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Amount of sympathetic sprouting in the dorsal root ganglia is not correlated to the level of sympathetic dependence of neuropathic pain in a rat model
Neuroscience Letters 245 (1998) 21–24
Amount of sympathetic sprouting in the dorsal root ganglia is not correlated to the level of sympathetic dependence of neuropathic pain in a rat model Hee Jin Kim a, Heung Sik Na a , b ,*, Backil Sung b , c, Seung Kil Hong a , b a
Neuroscience Research Institute and Department of Physiology, Korea University College of Medicine, 126-1 Anam-dong 5 Ga, Sungbuk-gu, Seoul 136–705, South Korea b Graduate School of Biotechnology, Korea University; Nowon-gu, Seoul 139–742, South Korea c Department of Rehabilitation Therapy, Sahmyook University, 26–21 Gongnung-dong, Nowon-gu, Seoul 139–742, South Korea Received 30 January 1998; received in revised form 11 February 1998; accepted 11 February 1998
Abstract Incomplete peripheral nerve injury often leads to neuropathic pains, some of which are relieved by sympathectomy, and results in sympathetic postganglionic nerve fiber sprouting in the dorsal root ganglion (DRG). This study was performed to see whether the sprouting in the DRG plays a key role in the sympathetic dependence of neuropathic pain. To this aim, we compared two groups of rats, both of which were subjected to unilateral transection of the inferior and superior caudal trunks at the levels between the S1 and S2, S2 and S3, and S3 and S4 spinal nerves, with respect to sympathetic fiber sprouting; one group showed neuropathic pain behaviours (i.e. mechanical and cold allodynia signs) which were very sensitive to phentolamine, alpha adrenergic blocker, and the other group exhibited no sensitivity. Immuno-histochemical staining with tyrosine hydroxylase antibody of the S1–S3 DRGs was not correlated with the sensitivity to phentolamine. These results suggest that the degree of sympathetic dependence of neuropathic pain is not a function of the extent of the sympathetic postganglionic nerve fiber sprouting in the DRG. 1998 Elsevier Science Ireland Ltd.
Keywords: Peripheral nerve injury; Dorsal root ganglion; Hyperalgesia; Allodynia; Sympathetically maintained pain; Phentolamine; Neuropathic pain
Partial peripheral nerve injury sometimes leads to neuropathic pain. This type of pain is characterized by spontaneous pain accompanied by allodynia and hyperalgesia [1,6,12]. It is widely accepted that neuropathic pain is divided into two types according to the association with the activity in the sympathetic nervous system: sympathetically independent pain (SIP) and sympathetically maintained pain (SMP) [2]. At present, the underlying mechanisms of sympathetic dependence of neuropathic pain remain unclear. Peripheral nerve injury elicits an
* Corresponding author. Department of Physiology, Korea University College of Medicine, 126-1, Anam-dong 5 ga, Sungbuk-gu, Seoul 136–705, South Korea. Tel.: +82 2 9206186; fax: +82 2 9255492.
