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ANALGESIA

The Effects of Ginkgo Biloba Extract EGb 761 on Mechanical and Cold Allodynia in a Rat Model of Neuropathic Pain

From the Department of Anesthesiology and Pain Medicine, School of Medicine, The Catholic University of Korea, Seoul, Korea.

Address correspondence and reprint requests to Hae Jin Lee, MD, Department of Anesthesiology and Pain Medicine, St. Mary’s Hospital, #62 Youido-dong, Yongdeungpo-gu, Seoul, 150-713, Korea. Address e-mail to lehaji{at}catholic.ac.kr.

Abstract

BACKGROUND: Neuropathic pain is chronic pain that is caused by an injury to the peripheral or central nervous system. The symptoms of neuropathic pain are continuing pain, hyperalgesia, and allodynia. Ginkgo biloba extract is an oriental herbal medicine that has various pharmacological actions. We examined the effect of Ginkgo biloba extract, EGb 761, on the mechanical and cold allodynia in a rat model of neuropathic pain.

METHODS: Male Sprague-Dawley rats were prepared by tightly ligating the left L5 and L6 spinal nerves. All the rats developed mechanical and cold allodynia 7 days after surgery. Fifty neuropathic rats were assigned into five groups for the intraperitoneal administration of drugs. The study was double-blind and the order of the treatments was randomized. Normal saline and EGb 761 (50, 100, 150, and 200 mg/kg) were administered, respectively, to the individual groups. We examined mechanical and cold allodynia at preadministration and at 15, 30, 60, 90, 120, 150, and 180 min after intraperitoneal drug administration. Mechanical allodynia was quantified by measuring the paw withdrawal threshold to stimuli with von Frey filaments of 1.0, 1.4, 2.0, 4.0, 6.0, 8.0, 10.0, 12.0, 15.0, and 26.0 g. Cold allodynia was quantified by measuring the frequency of foot lift with applying 100% acetone. We measured the locomotor function of the neuropathic rats by using the rotarod test to reveal if EGb 761 has side effects, such as sedation or reduced motor coordination.

RESULTS: The control group showed no differences for mechanical and cold allodynia. For the EGb 761 groups, the paw withdrawal thresholds to mechanical stimuli and withdrawal frequencies to cold stimuli were significantly reduced versus the preadministration values and versus the control group. The duration of antiallodynic effects increased in a dose-dependent fashion, and these were maintained for 120 min at the highest dose (P < 0.05). Only at the highest dose (200 mg/kg) did EGb 761 reduce the rotarod performance time.

CONCLUSION: We conclude that Ginkgo biloba extract, EGb 761, attenuates mechanical and cold allodynia in a rat model of neuropathic pain, and it may be useful for the management of neuropathic pain.

Neuropathic pain is intractable pain that is characterized by allodynia, hyperalgesia, and continuing pain. The exact mechanism for the development and maintenance of neuropathic pain has not been elucidated. Neuropathic pain responds poorly to conventional nonsteroidal antiinflammaotry drugs and opioids. At present, anticonvulsants, such as gabapentin and carbamazepine, antidepressants and N-methyl-d-aspartate (NMDA) antagonists, are prescribed for the management of neuropathic pain, but their effects are limited.1,2

Ginkgo biloba extract is an extract from Ginkgo biloba tree leaves. It is known for its beneficial effect on brain functioning3; it increases the walking distance inpatients with intermittent claudication4; it decreases gastrointestinal injury caused by stress5; and it has a protective effect against hepatic injury caused by CCL4 in rats.6 Ginkgo biloba extract is composed of 24% ginkgo flavone glycosides and 6% terpene lactones. The main components of the ginkgo flavone glycosides are quercetin, kaempferol, and isorhamnetin, and those of terpenes are ginkgolides A, B, and C and bilobalide.7 Gingko flavone glycosides are free radical scavengers8 and the ginkgolides are known as potent platelet activating factor antagonists.9

There is a report that Ginkgo biloba extract shows antiinflammatory and analgesic effects in a formalin-induced acute inflammatory pain rat model,10 and it also decreases thermal hyperalgesia in a carrageenan-induced inflammatory pain model.11 Moreover, quercetin decreased the thermal hyperalgesia and cold allodynia in streptozocin-induced diabetic neuropathy.12 Yet, there have been no reports about the effect of Ginkgo biloba extract on the neuropathic pain induced by spinal nerve ligation.

