 7367.

336 Following the lesion, grot~ps of rats were sacrificed at 3 days (10 lesioned, 10 normal), 14 days (8 lesioned, 8 normal), 28 days (10 lesioned, 9 normal), 49 days (10 lesioned, 10 normal) and 76-79 days (10 lesioned). Brains were processed for tissue sampling using previously described methods 2°. Briefly, following decapitation, brains were frozen on dry ice and 340 ~m transverse sections were cut from SpVc and SpVi, at - 7 ° C in a cryostat. Gross and cytoarchitectonic landmarks were used to delineate the borders of SpVc and SpVi. Using the middle one-third of the dorsoventral axis of the trigeminal spinal tract as a guide, 1 mm 2 and 2.25 mm 2 samples were respectively taken from the infraorbital region of the SpVc and SpVi cryostat sections. The remaining portions of the brainstem sections were fixed in formalin, re-sectioned at 51-68 # m and stained with Cresyl violet to verify the location of removed samples. Brain indoleamines were analyzed by HPLC-ED using the procedure of Mayer and Shoup 25. Frozen tissue samples were homogenized in 0.04 N perchloric acid, containing the internal standard isoproterenol. After centrifuging, the supernatant was immediately

injected onto the HPLC. Pellet protein content was determined by the method of Lowry et al. 23. For immunocytochemistry, 6 adult male SpragueDawley rats were used. All rats had the left ION transected as noted above. Forty-seven to fifty-one days aftger the lesion, rats were perfused transcardially and tissue was processed for 5-HTIR using methods outlined previously 2°. Briefly, rats were deeply anesthetized with sodium pentobarbital and perfused with 0.1 M phosphate-buffered saline (PBS), 4% paraformaldehyde in 0.1 M sodium acetate buffer and 4% paraformaldehyde in 0.1 M sodium borate buffer. Brains were post-fixed in the latter fixative and placed in 10% sucrose overnight. Transverse 17 /zm cryostat sections were sequentially incubated in (1) 10% normal goat serum containing 0.15% Triton X-100, (2) PBS and (3) rabbit antiserum to 5-HT/BSA (lncstar Corp., Stillwater, MN) ~n PBS with 0.15% Triton X-100 (1000:1, 1500:1, o~" 2000:1 dilutions). Tissue was then processed by avidinbiotin histochemistry, using a Vectastain kit (Vector Labs, Burlingame, CA) and diaminobenzidine. Selected sections were used for primary antibody omis-

TABLE !

Mean concentrations of 5.1tT and 5-HIAA in subm~clei interpolaris and caudalis of k,sioned and normal rats Concentrations are expressed as pmol/mg protein + S,E.M. (n). Intact sample is from side contralateral to the lesion. * denotes a significant difference from the value in normal rats (P < 0,05), ** denotes a significant difference between samples in the 76-79 day survival group (P < 0.05),

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Sample

5.HT

5.HIAA

5-HIAA / 5-HT

3 days

lnterpolaris

Lesioned Intact Normal Lesioned Intact Normal

15,8 4- 1,4 (10) 15.3 + 0,9 (10) 17,8+ 1,2 (10) 13.1 4. i.3 (10) 16,7 4- 2.0 (10) 13.6 4-1. ! (10)

14,6 ± !, I (I{}) 12,6 4. 0.8 (10) 12,94.0.9 (10) 9.2 4-1.0 (10) 9.3 4- 0.8 (10) 8.1 4- 0.6 (10)

0,939 4- 0.043 (10) * 0.835 + 0.048 (10) 0.731 4.0,033 (10) 0.706 4- 0.039 (10) 0.637 4- 0.053 (10) 0.602 4- 0.022 (10)

Lesioned Intact Normal Lesioned Intact Normal

26.6 + 2.6 (8) 27.1 + i.9 (8) 28.4 4. 3.3 (8) 40.8 + 2. I (8) 42.2 + 1.8 (8) 38.1 4- 3.6 (8)

24.4 ± 1.6 (7) 23.2 + 2.4 (7) 24.7 + 1.2 (8) 24.8 + i.2 (8) 24.8 4. 0.8 (8) 23.7 4- 1.9 (8)

0.971 + 0.106 (7) 0.887 + 0.107 (7) 1.020 + 0.206 (8) 0.616 + 0.034 (8) 0.599 4- 0.033 (8) 0.640 4- 0.046 (8)

Lesioned Intact Normal Lesioned Intact Normal

20.1 ± 1.4 (9) 21.5 + !.6 (10) 19.6 + 1.1 (9) 25.4 4- 2.2 (10) 25.04- I.i (10) 25.7 + 3. ! (9)

14.3 4- 0.7 (10) 15.8 4. 0.8 (I 0) 13.5 4. 0.5 (10) 12.2 4- 0.6 (10) 11.94-0.5 (10) 1i .2 ± 0.5 (9)

0.745 4- 0.051 (9) 0.755 4. 0.040 (10) 0.705 4- 0.045 (9) 0.494 4- 0.022 (10) 0.4834-0.024(10) 0.460 ± 0.032 (9)