increased sympathetic nerve sprouting in the injured nerve and corresponding dorsal root ganglion (DRG) [4,9]. The functional interactions between the sympathetic fiber sprouting and DRG following the nerve injury were assumed to be important to determine the sympathetic dependence of neuropathic pain [11]. Furthermore, recent studies have proposed that the amount of sympathetic sprouting in the DRG may be a key factor that determines the severity of and the sympathetic dependence of neuropathic pain [3,5]. The present study, using a rat model of neuropathic pain subjected to the partial injury of the nerve innervating the tail [10,13], was performed to examine the relationship between the extent of sympathetic fiber sprouting in the DRG and the degree of sympathetic dependence. To this aim, we compared the extent of sympathetic fiber sprouting
0304-3940/98/$19.00 1998 Elsevier Science Ireland Ltd. All rights reserved PII S0304- 3940(98) 00167- 0
22
H.J. Kim et al. / Neuroscience Letters 245 (1998) 21–24
in the DRG between two groups: one group exhibited mechanical and cold allodynia signs which were clearly relieved by phentolamine, and the other group showed no sensitivity to phentolamine. Preliminary data for this study have been presented in abstract form [14]. Young adult male rats (Sprague–Dawley, 150–200 g) were used in this study. Under enflurane anesthesia (0.5– 2%) the left inferior and superior caudal trunks were transected at the levels between the S1 and S2, between S2 and S3 and between S3 and S4 spinal nerves. The behavioral tests for mechanical and cold allodynia were conducted 1 day prior to the nerve injury, 1, 4 and 14 day(s) postoperatively. As described previously [9,10,13], the mechanical allodynia of the tail was measured by tail withdrawal response occurred by the application with von Frey hair (19.6 mN, 2.0 g). A von Frey hair was applied 10 times to the most sensitive area. The most sensitive spot was first located by poking various areas of the tail systematically with von Frey hair. To test for cold allodynia, the tail was immersed into cold water (4°C) and measured the latency of tail withdrawal response with a cut-off time of 15 s. Fourteen days after the neuropathic injury, the effects of a single intraperitoneal injection of phentolamine mesylate (2 mg/kg) on the behavioral signs of mechanical and cold allodynia were assessed 30, 90, 240 min and 24 h after the injection on 30 rats. After the phentolamine test, we compared two groups of rats with respect to sympathetic fiber sprouting; one group showed mechanical and cold allodynia signs which were clearly relieved by phentolamine, we called this SMP group, and the other group exhibited no changes, we called this SIP group. Animals which exhibited neither marked nor no sensitivity to phentolamine (middle group) were excluded. Although the selection of SMP and SIP groups from all experimental animals was made subjectively by the investigator, there was a clear difference in the sensitivity to phentolamine between these two groups. Two groups of animals were anesthetized with sodium pentobarbital (50 mg/kg, i.p.) and perfused with heparinized saline followed by a fixative (4% paraformaldehyde in 0.1 M phosphate buffer, pH 7.2). The S1–S3 DRG on both sides were removed from the rat, sectioned at 10 mm thickness and reacted with anti-TH antibody at a dilution of 1:1200 (Pel Freeze; Rogers, AR, USA) according to the ABC method (Vector Elite Kit; Vector, Burlingame, CA, USA). To quantify the extent of the sprouting, we counted THimmunoreactive fibers in the DRG (other than perivascular plexuses) using a light microscope equipped with a micrometer graticule (10 × 10 squares; 500 × 500 mm), i.e. we counted the squares of the micrometer graticule that contained TH-immunoreactive fibers for each of 4–8 randomly selected DRG sections. The results of the von Frey hair and cold water tests are shown in Fig. 1A,B. Before the nerve injury, the rats almost did not show a tail-withdrawal response to the mechanical stimuli with the von Frey hair and cold stimuli with cold
water. However, after the nerve injury, rats showed the increased sensitivities to mechanical and cold stimuli. We interpreted these data as signs of mechanical and cold allodynia. To examine the sympathetic dependence of mechanical and cold allodynia signs, intraperitoneal injection of phentolamine was made 14 days after the nerve injury. As shown in Fig. 1A,B, six rats (SMP group) showed a marked reduction in sensitivities to mechanical and cold stimuli lasting 4 h after phentolamine injection, and six rats (SIP group) exhibited no changes. Friedman followed by pairwise post-hoc tests indicated significant differences before and after the injection of phentolamine in SMP group, but not in SIP group. The results of the TH-immunocytochemistry are summarized in Fig. 2. The light micrographs in Fig. 2A illustrate
Fig. 1. Phentolamine effects of tail response to mechanical (A) and cold allodynia (B). The mean (±SEM) response frequency in the case of mechanical stimulation and the mean (±SEM) response latency in the case of cold stimulation are plotted against the experimental days. PRE and N; days prior to and after nerve injury, respectively; PH, minute (M) or hour (H) after the intraperitoneal injection of phentolamine (2 mg/kg, vertical dotted line). All scores of both groups at N1–N14 were significantly different from the presurgical score. SMP group (n = 6) showed a dramatic reduction in sensitivities to mechanical and cold stimulation near to pre-surgical level after the injection, whereas SIP group (n = 6) showed no changes. *Significantly different from the value at N14 (P , 0.05 by the Friedman test followed by pairwise post-hoc test).