We investigated the effect of Ginkgo biloba extract on the mechanical and cold allodynia in a rat model of neuropathic pain to determine whether Ginkgo biloba extract may be a new treatment option for neuropathic pain diseases.

METHODS

Animals
All the experimental procedures were approved by our institutional animal investigation committee. Male Sprague-Dawley rats weighing 100–150 g each were used. Food and water were provided ad libitum. The rats were housed in groups of 3–4 in plastic cages with soft bedding and they were maintained on a 12:12-h light-dark cycle. The experimental rats were allowed to adjust to their environment for at least 5 days before conducting this experiment.

Spinal Nerve Ligation
The method of Kim and Chung13 was used to produce the neuropathic pain model by ligating the left L5 and L6 spinal nerves. After the surgery, the rats were allowed to recover for 7 days before starting the behavioral testing. Those animals that showed a foot withdrawal response to von Frey filaments (Semmes Weinstein von Frey aesthesiometer, Stoelting CO, IL) with an applied bending force of 4 g or less were considered neuropathic, and they were then used in the tests. The rats that exhibited motor deficiency (such as paw dragging or limping) or those which failed to exhibit subsequent mechanical allodynia were excluded from any further testing.

Drug Administration
Fifty neuropathic rats were randomly divided into five groups (n = 10 in each group) before the intraperitoneal administration of drugs. The intraperitoneal injections were performed under enflurane (2.0 vol%) anesthesia. The control group received 0.9% normal saline 10 mL/kg (the NS group). There were four experimental groups (the GB 50, GB 100, GB 150, and GB 200 groups) and different doses of EGb 761(Tanamin®, Yuyu, Seoul, Korea) were administered to each group: 50, 100, 150, and 200 mg/kg, respectively.

Behavioral Tests
To avoid circadian rhythm errors, all the behavioral tests were conducted at fixed times (1:00–6:00 pm) by the same person who was unaware of which injected solution had been administered and which dose was used. After intraperitoneal injection, the rats were placed on a metal mesh covered with a plastic dome (8 x 8 x 18 cm) for the assessment of mechanical and cold allodynia. Mechanical and cold allodynia were assessed before intraperitoneal injection and also at 15, 30, 60, 90, 120, 150, and 180 min after injection. The dosage regimen and observation times were based on the preliminary experimental results and our previous experience.

The thresholds for mechanical allodynia were measured with a series of von Frey filaments (1.0, 1.4, 2.0, 4.0, 6.0, 8.0, 10.0, 12.0, 15.0, and 26.0 g). The third metatarsal bone area of the left hindpaw was stimulated with von Frey filaments at 3–4 s intervals with using the up-down method.14 The minimal pressure level (in grams [g]) that initiated a response was recorded. If the strongest hair did not elicit a response, the threshold was recorded as 26.0 g.

Cold allodynia was measured as the number of foot withdrawal responses after application of cold stimuli to the plantar surface of the paw.15 At the preliminary tests, the normal rat did not respond to acetone application, but the neuropathic rat showed pain responses, such as foot biting. The testing was repeated five times with an interval of approximately 3–5 min between each test. The response frequency to acetone was expressed as a percent response frequency ([number of paw withdrawals/number of trials] x 100). Locomotor function changes in the neuropathic rats were evaluated by rotarod testing (Acceler rota-rod for rats 7750; Ugo Basile, Comerio-Varese, Italy). The neuropathic rats were acclimatized to the revolving drums, and they were habituated to handling to ameliorate any stress during testing. The rats were given three training trials on the revolving drums (10–15 rpm) for 2 days before the actual day of testing. The rats that were able to remain on the revolving drum for a minimum of 150 s were selected for drug testing. The mean of three training runs served as a control performance time. The rotarod performance time was measured at 15, 30, 60, 90, 120, and 150 min after intraperitoneal injection. Each test was performed three times at 5-min intervals, and the mean values were compared.

