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Anesth Analg 2008; 107:1064-1069
© 2008 International Anesthesia Research Society
doi: 10.1213/ane.0b013e31817e7a59
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ANALGESIA

The Antiallodynic Effect of Neurotropin® Is Mediated via Activation of Descending Pain Inhibitory Systems in Rats with Spinal Nerve Ligation

Ryohei Okazaki, Hiroyoshi Namba, Hiroyuki Yoshida, Hisashi Okai, Tomoshi Miura, and Minoru Kawamura

From the Department of Development Research, Institute of Bio-active Science, Nippon Zoki Pharmaceutical Co., Ltd., 442-1, Kinashi, Kato, Hyogo, 673-1461, Japan.

Abstract

BACKGROUND: Neurotropin®, a nonprotein extract isolated from inflamed skin of rabbits inoculated with vaccinia virus, is widely used in Japan to treat chronic pain such as neuropathic pain. Although some studies have been conducted on the mechanism of the antiallodynic action of Neurotropin, this mechanism has yet to be adequately clarified.

METHODS: The left fifth lumbar nerve of rats was tightly ligated with silk sutures under pentobarbital anesthesia. Mechanical allodynia was confirmed by measuring the hindpaw withdrawal threshold in response to application of von Frey filaments. Behavioral tests were performed at 28 days after nerve ligation. Neurotropin was administered IV, intrathecally or intracerebroventricularly in L5 spinal nerve ligation (L5-SNL) rats. We examined the effects of noradrenergic, serotonergic and {gamma}-aminobutyric acid (GABA)ergic antagonists on the antiallodynic action of Neurotropin in L5-SNL rats. Yohimbine hydrochloride (yohimbine) was used as an {alpha}2 adrenoceptor antagonist, ketanserin tartrate (ketanserin) as a 5-HT2A receptor antagonist, MDL72,222 as a 5-HT3 receptor antagonist, (-)-bicuculline methobromide (bicuculline) as a GABAA receptor antagonist, and CGP35,348 as a GABAB receptor antagonist, and intrathecally injected.

RESULTS: IV (50–100 NU/kg) doses of Neurotropin elicited an antiallodynic action in L5-SNL rats. Moreover, intracerebroventricular (400 mNU/rat), but not intrathecal, injection of Neurotropin inhibited allodynia. The antiallodynic action of Neurotropin (100 NU/kg, IV) was antagonized by intrathecal injections of yohimbine (10 nmol/rat), ketanserin (30 nmol/rat), MDL72,222(30 nmol/rat), bicuculline (0.6 nmol/rat) and CGP35348 (30 nmol/rat). On the other hand, the antiallodynic action of intrathecally injected m-CPBG (5-HT3 receptor agonist) was reversed by intrathecal injection of bicuculline and CGP35348, suggesting interaction of 5-HT3 receptors and spinal inhibitory (GABAergic) interneurons.

CONCLUSIONS: These results suggest that the antiallodynic effect of Neurotropin is mediated via activation of descending pain inhibitory systems, such as the noradrenergic and serotonergic systems, which project from supraspinal sites to the spinal dorsal horn. In addition, activation of inhibitory GABAergic interneurons via 5-HT3 receptors by serotonin released in the spinal dorsal horn may also be involved in the antiallodynic action of Neurotropin.

Neuropathic pain is initiated by a primary lesion or dysfunction of the peripheral and/or central nervous systems. Persistent allodynia, or pain resulting from a nonpainful stimulus, such as a light touch, is also a common characteristic of neuropathic pain. Neuropathic pain is often chronic. It tends to be unresponsive to opioids but may respond well to other drugs, such as anticonvulsants and antidepressants.