H.J. Kim et al. / Neuroscience Letters 245 (1998) 21–24
TH-immunoreactive fibers in the contralateral (top) and injured (bottom) S1 DRG. TH-immunoreactive fibers were sparse in the contralateral DRG, whereas there was a massive increase in TH-immunoreactive fibers in the injured DRG. These data suggest that peripheral nerve injury induces sympathetic nerve sprouting in the DRG. The pattern of TH-immunolabeling in the DRG was similar to that reported in previous studies [4,9]. On the neuropathic side, the TH-immunoreactive fibers penetrated extensively into the DRG and occasionally surrounded
Fig. 2. (A) Light micrographs illustrating tyrosine hydroxylase (TH)immunoreactive fibers in the S1 DRG. Top, contralateral to the nerve injury; bottom, neuropathic side. Scale bar, 50 mm. (B) Numbers of squares containing TH-immunoreactive fibers. DRG sections (10 mm) were viewed under microscope with a calibrated ocular grid (10 × 10 squares). There is no difference between the SMP (n = 6) and SIP (n = 6) groups.
23
DRG cell bodies. Fig. 2B illustrates schematically the extent of TH-immunoreactive fiber sprouting in the S1–S3 DRG on the injured side of SMP and SIP groups. There is no significant difference in the mean number of the micrometer graticule squares containing TH-immunoreactive fibers in sections of the S1, S2 and S3 DRG between two groups (Bonferroni t-test). The present study shows that the degree of sympathetic dependence of mechanical and cold allodynia signs is not correlated with the extent of sympathetic fiber sprouting in the DRG after peripheral nerve injury. Sympathetic dependence may result from functional interactions between the sympathetic efferents and somatic afferents. Previous studies suggest that sympathetic sprouting in the DRG and the injured peripheral nerve is an anatomical substrate for the functional interactions [4,9,11], and the level of neuropathic pain behaviours is dependent on the amount of sympathetic sprouting [5]. In addition, Chung et al. [3] have proposed that the amount of sympathetic sprouting in the DRG is correlated with the degree of sympathetic dependence of neuropathic pain. These investigators reported that Lewis rats demonstrated mechanical allodynia sign which was more sensitive to phentolamine, and greater amount of sympathetic sprouting in the DRG than ACI, Brown Norway and Sprague–Dawley rats. In the present results, using Sprague–Dawley rats, there was no difference in the extent of sympathetic fiber sprouting between SMP and SIP groups both of which were clearly differentiated by the sensitivity of mechanical and cold allodynia signs to phentolamine. Presently, we can not explain exactly the disparity between these two results. However, the difference in the animal model (tail model versus hind paw model) or in species seems to be main cause. Alternatively, it might be due to the fact that the type(s) of DRG cells surrounded by sympathetic sprouts were different between the two studies. In fact, McLachlan et al. [11] reported that, after sciatic nerve ligation, sympathetic sprouting wrapped mainly large diameter axotomized sensory neurons and sympathetic stimulation activated such neurons. Studies in electrophysiology and molecular biology also suggest the interactions between sympathetic efferents and somatic afferents following peripheral nerve injury. Devor et al. [7] showed that electrical stimulation to sympathetic fibers innervating the axotomized DRG gave rise to an increase in spontaneous ectopic discharge from the DRG. In addition, peripheral nerve injury enhances alpha 2-adrenergic receptor expression in some DRG neurons [8,15]. Together with these results, our data suggest that the degree of sympathetic dependence of neuropathic pain may be correlated to the development of abnormal adrenergic sensitivity of the injured afferent neurons and/or to the development of abnormal sympathetic activity. In conclusion, we have found in the present study that the degree of sympathetic dependence of neuropathic pain is not correlated to the extent of sympathetic fiber sprouting in the DRG after peripheral nerve injury.