Statistical Analysis
The results were expressed as the mean ± sd. Statistical analysis was performed with Sigma-Stat (version 2.03; SPSS, Chicago, IL). The percent withdrawal frequency and rotaroad performance time were assessed using repeated measure of analysis of variance, followed by post hoc Dunnet’s tests for multiple comparisons. A P value of <0.05 was considered significant.

RESULTS

Mechanical Allodynia
After spinal nerve ligation, all the rats developed mechanical allodynia with a foot withdrawal threshold <1.5 g. In the control group, the withdrawal thresholds were 1.0 ± 0.1, 2.9 ± 1.0, 1.9 ± 1.0, 1.8 ± 1.0, 1.4 ± 0.6, 1.5 ± 1.1, 1.3 ± 0.6, and 1.1 ± 0.1 g at before normal saline administration and at 15, 30, 60, 90, 120, 150, and 180 min after normal saline administration, respectively. After administering 50 mg/kg of EGb 761, the withdrawal threshold increased for 120 min after drug administration as compared with preadministration, but there was no significant difference compared with the control group. The withdrawal threshold increased from 15 to 90 min for 100 mg/kg and from 15 to 120 min for 150 and 200 mg/kg, compared with the control group (Fig. 1).

View larger version (13K): [in this window] [in a new window]   Figure 1. Time course of the paw withdrawal threshold to mechanical stimuli applied to the plantar surface of the affected left paw with von Frey filaments in the neuropathic pain model of rats. The withdrawal threshold was measured before (pre) and after intraperitoneal administration of saline (NS), EGb 761 50 mg/kg (GB 50), EGb 761 100 mg/kg (GB 100), EGb 761 150 mg/kg (GB 150), and EGb 761 200 mg/kg (GB 200). The results are expressed as the mean ± sd (n = 10 in each group). *P < 0.05 versus the saline group by repeated measures analysis of variance (ANOVA) and Dunnett’s test. P < 0.05 versus the preadministration time by repeated measures ANOVA and Dunnett’s test.

Cold Allodynia
Before drug administration, all the rats showed a withdrawal frequency from 90% to 100% when acetone was applied, without any difference among the groups. Administration of EGb 761 reduced the withdrawal frequency to acetone application from 15 to 30 min for 50 mg/kg, from 15 to 60 min for 100 mg/kg and 150 mg/kg, and from 15 to 120 min for 200 mg/kg (Fig. 2).

View larger version (16K): [in this window] [in a new window]   Figure 2. Time course of the paw withdrawal frequency to cold stimuli with 100% acetone. Acetone was applied to the plantar surface of the affected hindpaw in the neuropathic pain model of rats. *P < 0.05 versus the saline group by repeated measures analysis of variance (ANOVA) and Dunnett’s test. P < 0.05 versus the preadministration time by repeated measures ANOVA and Dunnett’s test.

Rotarod Performance
Compared with the saline-treated rats, treatment with 50–150 mg/kg of EGb 761 did not significantly decrease the rats’ competency for performing the rotarod test. However, at 200 mg/kg of EGb 761, the rotarod performance was decreased to 97.5 ± 9.0, 130.0 ± 13.4, 135.3 ± 15.0, 138. 9 ± 11.7, 141.1 ± 14.4, and 150 ± 0.0 at 15, 30, 60, 90, 120, and 150 min, respectively (Fig. 3).