Lesioned Intact Normal Lesioned Intact Normal

16.1 ± 1.2 ( ! 0) 14,8 ± 1.5 (10) 20.1 + 1.6 (10) 13.3 + 2.0 ( ! 0) 12.5 ± 1.1 (10) 13.2 ± 1.6 (I 0)

13.4 + 0.7 (10) 12.2 ± 0.7 (10) 13.6 ± 0.9 (10) 8.7 ± 0.9 (10) 8.7±0.8 (10) 7.3 4- 0.8 (10)

0.853 + 0.043 (10) * 0.868 + 0.060 (10) * 0.694 ± 0.046 (10) 0.708 ± 0.037 (10) 0.712+0.045 (10) 0.581 + 0.049 (10)

Lesioned Intact

22.3+2.1 (10) ** 16.7+ 1.8 (10)

20.2+ 1.7 (10) ** 17.1 ± !.2 (10)

0.920+0.031 (10) 1.100±0.093 (10)

Caudalis

14 oays

lnterpolaris

Caudalis

28 days

lnterpolaris

Caudalis

49 days

Interpolaris

Caudalis

76-79 days

Interpolaris

337 sion or preabsorption controls. Brainstem raphe nuclei were used for positive controls• Non-reacted tissue and every third reacted section was stained with Cresyl violet. In SpVi, the density of 5-HTIR varicosities was determined at l l l l X using a drawing tube and a 2500 p,m 2 counting grid, as previously described 2°. Counts of varicosities from the infraorbital region of a transverse section were made at 250 and 500/~m medial to the medial border of the spinal trigeminal tract, along a mediolaterally oriented line which divided the tract into dorsal and ventral halves• The sample proximal to the tract was termed the lateral sample and that distal to the tract was termed the medial sample• For dependent variables examined using HPLC-ED, means were compared using one-way analysis of variance (alpha level = 0.05) with post-hoe comparisons (SYSTAT, Evanston, IL). For the 76-79 day survival group, where only the lesioned and intact sides of SpVi were examined, comparisons were made using a twotailed t-test (alpha level ffi 0.05) on the difference scores for matched pairs. This procedure was also used to



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compare the lesioned and intact sides of brainstem sections examined using immunocytochemistry. For post-lesion survival times from 3 to 49 days, the only significant difference in 5-HT concentration was between normal rats and the intact side of lesioned rats for SpVi of the 49 day survival group (F2.27 = 3.69, P = 0.038) (Table I). No significant differences in 5HIAA concentration were observed among any groups within these post-operative survival periods. However, significant increases in the 5-HIAA/5-HT ratio in SpVi, with respect to normal rats, were observed on the lesioned side at 3 days after nerve c u t (F2,27 = 6.24, P = 0.006) and on both the lesioned and intact sides at 49 days after nerve transection (F2,27 = 3.73, P = 0.037). In a previous report (see ref. 20), we demonstrated a significant increase in 5-HT concentration on the lesioned side over the intact side of SpVi, 76-79 days following ION transection. Given the absence of similar changes in 5-HT concentration between 3 and 49 days following the lesion, we repeated the comparison between lesioned and intact sides of SpVi in an additional group of rats, surviving 76 to 79 days after the

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Fig. 1. Darkfield and higher magnification brightfield photomicrographs of the lesioned (A and B) and intact (C and D) sides of a 17 p,m section from SpVi, showing 5-HTIR immunoreactivity at 49 days after ION transection. The inset in C is a brightfield image of an adjacent Cresyl violet stained section• Arrows in A and B indicate corresponding points in the two photomicrographs. The same is true for the arrows in C and D.

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Fig. 2. Density of 5-HTIR axonal varicosities in SpVi, on the lesioned and intact sides, for the lateral and medial sample fields of 6 rats. Each bar presents the mean and standard error for counts of serial transverse sections within a given animal.

lesion (Table l). Again, a significant increase in 5-HT concentration (38%) was observed on the lesioned side over the intact side (td(9)= 2.56, P = 0.031). A significant increase in 5-HIAA concentration (18.1%) was also detected (td(9) = 2.34, P = 0.044). Reproducing this increase in concentration, which was observed only in SpVi ipsilateral to the lesion in our earlier work, argues against a systematic technical flaw being responsible for our negative results in the present study, observed 3 to 49 days after ION transection. Fig. 1 shows the distribution of 5-HTIR axons along the dorsoventral and mediolateral axes of SpVi, on the intact and lesioned sides of a rat surviving 49 days after ION transection. Quantitative analysis of the mean density of 5-HTIR varicosities failed to detect a significant difference between lesioned and intact sides, for either the lateral or medial sample fields (Fig. 2). The data presented above, considered in light of our previous analysis (see ref. 20), suggest that the anatomical and biochemical changes in 5-HT afferents to SpVi following ION transection exhibit a slow or delayed development, that does not reach detectable proportions until at least 7 weeks following the lesion. Furthermore, 5-HT concentration within SpVc does not appear to change at any time point, up to 11 weeks after cutting the ION. Other prior studies of heterotypic and homotypic sprouting of spared afferents in the mammalian central nervous system suggest that the time courses of such responses are quite variable. Such variability exits across different neural systems, across different regions of a given system, across different transmitters within a single region and across type of lesion L~-~s,24,2~,,32,33. In the rat somatosensory system, heterotypic increases in 5-HT immunoreactivity within superficial laminae of the spinal cord dorsal horn have been reported as early as 10 days following complete unilat-