24
H.J. Kim et al. / Neuroscience Letters 245 (1998) 21–24
This study was supported by Postdoctoral Fellowship Fund 1997 of the Korea Research Foundation. [1] Blumberg, H. and Ja¨nig, W., Changes of reflexes in vasoconstrictor neurons supplying the cat hind limb following chronic nerve legions: a model for studying mechanisms of sympathetic dystrophy, J. Autonomic Nerv. Syst., 7 (1983) 399–411. [2] Campbell, J.N., Raja, S.N. and Meyer, R.A., Pain and the sympathetic nervous system: connecting the loop. In L. Vecchiet, D. Albe-Fessard, U. Lindblom and M.A. Giamberardino (Eds.), New Trends in Referred Pain and Hyperalgesia, Pain Research and Clinical Management, Vol. 7, Elsevier, Amsterdam, 1993, pp. 99–108. [3] Chung, J.M., Lee, D.H. and Chung, K., Strain differences in sympathetic dependency of neuropathic pain in a rat model, Neurosci. Abstr., 23 (1997) 2356. [4] Chung, K., Kim, H.J., Na, H.S., Park, M.J. and Chung, J.M., Abnormalities of sympathetic innervation of the area of injured peripheral nerve in a rat model of neuropathic pain, Neurosci. Lett., 162 (1993) 85–88. [5] Chung, K., Lee, B.H., Yoon, Y.W. and Chung, J.M., Sympathetic sprouting in the dorsal root ganglia of the injured peripheral nerve in a rat neuropathic pain model, J. Comp. Neurol., 376 (1996) 241–252. [6] Devor, M., Nerve pathophysiology and mechanisms of pain in causalgia, J. Autonomic Nerv. Syst., 7 (1983) 371–384. [7] Devor, M., Jaenig, W. and Michaelis, M., Modulation of activity in dorsal root ganglion neurons by sympathetic activation in nerve-injured rats, J. Neurophysiol., 71 (1994) 38–47. [8] Fareed, M.U., Lee, D.H., Noh, H.R., Chung, J.M. and Davar,
[9]
[10]
[11]
[12] [13]
[14]
[15]
G., Identification and increased expression of a novel alpha-2 adrenoreceptor mRNA in a rat model of experimental painful neuropathy. In T.S. Jensen, J.A. Turner and Z. WiesenfeldHallin (Eds.), Proceedings of the 8th World Congress on Pain, Progress in Pain Research and Management, Vol. 8, IASP press, Seattle, WA, 1997, pp. 539–546. Kim, H.J., Na, H.S., Nam, H.J., Park, K.A. and Hong, S.K., Sprouting of sympathetic nerve fibers into the dorsal root ganglion following peripheral nerve injury depends on the injury site, Neurosci. Lett., 212 (1996) 191–194. Kim, Y.I., Na, H.S., Han, J.S. and Hong, S.K., Critical role of the capsaicin-sensitive nerve fibers in the development of the causalgic symptoms produced by transecting some but not all of the nerves innervating the rat tail, J. Neurosci., 15 (1995) 4133–4139. McLachlan, E.M., Jaenig, W., Devor, M. and Michaelis, M., Peripheral nerve injury triggers noradrenergic sprouting within dorsal root ganglia, Nature, 363 (1993) 543–546. Mitchell, S.W., Injuries of nerves and their consequences, J.B. Lippincott, Philadelphia, PA, 1872, 252 pp. Na, H.S., Han, J.S., Ko, K.H. and Hong, S.K., A behavioral model for peripheral neuropathy produced in rat’s tail by inferior caudal trunk injury, Neurosci. Lett., 177 (1994) 50–52. Na, H.S., Kim, H.J., Sung, B. and Hong, S.K., Role of sympathetic nerve fiber sprouting in the DRG in the sympathetic dependence of neuropathic pain, Neurosci. Abstr., 23 (1997) 2356. Nishiyama, K., Brighton, B.W., Bassut, D.F. and Perl, E.R., Peripheral nerve injury enhances alpha-2 adrenergic receptor expression by some DRG neurons, Neurosci. Abstr., 19 (1993) 449.