View larger version (28K): [in this window] [in a new window]   Figure 3. Effect of the intraperitoneal administration of EGb 761 on the rotarod performance time. The rotarod performance time was measured before (pre) and at 15, 30, 60, 90, 120, and 150 min after drug administration. The rotarod performance time was not reduced by administration of normal saline or with administering 50, 100, and 150 mg/kg of EGb 761. The rotarod performance time was decreased at 15, 30, 60, 90, and 120 min after administration of 200 mg/kg EGb 761. The results are expressed as the mean ± sd (n = 10 in each group). *P < 0.05 versus the saline group by repeated measures ANOVA and Dunnett’s test. P < 0.05 versus the preadministration time by repeated measures ANOVA and Dunnett’s test.

DISCUSSION

This study demonstrates that intraperitoneal administration of Ginkgo biloba extract is associated with a dose-dependent antiallodynic effect in a rat neuropathic model.

Abdel-Salam et al.10 reported that Ginkgo biloba extract (25, 50, or 100 mg/kg) decreased in a dose-dependent manner the capsaicin-induced hindpaw licking time. It was effective at the highest dose (100 mg/kg) for tail-electric stimulation, but neither hyperalgesia nor allodynia was assessed in that study. Biddlestone et al.11 reported that oral administration of EGb 761 dose-dependently inhibited thermal hyperalgesia in the carrageenan and hindpaw incision model, but it had had no effect on carrageenan-induced or incision-induced mechanical allodynia, in contrast to our study. As compared with Biddlestone et al.’s experiment,11 we used the spinal nerve ligation model and we administered the drug intraperitoneally. Anjaneyulu and Chopra12 reported that quercetin, a component of Ginkgo biloba extract, reduced thermal hyperalgesia and cold allodynia in streptozocin-induced diabetic neuropathic rats, but they did not assess mechanical allodynia. We used EGb 761, a highly standardized extract of Ginkgo biloba, to perform spinal nerve ligation, and we evaluated the mechanical and cold allodynia but did not assess thermal hyperalgesia.

It is not clear how EGb 761 exerts an antiallodynic effect on neuropathic pain.

EGb 761 is composed of 24% flavone glycosides and 6% terpene lactones. The main components of flavone glycosides are quercetin, kaempferol, and isorhamnetin, and the main components of the terpene lactones are ginkgolides A, B, and C and bilobalide.7 Quercetin is reported to possess an antinociceptive effect on the tail flick test and the hotplate test, and it has a synergistic effect with the -2 agonist clonidine. The antinociception effect of quercetin alone or the quercetin/clonidine combination suggests that the analgesic effect of quercetin may be via modulation of the adrenergic pathway.16 In addition, quercetin has an antioxidant effect8 and attenuates NMDA-induced neurotoxicity.17 Kaempferol showed an antinociceptive effect on a benzoquinone-induced writhing test and reduced carrageenan-induced hindpaw edema, indicating that it has an antiinflammatory effect.18 Kaempferol also shows an antioxidant effect at certain concentrations, but it is a prooxidant above an optimum antioxidant concentration.8 In addition, kaempferol was shown to protect against NMDA-induced neuronal toxicity in vitro in rat cortical cultures.19 The antinociceptive or antiinflammatory effects of isorhamnetin have not still been found, but isorhamnetin was reported to have an antioxidant effect.20 Ginkgolide A suppresses the production of nitric oxide (NO),21 interleukin-1, and tumor necrosis factor (TNF)-,22 and it protects against NO-induced neuronal toxicity.23 However, there are no reports of it having any analgesic effect. Ginkgolide B has antiinflammatory effects by suppressing the chemotaxis induced by platelet activating factor24 and the reduced interleukin-1, TNF- and NO like ginkgolide A.22 Ginkgolide C also acts as a platelet activating factor antagonist.25 Bilobalide protects against NO-induced neurotoxicity26 and suppresses NMDA-induced phospholipase A2activation and phospholipid breakdown.27