eral lumbosacra132 or partial thoraco-lumbar 24 deafferentation by dorsal rhizotomy. In the ventrobasal thalamus, synaptogenesis by spared fibers was not observed until 30 days after unilateral lesions of rat dorsal column nuclei 33. Differences in sprouting capacity and sprouting time course between substance-P, 5-HT and dopamine-B-hydroxylase immunoreactive fibers have been observed within the spinal cord 3a. It is unclear what mechanism may account for the delayed increase in 5-HT concentration in SpVi following the lesion. This could be related to the magnitude of deafferentation produced by adult ION transection. Dorsal rhizotomy produces a permanent functional deafferentation by the severed central axons 6'3°. In comparison, peripheral nerve cut leaves the majority of ganglion ceils and their central synaptic terminals intact or able to recover from damage a'3L35. Only about 10-17% of all trigeminal ganglion cells projecting to the trigeminal brainstem die following adult ION transection ~. Similarly, destruction of dorsal column afferents to the ventrobasal complex removes only about 3% of the total number of synapses within this region 33. It is also possible that the time course of the increase in 5-HT concentration in SpVi is related to the time course of primary afferent degeneration following the lesion. As noted above, small but significant trigeminal ganglion cell death has been reported following peripheral trigeminal axotomy in adult rats ~-3'36. Transganglionic degeneration of central axons of trigeminal ganglion cells has been observed between 6 and 80 days after transection of adult vibrissal nerves 3. A slow rate of damaged cell loss has also been repurted in spinal ganglia following peripheral axotomy ~0. Studies of sprouting and synaptogenesis in hippocampus have given rise to the theory that these processes are mediated by trophic factors secreted within the deafferented region and that a critical amount of substance would have to be secreted to stimulate growth 27. Perhaps the slow rate of primary afferent degeneration following peripheral nerve damage is responsible for a slow rate of increase in trophic factor secretion in the deafferented region, which delays the attainment of a trophic factor threshold necessary for the reaction of 5-HT afferents, it has also been demonstrated that the responses of glia, in deafferented regions, are correlated with the onset of sprouting and synaptogenesis 9'34. However, the causative nature of this relationship is still equivocal. Another factor which could account for our results is the sensitivity of our biochemical measurements. A monotonic increase in 5-HT concentration with a very small slope, could have escaped detection by HPLC-

339

ED, until 76-79 days after the lesion. However, this is unlikely since no increasing trend was observed in mean 5-HT concentration up to 49 days. In addition, our immunocytochemical analysis, which examined two separate regions of SpVi, supported out biochemical results at 49 days after nerve transection. Although some changes in 5-HIAA/5-HT ratios were noted iN SpVi between lesioned and normal rats, these alterations were not consistent with significant changes in transmitter levels on the lesioned side. The significant difference between intact and normal rats in 5-HT concentration and in 5-HIAA/5-HT ratio at 49 days after the lesion, may be attributable to a sampling error since these conditions represent different groups of rats. The results of the present study suggest that plasticity of 5-HT afferents to SpVi may be a substrate for functional changes which occur with a long latency (> 49 days) following the lesion. Future analysis of the time course of alterations in response properties of SpVi neurons, following ION transection, should provide a clearer picture of the specific types of functional changes associated with 5-HT afferent plasticity. Such functional data will also allow us to focus our future efforts in attempting to more accurately specify the period, between 49 and 79 days, where changes in 5-HT afferents to SpVi reach detectable proportions. The role of 5-HT afferent plasticity in functional changes within SpVi may not be restricted to a simple quantitative modulation of normal transmitter-receptor interactions, but ma~ extend to regulation of plasticity of other afferent systems to, or neurons within, SpVi. Indeed, it has been shown that monoamines play a crucial role in regulating changes in cortical barrel size induced by selective whisker stimulation 2m'22. In :ddition, in spinal cord, it has been shown that 5-HT afferent systems regulate degeneration of enkephalinergic interneurons following sciatic nerve transection i~. The role of 5-HT in mediating functional alterations in SpVi, following ION cut, need not be restricted to periods following 5-HT afferent plasticity. For example, the normal presence of 5-HT in SpVi could be a necessary condition for lesion induced functional changes mediated by alterations in 5-HT receptor number or distribution. Irrespective of the ultimate mechanism(s), the role of 5-HT in lesion-induced plasticity within SpVi remains to be elucidated. We would like to thank Janette Duffin for her technical assistance and the Ultrastructure Laboratory of the Virginia-Maryland Regional College of Veterinary Medicine for use of their darkroom facilities. This work was supported by Grant ROI DE08966 (B.G.K.) from NIDR of the NIH.

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Time course of serotonergic afferent plasticity within rat spinal trigeminal nucleus following infraorbital nerve transection.

High-performance liquid chromatography with electrochemical detection (HPLC-ED) and immunocytochemistry were used to examine the time course of seroto...
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