Neurotropin, a nonprotein extract isolated from inflamed skin of rabbits inoculated with vaccinia virus, is widely used in Japan and China to treat neuropathic pain such as post-herpetic neuralgia and other chronic pain conditions. A double-blind placebo-controlled crossover study, which aims to investigate the effectiveness of Neurotropin in the treatment of acute pain after tooth extraction and complex regional pain syndrome, is currently underway at the National Institute of Nursing Research in the United States. Although some studies have been conducted on the mechanism of the antiallodynic action of Neurotropin, the mechanism has yet to be adequately clarified. Neurotropin reduced thermal hyperalgesia in chronic constriction injury rats.1 Suzuki et al.2 reported that Neurotropin inhibited tactile allodynia, as well as mechanical and thermal hyperalgesia, via the noradrenergic system, but not the serotonergic system, in L5 spinal nerve ligation (SNL) mice. Specific alternation of rhythm in temperature (SART) stress induces hypersensitivity to noxious stimuli, such as mechanical, heat and chemical stimuli.3 The antinociceptive effects of Neurotropin have been reported in SART-stressed animals. Kawamura et al.4 reported that the antinociceptive action of Neurotropin is mediated via enhancement of the endogenous descending pain inhibitory pathway of the noradrenergic and serotonergic systems, but not opioidergic system. It has been reported that simultaneous inhibition of noradrenaline and serotonin (5-HT) reuptake in the spinal cord effectively suppressed allodynia in L5/L6 SNL rats.5 These findings suggest that Neurotropin may be useful for the treatment of neuropathic pain. Thus, in order to find the action site of Neurotropin, we examined the antiallodynic effect of Neurotropin after IV, intracerebroventricular, and intrathecal administration.

Next, in order to clarify the action mechanism of the antiallodynic effect of Neurotropin, we examined not only the involvement of noradrenergic and serotonergic systems but that of {gamma}-aminobutyric acid (GABA) ergic systems on the antiallodynic action of Neurotropin in the rat L5-SNL model.

METHODS

All experiments were approved by the Animal Care and Use Committee of our institution and performed in accordance with the ethical guidelines for investigations of experimental pain in conscious animals issued by the International Association for the Study of Pain.6 Nine-wk old male Wistar rats were purchased from Japan SLC Inc. (Hamamatsu, Shizuoka, Japan) for use in the study. At the time of the experiment, the animals were aged 10 wk. The animals were housed at 22 ± 2°C with a 12-h light and dark cycle (light turned on from 8:00 to 20:00). Laboratory chow and tap water were available ad libitum. The left fifth lumbar nerve of rats was isolated and tightly ligated with 5–0 silk sutures under pentobarbital (40 mg/kg, i.p.) anesthesia. After surgery, rats were housed in a cage in groups of three with free access to food and water and allowed to recover for 28 days. Left paw mechanical allodynia was confirmed at 14 and 28 days by measuring the hindpaw withdrawal threshold in response to application of von Frey filaments using the up-down method.7,8 Only rats with a withdrawal threshold of <4 g were used; those with evidence of neuromuscular dysfunction were omitted from this study. Behavioral tests were performed at 28 days after nerve ligation. Neurotropin was prepared by Nippon Zoki Pharmaceutical Co., Ltd. (Osaka, Japan). The biological activity of Neurotropin is standardized by an analgesic test in SART-stressed mice and expressed as Neurotropin Units (NU). Neurotropin was administered IV, intrathecally or intracerebroventricularly. The intrathecal injection was performed according to the method of Hylden and Wilcox.9 The intracerebroventricular injection was performed as follows: 7 days before the experiment, rats were anesthetized with pentobarbital (40 mg/kg, i.p.) and immobilized using a stereotaxic apparatus. A guide cannula was then aseptically implanted into the right lateral ventricle. The lower tip of the guide cannula was positioned 3.5 mm from the center of the lateral ventricle (distance from interaural: anterior, +8.2 mm; lateral, +1.5 mm; vertical, +9.4 mm). An injection needle was inserted through the guide cannula into the lateral ventricle (3.5 mm beyond the guide cannula). Neurotropin was injected into the lateral ventricle at a volume of 10 µL. Yohimbine hydrochloride (yohimbine, Sigma, St. Louis, MO) was used as an {alpha}2 adrenoceptor antagonist, ketanserin tartrate (ketanserin, Sigma) as a 5-HT2A receptor antagonist, m-CPBG hydrochloride (m-CPBG, Sigma) as a 5-HT3 receptor agonist, MDL72,222 (Tocris Cookson Inc., Ellisville, MO) as a 5-HT3 receptor antagonist, (-)-bicuculline methobromide (bicuculline, Sigma) as a GABAA receptor antagonist and CGP35,348 (Tocris Cookson Inc.) as a GABAB receptor antagonist, and intrathecally injected. These experiments were performed under open-label and data on the time course of effects of Neurotropin were analyzed using a two way analysis of variance followed by Tukey‘s post hoc comparison test. The effects of antagonists were assessed by Tukey‘s post hoc comparison test. Differences were considered to be statistically significant when P < 0.05.