A number of receptors and neurotransmitters in the central and peripheral nervous systems are involved in the development and maintenance of neuropathic pain. The NMDA receptor plays a very important role in the development and maintenance of neuropathic pain, with increased phosphorylation of NMDA receptors in the spinal dorsal horn and nucleus gracilis in rats that underwent spinal nerve ligation.28 Reactive oxygen species are involved in the development of neuropathic pain, as evidenced by the attenuation of thermal hyperalgesia by the systemic administration of antioxidants in the neuropathic rat model,29,30 and the reduction of mechanical allodynia by phenyl-N-tert butylnitrone, a reactive oxygen species scavenger, in rats that underwent spinal nerve ligation.31 TNF receptors are increased in the spinal dorsal root ganglion after spinal nerve ligation, and hyperalgesia was decreased by TNF receptor antagonist; this indicates that TNF- plays an important role in the development and maintenance of neuropathic pain.32 In addition, after spinal nerve ligation, NO synthase was increased in the lumbar spinal cord, suggesting that NO is important in neuropathic pain.33 Platelet activating factor acts as a potent inflammatory mediator, and intrathecal administration of platelet activating factor induces tactile allodynia and thermal hyperalgesia, and this is blocked by NMDA receptor antagonist and NO synthase inhibitor.34

Therefore, the beneficial effect of Ginkgo biloba extract on neuropathic pain in the present study is likely due to a combination of an antioxidant effect, an antiinflammatory effect, a platelet activating factor antagonist effect and a protective effect against NMDA-induced neurotoxicity.

The side effects of Ginkgo biloba extract are tinnitus, dizziness,35 gastrointestinal disturbance, headache,36 motor disturbance, and sedation.37 Side effects are clinically important because they restrict continuous treatment in chronic pain patients. Moreover, if the neuropathic rats in our study were sedated by EGb 761, the effect on mechanical and cold allodynia would have been exaggerated. We therefore performed the rotarod test to evaluate the effect of EGb 761 on motor coordination to exclude the sedation-induced antiallodynic effect, and we investigated the side effects, such as sedation or motor disturbance, by administering different concentrations of EGb 761. Only the highest dosed (200 mg/kg) rats showed a reduction of rotarod performance from 15 to 120 min. Because the rotarod performance was decreased only at the highest dose, the antiallodynic effect of EGb 761 50–150 mg/kg is not thought to be due to the sedative effect of EGb 761.

In conclusion, intraperitoneal administration of Ginkgo biloba extract, EGb 761, attenuated the mechanical and cold allodynia displayed by spinal nerve-ligated rats, but sedation and motor disturbance were observed at the highest doses. This suggests that Ginkgo biloba extract, EGb 761 may exert an analgesic effect in neuropathic pain patients. However, side effects, such as sedation or motor disturbance, must be considered at the highest doses.

Footnotes

Accepted for publication December 8, 2008.