Amount of sympathetic sprouting in the dorsal root ganglia is not correlated to the level of sympathetic dependence of neuropathic pain in a rat model Hee Jin Kim a, Heung Sik Na a , b ,*, Backil Sung b , c, Seung Kil Hong a , b a
Neuroscience Research Institute and Department of Physiology, Korea University College of Medicine, 126-1 Anam-dong 5 Ga, Sungbuk-gu, Seoul 136–705, South Korea b Graduate School of Biotechnology, Korea University; Nowon-gu, Seoul 139–742, South Korea c Department of Rehabilitation Therapy, Sahmyook University, 26–21 Gongnung-dong, Nowon-gu, Seoul 139–742, South Korea Received 30 January 1998; received in revised form 11 February 1998; accepted 11 February 1998
Abstract Incomplete peripheral nerve injury often leads to neuropathic pains, some of which are relieved by sympathectomy, and results in sympathetic postganglionic nerve fiber sprouting in the dorsal root ganglion (DRG). This study was performed to see whether the sprouting in the DRG plays a key role in the sympathetic dependence of neuropathic pain. To this aim, we compared two groups of rats, both of which were subjected to unilateral transection of the inferior and superior caudal trunks at the levels between the S1 and S2, S2 and S3, and S3 and S4 spinal nerves, with respect to sympathetic fiber sprouting; one group showed neuropathic pain behaviours (i.e. mechanical and cold allodynia signs) which were very sensitive to phentolamine, alpha adrenergic blocker, and the other group exhibited no sensitivity. Immuno-histochemical staining with tyrosine hydroxylase antibody of the S1–S3 DRGs was not correlated with the sensitivity to phentolamine. These results suggest that the degree of sympathetic dependence of neuropathic pain is not a function of the extent of the sympathetic postganglionic nerve fiber sprouting in the DRG. 1998 Elsevier Science Ireland Ltd.
Keywords: Peripheral nerve injury; Dorsal root ganglion; Hyperalgesia; Allodynia; Sympathetically maintained pain; Phentolamine; Neuropathic pain
Partial peripheral nerve injury sometimes leads to neuropathic pain. This type of pain is characterized by spontaneous pain accompanied by allodynia and hyperalgesia [1,6,12]. It is widely accepted that neuropathic pain is divided into two types according to the association with the activity in the sympathetic nervous system: sympathetically independent pain (SIP) and sympathetically maintained pain (SMP) [2]. At present, the underlying mechanisms of sympathetic dependence of neuropathic pain remain unclear. Peripheral nerve injury elicits an
* Corresponding author. Department of Physiology, Korea University College of Medicine, 126-1, Anam-dong 5 ga, Sungbuk-gu, Seoul 136–705, South Korea. Tel.: +82 2 9206186; fax: +82 2 9255492.