RESULTS

The Antiallodynic Effects of Neurotropin After IV, Intracerebroventricular and Intrathecal Administration in L5-SNL Rats
When Neurotropin was administered IV to L5-SNL rats at 20 NU/kg, the withdrawal threshold was unchanged whereas a significant increase was seen at higher doses of 50 and 100 NU/kg (P = 0.0004 and P = 0.0031 at 20 min). The antiallodynic effect peaked 20 min after IV administration (Fig. 1a). When Neurotropin was administered by intracerebroventicular injection, a dose-dependent increase in the withdrawal threshold was observed, with allodynia significantly inhibited at 400 mNU/rat (P = 0.0003 at 5 min). The antiallodynic effect peaked 5 min after the injection (Fig. 1b). In contrast, when Neurotropin was administered intrathecally at the same dose, it had no effect on allodynia in L5-SNL rats (Fig. 1c).


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  		Figure 1. The antiallodynic effect of Neurotropin after IV, intracerebroventricular and intrathecal administration in L5-spinal nerve ligation rats. Withdrawal threshold was measured using von Frey filaments before and after (a)IV, (b)intracerebroventricular and (c)intrathecal administration of Neurotropin. Data are expressed as mean ± se (n = 7–9). *Significant difference at P < 0.05 versus the control group (a two-way analysis of variance followed by Tukey's multiple comparison test, P < 0.05).

 

The Action Mechanism of the Antiallodynic Effect of Neurotropin in L5-SNL Rats
Intrathecal injection of yohimbine ({alpha}2 adrenoceptor antagonist) at 10 nmol/rat significantly reversed the antiallodynic effect of Neurotropin at 100 NU/kg (P = 0.014, Fig. 2). Similarly, intrathecal injection of ketanserin (5-HT2A receptor antagonist) at 30 nmol/rat (P = 0.025) and MDL72,222 (5-HT3 receptor antagonist) at 30 nmol/rat (P < 0.0001) significantly inhibited the antiallodynic effect of IV administration of Neurotropin at 100 NU/kg in L5-SNL rats (Fig. 3).


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  		Figure 2. Effect of yohimbine on the antiallodynic action of Neurotropin in L5-spinal nerve ligation rats. Withdrawal threshold was measured using von Frey filaments before and 20 min after IV administration of Neurotropin. Yohimbine was intrathecally injected 5 min before administration of Neurotropin. Data are expressed as mean ± se (n = 9). *Significant difference at P < 0.05 (Tukey's multiple comparison test).

 

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  		Figure 3. Effects of ketanserin (a) and MDL72222 (b) on the antiallodynic action of Neurotropin in L5-spinal nerve ligation rats. Withdrawal threshold was measured using von Frey filaments before and 20 min after IV administration of Neurotropin. Ketanserin (a) and MDL72222 (b) were intrathecally injected 5 min before administration of Neurotropin. Data are expressed as mean ± se (n = 8). *Significant difference at P < 0.05 (Tukey's multiple comparison test).

 

The antiallodynic effect of IV administration of Neurotropin at 100 NU/kg was attenuated by intrathecal injection of bicuculline (GABAA receptor antagonist) at 0.6 nmol/rat (P = 0.012) and CGP35,348 (GABAB receptor antagonist) at 30 nmol/rat (P < 0.0001, Fig. 4).


Figure 458
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  		Figure 4. Effects of bicuculline (a) and CGP35348 (b) on the antiallodynic action of Neurotropin in L5-spinal nerve ligation rats. Withdrawal threshold was measured using von Frey filaments before and 20 min after IV administration of Neurotropin. Bicuculline (a) and CGP35348 (b) were intrathecally injected 5 min before administration of Neurotropin. Data are expressed as mean ± se (n = 8). *Significant difference at P < 0.05 (Tukey's multiple comparison test).