REFERENCES

1. McCleane G. Pharmacological management of neuropathic pain. CNS Drugs 2003;17:1031–43[Web of Science][Medline]
2. Colombo B, Annovazzi PO, Comi G. Medications for neuropathic pain: current trends. Neurol Sci 2006;27:S183–S189[Web of Science][Medline]
3. Ahlemeyer B, Krieglstein J. Neuroprotective effects of Ginkgo biloba extract. Cell Mol Life Sci 2003;60:1779–92[Web of Science][Medline]
4. Pittler MH, Ernst E. Ginkgo biloba extract for the treatment of intermittent claudication: a meta-analysis of randomized trials. Am J Med 2000;108:276–81[Web of Science][Medline]
5. Wang Q, Zhao WZ, Ma CG. Protective effects of Ginkgo biloba extract on gastric mucosa. Acta Pharmacol Sin 2000;21:1153–6[Web of Science][Medline]
6. He SX, Luo JY, Wang YP, Wang YL, Fu H, Xu JL, Zhao G, Liu EQ. Effects of extract from Ginkgo biloba on carbon tetrachloride-induced liver injury in rats. World J Gastroenterol 2006;12:3924–8[Web of Science][Medline]
7. EGb 761: ginkgo biloba extract, Ginkor. Drugs R D 2003;4:188–93[Medline]
8. Hibatallah J, Carduner C, Poelman MC. In-vivo and in-vitro assessment of the free-radical-scavenger activity of Ginkgo flavone glycosides at high concentration. J Pharm Pharmacol 1999;51:1435–40[Web of Science][Medline]
9. Stromgaard K, Saito DR, Shindou H, Ishii S, Shimizu T, Nakanishi K. Ginkgolide derivatives for photolabeling studies: preparation and pharmacological evaluation. J Med Chem 2002;45:4038–46[Web of Science][Medline]
10. Abdel-Salam OM, Baiuomy AR, El-batran S, Arbid MS. Evaluation of the anti-inflammatory, anti-nociceptive and gastric effects of Ginkgo biloba in the rat. Pharmacol Res 2004;49:133–42[Web of Science][Medline]
11. Biddlestone L, Corbett AD, Dolan S. Oral administration of Ginkgo biloba extract, EGb-761 inhibits thermal hyperalgesia in rodent models of inflammatory and post-surgical pain. Br J Pharmacol 2007;151:285–91[Web of Science][Medline]
12. Anjaneyulu M, Chopra K. Quercetin attenuates thermal hyperalgesia and cold allodynia in STZ-induced diabetic rats. Indian J Exp Biol 2004;42:766–9[Medline]
13. Kim SH, Chung JM. An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 1992;50:355–63[Web of Science][Medline]
14. Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL. Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 1994;53:55–63[Web of Science][Medline]
15. Choi Y, Yoon YW, Na HS, Kim SH, Chung JM. Behavioral signs of ongoing pain and cold allodynia in a rat model of neuropathic pain. Pain 1994;59:369–76[Web of Science][Medline]
16. Kaur R, Singh D, Chopra K. Participation of alpha2 receptors in the antinociceptive activity of quercetin. J Med Food 2005;8:529–32[Web of Science][Medline]
17. Ha HJ, Kwon YS, Park SM, Shin T, Park JH, Kim HC, Kwon MS, Wie MB. Quercetin attenuates oxygen-glucose deprivation- and excitotoxin-induced neurotoxicity in primary cortical cell cultures. Biol Pharm Bull 2003;26:544–6[Web of Science][Medline]
18. Toker G, Kupeli E, Memisoglu M, Yesilada E. Flavonoids with antinociceptive and anti-inflammatory activities from the leaves of Tilia argentea (silver linden). J Ethnopharmacol 2004;95:393–7[Web of Science][Medline]
19. Sloley BD, Urichuk LJ, Morley P, Durkin J, Shan JJ, Pang PK, Coutts RT. Identification of kaempferol as a monoamine oxidase inhibitor and potential Neuroprotectant in extracts of Ginkgo biloba leaves. J Pharm Pharmacol 2000;52:451–9[Web of Science][Medline]
20. Bao M, Lou Y. Isorhamnetin prevent endothelial cell injuries from oxidized LDL via activation of p38MAPK. Eur J Pharmacol 2006;547:22–30[Web of Science][Medline]
21. Cheung F, Siow YL, O K. Inhibition by ginkgolides and bilobalide of the production of nitric oxide in macrophages (THP-1) but not in endothelial cells (HUVEC). Biochem Pharmacol 2001;61:503–10[Web of Science][Medline]