increased sympathetic nerve sprouting in the injured nerve and corresponding dorsal root ganglion (DRG) [4,9]. The functional interactions between the sympathetic fiber sprouting and DRG following the nerve injury were assumed to be important to determine the sympathetic dependence of neuropathic pain [11]. Furthermore, recent studies have proposed that the amount of sympathetic sprouting in the DRG may be a key factor that determines the severity of and the sympathetic dependence of neuropathic pain [3,5]. The present study, using a rat model of neuropathic pain subjected to the partial injury of the nerve innervating the tail [10,13], was performed to examine the relationship between the extent of sympathetic fiber sprouting in the DRG and the degree of sympathetic dependence. To this aim, we compared the extent of sympathetic fiber sprouting
0304-3940/98/$19.00 1998 Elsevier Science Ireland Ltd. All rights reserved PII S0304- 3940(98) 00167- 0
22
H.J. Kim et al. / Neuroscience Letters 245 (1998) 21–24
in the DRG between two groups: one group exhibited mechanical and cold allodynia signs which were clearly relieved by phentolamine, and the other group showed no sensitivity to phentolamine. Preliminary data for this study have been presented in abstract form [14]. Young adult male rats (Sprague–Dawley, 150–200 g) were used in this study. Under enflurane anesthesia (0.5– 2%) the left inferior and superior caudal trunks were transected at the levels between the S1 and S2, between S2 and S3 and between S3 and S4 spinal nerves. The behavioral tests for mechanical and cold allodynia were conducted 1 day prior to the nerve injury, 1, 4 and 14 day(s) postoperatively. As described previously [9,10,13], the mechanical allodynia of the tail was measured by tail withdrawal response occurred by the application with von Frey hair (19.6 mN, 2.0 g). A von Frey hair was applied 10 times to the most sensitive area. The most sensitive spot was first located by poking various areas of the tail systematically with von Frey hair. To test for cold allodynia, the tail was immersed into cold water (4°C) and measured the latency of tail withdrawal response with a cut-off time of 15 s. Fourteen days after the neuropathic injury, the effects of a single intraperitoneal injection of phentolamine mesylate (2 mg/kg) on the behavioral signs of mechanical and cold allodynia were assessed 30, 90, 240 min and 24 h after the injection on 30 rats. After the phentolamine test, we compared two groups of rats with respect to sympathetic fiber sprouting; one group showed mechanical and cold allodynia signs which were clearly relieved by phentolamine, we called this SMP group, and the other group exhibited no changes, we called this SIP group. Animals which exhibited neither marked nor no sensitivity to phentolamine (middle group) were excluded. Although the selection of SMP and SIP groups from all experimental animals was made subjectively by the investigator, there was a clear difference in the sensitivity to phentolamine between these two groups. Two groups of animals were anesthetized with sodium pentobarbital (50 mg/kg, i.p.) and perfused with heparinized saline followed by a fixative (4% paraformaldehyde in 0.1 M phosphate buffer, pH 7.2). The S1–S3 DRG on both sides were removed from the rat, sectioned at 10 mm thickness and reacted with anti-TH antibody at a dilution of 1:1200 (Pel Freeze; Rogers, AR, USA) according to the ABC method (Vector Elite Kit; Vector, Burlingame, CA, USA). To quantify the extent of the sprouting, we counted THimmunoreactive fibers in the DRG (other than perivascular plexuses) using a light microscope equipped with a micrometer graticule (10 × 10 squares; 500 × 500 mm), i.e. we counted the squares of the micrometer graticule that contained TH-immunoreactive fibers for each of 4–8 randomly selected DRG sections. The results of the von Frey hair and cold water tests are shown in Fig. 1A,B. Before the nerve injury, the rats almost did not show a tail-withdrawal response to the mechanical stimuli with the von Frey hair and cold stimuli with cold
water. However, after the nerve injury, rats showed the increased sensitivities to mechanical and cold stimuli. We interpreted these data as signs of mechanical and cold allodynia. To examine the sympathetic dependence of mechanical and cold allodynia signs, intraperitoneal injection of phentolamine was made 14 days after the nerve injury. As shown in Fig. 1A,B, six rats (SMP group) showed a marked reduction in sensitivities to mechanical and cold stimuli lasting 4 h after phentolamine injection, and six rats (SIP group) exhibited no changes. Friedman followed by pairwise post-hoc tests indicated significant differences before and after the injection of phentolamine in SMP group, but not in SIP group. The results of the TH-immunocytochemistry are summarized in Fig. 2. The light micrographs in Fig. 2A illustrate
Fig. 1. Phentolamine effects of tail response to mechanical (A) and cold allodynia (B). The mean (±SEM) response frequency in the case of mechanical stimulation and the mean (±SEM) response latency in the case of cold stimulation are plotted against the experimental days. PRE and N; days prior to and after nerve injury, respectively; PH, minute (M) or hour (H) after the intraperitoneal injection of phentolamine (2 mg/kg, vertical dotted line). All scores of both groups at N1–N14 were significantly different from the presurgical score. SMP group (n = 6) showed a dramatic reduction in sensitivities to mechanical and cold stimulation near to pre-surgical level after the injection, whereas SIP group (n = 6) showed no changes. *Significantly different from the value at N14 (P , 0.05 by the Friedman test followed by pairwise post-hoc test).