 

The antiallodynic effect of m-CPBG (5-HT3 receptor agonist) at 60 nmol/rat in L5-SNL rats was significantly reversed by intrathecal injection of bicuculline (GABAA receptor antagonist) at 0.6 nmol/rat (P = 0.0004) and CGP35,348 (GABAB receptor antagonist) at 30 nmol/ rat (P = 0.0006, Fig. 5).


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  		Figure 5. Effects of {gamma}-aminobutyric acid (GABA) receptor antagonists on the antiallodynic action of 5-HT3 receptor agonist in L5-spinal nerve ligation rats. Withdrawal threshold was measured before and 30 min after intrathecal injection of m-CPBG (5-HT3 receptor agonist). Bicuculline or CGP35348 was intrathecally injected with m-CPBG. Data are expressed as mean ± se (n = 7). *Significant difference at P < 0.05 (Tukey's multiple comparison test).

 

The dosages of these antagonists used in this study had no significant effects on the withdrawal threshold and did not elicit abnormal behavior in rats.

DISCUSSION

In this study, we examined the antiallodynic effect of Neurotropin after IV, intracerebroventricular and intrathecal administration in order to find the action site. In the case of IV administration of Neurotropin, an antiallodynic effect was observed in L5-SNL rats. As Ohara et al.10 reported that Neurotropin inhibited the release of bradykinin at a peripheral site, it is expected that the peripheral effect of Neurotorpin is involved in the antiallodynic effect. However, intracerebroventricular, but not intrathecal, injection of Neurotropin very strongly inhibited allodynia in L5-SNL rats. Additionally, Suzuki et al. found that intraplantar injection of Neurotropin had no effect on L5-SNL mice.2 According to these data, we think that Neurotropin might act mainly at a supraspinal site rather than a peripheral site in L5-SNL rats.

It is reported that nerve injury induced the activation of the descending inhibitory noradrenergic system.11,12 These findings mean that the descending inhibitory noradrenergic system might play an important role in neuropathic pain. Yaksh et al.13 reported that {alpha}2 adrenoceptors were involved in the regulation of allodynia in L5-SNL rats. Neurotropin showed analgesic effects via the noradrenergic system in SART-stressed animals,4,14 adjuvant rats15 and L5-SNL mice.2 Thus, we examined whether the noradrenergic system is involved in the antiallodynic action of Neurotropin in L5-SNL rats. In this study, the antiallodynic effect of Neurotropin was antagonized by yohimbine. This finding indicates that the noradrenergic system is involved in the antiallodynic action of Neurotropin in L5-SNL rats.

There is controversy over the identity of the descending serotonergic system responsible for the facilitatory or inhibitory effect in neuropathic pain.16–19

Suzuki et al. reported that the 5-HT3 receptor antagonist (ondansetron) inhibited allodynia in L5/ L6-SNL rats.20 However, we confirmed that the 5-HT3 receptor agonist (m-CPBG) showed the antiallodynic effect in L5-SNL rats.

5-HT3 receptors coupled with cation channels can excite cells by depolarization via an increased influx of cations.21 In the case of facilitation of neuropathic pain, ON cells in rostroventromedial medulla may activate 5-HT3 receptors on the primary afferent neuron in the dorsal horn19 and facilitate pain, probably by an increase of excitatory transmitters. In the case of inhibition of neuropathic pain, OFF cells in rostroventromedial medulla activate 5-HT3 receptors on the inhibitory interneuron in the dorsal horn, and inhibit pain by an increase of inhibitory transmitters.19 Our data support the notion that 5-HT plays an inhibitory role in neuropathic pain. Although we do not understand why the serotonergic system shows a facilitatory or inhibitory effect in neuropathic pain, the effect of 5-HT in neuropathic pain may be different according to the applied stimulus and the variable or timing of assessment.17,20,22

On the other hand, it was reported that the dysfunction of GABAergic systems23–25 is involved in the maintenance of neuropathic pain. However, Hwang and Yaksh26 found that GABAA and GABAB agonists produced powerful antiallodynic effects in L5-SNL rats. Kawamata et al.27 reported an intrathecal perfusion of a selective 5-HT3 receptor agonist could increase the GABA concentration without the change of glutamate and glycine levels in the spinal cord. We observed the antiallodynic effect of 5-HT3 receptor agonist (m-CPBG) was reversed by GABAA or GABAB receptor antagonist in L5-SNL rats. These results indicate that the relationship between 5-HT3 receptors and GABA receptors is involved in neuropathic pain.