22. Du ZY, Li XY. Effects of ginkgolides on interleukin-1, tumor necrosis factor-alpha and nitric oxide production by rat microglia stimulated with lipopolysaccharides in vitro. Arzneimittelforschung 1998;48:1126–30[Medline]
23. Zhao HW, Li XY. Ginkgolide A, B, and huperzine A inhibit nitric oxide-induced neurotoxicity. Int Immunopharmacol 2002;2:1551–6[Web of Science][Medline]
24. Smith PF, Maclennan K, Darlington CL. The neuroprotective properties of the Ginkgo biloba leaf: a review of the possible relationship to platelet-activating factor (PAF). J Ethnopharmacol 1996;50:131–9[Web of Science][Medline]
25. Vogensen SB, Stromgaard K, Shindou H, Jaracz S, Suehiro M, Ishii S, Shimizu T, Nakanishi K. Preparation of 7-substituted ginkgolide derivatives: potent platelet activating factor (PAF) receptor antagonists. J Med Chem 2003;46:601–8[Web of Science][Medline]
26. Song W, Guan HJ, Zhu XZ, Chen ZL, Yin ML, Cheng XF. Protective effect of bilobalide against nitric oxide-induced neurotoxicity in PC12 cells. Acta Pharmacol Sin 2000;21:415–20[Web of Science][Medline]
27. Weichel O, Hilgert M, Chatterjee SS, Lehr M, Klein J. Bilobalide, a constituent of Ginkgo biloba, inhibits NMDA-induced phospholipase A2 activation and phospholipid breakdown in rat hippocampus. Naunyn Schmiedebergs Arch Pharmacol 1999;360:609–15[Web of Science][Medline]
28. Gao X, Kim HK, Chung JM, Chung K. Enhancement of NMDA receptor phosphorylation of the spinal dorsal horn and nucleus gracilis neurons in neuropathic rats. Pain 2005;116:62–72[Web of Science][Medline]
29. Tal M. A novel antioxidant alleviates heat hyperalgesia in rats with an experimental painful peripheral neuropathy. Neuroreport 1996;7:1382–4[Web of Science][Medline]
30. Khalil Z, Liu T, Helme RD. Free radicals contribute to the reduction in peripheral vascular responses and the maintenance of thermal hyperalgesia in rats with chronic constriction injury. Pain 1999;79:31–7[Web of Science][Medline]
31. Kim HK, Park SK, Zhou JL, Taglialatela G, Chung K, Coggeshall RE, Chung JM. Reactive oxygen species (ROS) play an important role in a rat model of neuropathic pain. Pain 2004;111:116–24[Web of Science][Medline]
32. Schafers M, Sorkin LS, Geis C, Shubayev VI. Spinal nerve ligation induces transient upregulation of tumor necrosis factor receptors 1 and 2 in injured and adjacent uninjured dorsal root ganglia in the rat. Neurosci Lett 2003;347:179–82[Web of Science][Medline]
33. O’Rielly DD, Loomis CW. Increased expression of cyclooxygenase and nitric oxide isoforms, and exaggerated sensitivity to prostaglandin E2, in the rat lumbar spinal cord 3 days after L5–L6 spinal nerve ligation. Anesthesiology 2006;104:328–37[Web of Science][Medline]
34. Morita K, Morioka N, Abdin J, Kitayama S, Nakata Y, Dohi T. Development of tactile allodynia and thermal hyperalgesia by intrathecally administered platelet-activating factor in mice. Pain 2004;111:351–9[Web of Science][Medline]
35. Soholm B. Clinical improvement of memory and other cognitive functions by Ginkgo biloba: review of relevant literature. Adv Ther 1998;15:54–65[Web of Science][Medline]
36. Cohen AJ, Bartlik B. Ginkgo biloba for antidepressant-induced sexual dysfunction. J Sex Marital Ther 1998;24:139–43[Web of Science][Medline]
37. Kuribara H, Weintraub ST, Yoshihama T, Maruyama Y. An anxiolytic-like effect of Ginkgo biloba extract and its constituent, ginkgolide-A, in mice. J Nat Prod 2003;66:1333–7[Medline]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Kim, Y. S. Articles by Lee, H. J. PubMed PubMed Citation Articles by Kim, Y. S. Articles by Lee, H. J. Related Collections Mechanisms Pain Mechanisms Preclinical Pharmacology Pain Pharmacology