H.J. Kim et al. / Neuroscience Letters 245 (1998) 21–24
TH-immunoreactive fibers in the contralateral (top) and injured (bottom) S1 DRG. TH-immunoreactive fibers were sparse in the contralateral DRG, whereas there was a massive increase in TH-immunoreactive fibers in the injured DRG. These data suggest that peripheral nerve injury induces sympathetic nerve sprouting in the DRG. The pattern of TH-immunolabeling in the DRG was similar to that reported in previous studies [4,9]. On the neuropathic side, the TH-immunoreactive fibers penetrated extensively into the DRG and occasionally surrounded
Fig. 2. (A) Light micrographs illustrating tyrosine hydroxylase (TH)immunoreactive fibers in the S1 DRG. Top, contralateral to the nerve injury; bottom, neuropathic side. Scale bar, 50 mm. (B) Numbers of squares containing TH-immunoreactive fibers. DRG sections (10 mm) were viewed under microscope with a calibrated ocular grid (10 × 10 squares). There is no difference between the SMP (n = 6) and SIP (n = 6) groups.
23
DRG cell bodies. Fig. 2B illustrates schematically the extent of TH-immunoreactive fiber sprouting in the S1–S3 DRG on the injured side of SMP and SIP groups. There is no significant difference in the mean number of the micrometer graticule squares containing TH-immunoreactive fibers in sections of the S1, S2 and S3 DRG between two groups (Bonferroni t-test). The present study shows that the degree of sympathetic dependence of mechanical and cold allodynia signs is not correlated with the extent of sympathetic fiber sprouting in the DRG after peripheral nerve injury. Sympathetic dependence may result from functional interactions between the sympathetic efferents and somatic afferents. Previous studies suggest that sympathetic sprouting in the DRG and the injured peripheral nerve is an anatomical substrate for the functional interactions [4,9,11], and the level of neuropathic pain behaviours is dependent on the amount of sympathetic sprouting [5]. In addition, Chung et al. [3] have proposed that the amount of sympathetic sprouting in the DRG is correlated with the degree of sympathetic dependence of neuropathic pain. These investigators reported that Lewis rats demonstrated mechanical allodynia sign which was more sensitive to phentolamine, and greater amount of sympathetic sprouting in the DRG than ACI, Brown Norway and Sprague–Dawley rats. In the present results, using Sprague–Dawley rats, there was no difference in the extent of sympathetic fiber sprouting between SMP and SIP groups both of which were clearly differentiated by the sensitivity of mechanical and cold allodynia signs to phentolamine. Presently, we can not explain exactly the disparity between these two results. However, the difference in the animal model (tail model versus hind paw model) or in species seems to be main cause. Alternatively, it might be due to the fact that the type(s) of DRG cells surrounded by sympathetic sprouts were different between the two studies. In fact, McLachlan et al. [11] reported that, after sciatic nerve ligation, sympathetic sprouting wrapped mainly large diameter axotomized sensory neurons and sympathetic stimulation activated such neurons. Studies in electrophysiology and molecular biology also suggest the interactions between sympathetic efferents and somatic afferents following peripheral nerve injury. Devor et al. [7] showed that electrical stimulation to sympathetic fibers innervating the axotomized DRG gave rise to an increase in spontaneous ectopic discharge from the DRG. In addition, peripheral nerve injury enhances alpha 2-adrenergic receptor expression in some DRG neurons [8,15]. Together with these results, our data suggest that the degree of sympathetic dependence of neuropathic pain may be correlated to the development of abnormal adrenergic sensitivity of the injured afferent neurons and/or to the development of abnormal sympathetic activity. In conclusion, we have found in the present study that the degree of sympathetic dependence of neuropathic pain is not correlated to the extent of sympathetic fiber sprouting in the DRG after peripheral nerve injury.