Next, we examined the involvement of the serotonergic system on the antiallodynic action of Neurotropin in L5-SNL rats. As a result, 5-HT2A and 5-HT3 receptor antagonists could inhibit the antiallodynic effect of Neurotropin in L5-SNL rats. Although we have mainly investigated the analgesic mechanism of Neurotropin using SART-stressed animals, the antinociceptive effect of Neurotropin was significantly inhibited by a 5-HT3 antagonist, but not a 5-HT2A antagonist, in SART-stressed rats.4 Because the involvement of 5-HT receptor subtypes may differ according to pain models,28 the degree of involvement of the serotonergic system for pain control may be different between SART-stressed and L5-SNL mice, but details are unclear.

Concerning the GABAergic system, Ohara et al.14 reported that bicuculline had no influence on the antinociceptive effect of Neurotropin, but Hata et al.29 reported that bicuculline antagonized the antinociceptive effect of Neurotropin. Thus, it is controversial whether Neurotropin can show analgesic effect via the GABAergic system. In L5-SNL rats, the antiallodynic effect of Neurotropin was reversed by GABAA or GABAB receptor antagonist. Although Suzuki et al.2 could not determine the involvement of the serotonergic system on the antiallodynic effect of Neurotropin in L5-SNL mice, we suggest that Neurotropin might inhibit allodynia by activation of the inhibitory GABAergic system via 5-HT3 receptors in L5-SNL rats.

Both descending facilitatory or inhibitory systems may be related to pain control. Enhancement of descending pain inhibition and/or inhibition of descending pain facilitation may be important for improvement of neuropathic pain.30 Obata et al.5 reported that activation of both the noradrenergic and serotonergic systems is more important than activation of either one in terms of inhibiting allodynia in L5/L6-SNL rats. These reports indicate that interaction of serotonergic and noradrenergic descending pain control may be very important for improvement of neuropathic pain. It is important that Neurotropin could activate not only the serotonergic system but also the noradrenergic system.

In conclusion, it is clear that Neurotropin inhibits tactile allodynia in L5-SNL rats, as indicated by Neurotropin's mechanism of action in the central nervous system (Fig. 6). Neurotropin may activate descending pain inhibitory systems, such as the noradrenergic and serotonergic systems at supraspinal sites, nucleus raphe magnus, locus coeruleus, periaqueductal gray, hypothalamus and so on, thereby probably increasing the release of 5-HT and noradrenaline in the spinal dorsal horn. In addition, activation of the inhibitory GABAergic system via 5-HT3 receptors at a spinal site may also be involved in the antiallodynic action of Neurotropin. It is significant that the antiallodynic effect of Neurotropin is mediated by activation of the noradrenergic, serotonergic and GABAergic systems. These results suggest that Neurotropin may be useful for the treatment of neuropathic pain.


Figure 658
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  		Figure 6. Schematic representation of the anitiallodynic mechanism of Neurotropin. In L5-spinal nerve ligation (SNL) rats, {alpha}2 adrenoceptor, 5-HT2A receptor and 5-HT3 receptor in spinal cord are involved in the regulation of allodynia. In addition, activation of the inhibitory {gamma}-aminobutyric acid (GABA)ergic system via 5-HT3 receptors inhibits tactile allodynia in L5-SNL rats. Neurotropin may activate descending inhibitory noradrenergic and serotonergic systems at supraspinal sites, thereby probably increase the release of serotonin and noradrenaline in the spinal dorsal horn. In addition, Neurotropin might activate the inhibitory GABAergic system via 5-HT3 receptors at a spinal site.

 

Footnotes

Accepted for publication April 22, 2008.

Address of correspondence and reprint requests to Ryohei Okazaki, Department of Development Research, Institute of Bio-active Science, Nippon Zoki Pharmaceutical Co., Ltd., 442-1, Kinashi, Kato, Hyogo, 673-1461, Japan. Address e-mail to r-okazaki{at}nippon-zoki.co.jp.

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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2008 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press