24
H.J. Kim et al. / Neuroscience Letters 245 (1998) 21–24
This study was supported by Postdoctoral Fellowship Fund 1997 of the Korea Research Foundation. [1] Blumberg, H. and Ja¨nig, W., Changes of reflexes in vasoconstrictor neurons supplying the cat hind limb following chronic nerve legions: a model for studying mechanisms of sympathetic dystrophy, J. Autonomic Nerv. Syst., 7 (1983) 399–411. [2] Campbell, J.N., Raja, S.N. and Meyer, R.A., Pain and the sympathetic nervous system: connecting the loop. In L. Vecchiet, D. Albe-Fessard, U. Lindblom and M.A. Giamberardino (Eds.), New Trends in Referred Pain and Hyperalgesia, Pain Research and Clinical Management, Vol. 7, Elsevier, Amsterdam, 1993, pp. 99–108. [3] Chung, J.M., Lee, D.H. and Chung, K., Strain differences in sympathetic dependency of neuropathic pain in a rat model, Neurosci. Abstr., 23 (1997) 2356. [4] Chung, K., Kim, H.J., Na, H.S., Park, M.J. and Chung, J.M., Abnormalities of sympathetic innervation of the area of injured peripheral nerve in a rat model of neuropathic pain, Neurosci. Lett., 162 (1993) 85–88. [5] Chung, K., Lee, B.H., Yoon, Y.W. and Chung, J.M., Sympathetic sprouting in the dorsal root ganglia of the injured peripheral nerve in a rat neuropathic pain model, J. Comp. Neurol., 376 (1996) 241–252. [6] Devor, M., Nerve pathophysiology and mechanisms of pain in causalgia, J. Autonomic Nerv. Syst., 7 (1983) 371–384. [7] Devor, M., Jaenig, W. and Michaelis, M., Modulation of activity in dorsal root ganglion neurons by sympathetic activation in nerve-injured rats, J. Neurophysiol., 71 (1994) 38–47. [8] Fareed, M.U., Lee, D.H., Noh, H.R., Chung, J.M. and Davar,
[9]
[10]
[11]
[12] [13]
[14]
[15]
G., Identification and increased expression of a novel alpha-2 adrenoreceptor mRNA in a rat model of experimental painful neuropathy. In T.S. Jensen, J.A. Turner and Z. WiesenfeldHallin (Eds.), Proceedings of the 8th World Congress on Pain, Progress in Pain Research and Management, Vol. 8, IASP press, Seattle, WA, 1997, pp. 539–546. Kim, H.J., Na, H.S., Nam, H.J., Park, K.A. and Hong, S.K., Sprouting of sympathetic nerve fibers into the dorsal root ganglion following peripheral nerve injury depends on the injury site, Neurosci. Lett., 212 (1996) 191–194. Kim, Y.I., Na, H.S., Han, J.S. and Hong, S.K., Critical role of the capsaicin-sensitive nerve fibers in the development of the causalgic symptoms produced by transecting some but not all of the nerves innervating the rat tail, J. Neurosci., 15 (1995) 4133–4139. McLachlan, E.M., Jaenig, W., Devor, M. and Michaelis, M., Peripheral nerve injury triggers noradrenergic sprouting within dorsal root ganglia, Nature, 363 (1993) 543–546. Mitchell, S.W., Injuries of nerves and their consequences, J.B. Lippincott, Philadelphia, PA, 1872, 252 pp. Na, H.S., Han, J.S., Ko, K.H. and Hong, S.K., A behavioral model for peripheral neuropathy produced in rat’s tail by inferior caudal trunk injury, Neurosci. Lett., 177 (1994) 50–52. Na, H.S., Kim, H.J., Sung, B. and Hong, S.K., Role of sympathetic nerve fiber sprouting in the DRG in the sympathetic dependence of neuropathic pain, Neurosci. Abstr., 23 (1997) 2356. Nishiyama, K., Brighton, B.W., Bassut, D.F. and Perl, E.R., Peripheral nerve injury enhances alpha-2 adrenergic receptor expression by some DRG neurons, Neurosci. Abstr., 19 (1993) 449.