St. John s Wort Potentiates anti-nociceptive Effects of Morphine in Mice Models of Neuropathic Pain

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1 Pain Medicine 17; 18: doi: 1.193/pm/pnw241 NEUROPATHIC PAIN SECTION Original Research Article St. John s Wort Potentiates anti-nociceptive Effects of Morphine in Mice Models of Neuropathic Pain Maria Domenica Sanna, Carla Ghelardini, and Nicoletta Galeotti Section of Pharmacology and Toxicology, Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy Correspondence to: Maria Domenica Sanna, Department of NEUROFARBA, Viale G. Pieraccini 6, I-5139 Florence, Italy. Tel: þ ; maria.sanna@unifi.it. Funding sources: This work was supported by grants from Universita degli Studi di Firenze. Conflicts of interest: There are no conflicts of interest to report. Abstract Objective. In this study, we compared the efficacy of a combination of PKC-blocker St. John s Wort (SJW) and morphine in mice with painful antiretroviral (2,3-dideoxycitidine [ddc]) and chemotherapic (oxaliplatin) neuropathy. Methods. Morphine (1 and 5 mg/kg i.p.), SJW (1 and 5 mg/kg o.s.), or their combination was administered by systemic injection, and antinociception was determined by using the hot and cold plate tests. Results. Here we demonstrate the ability of SJW to relieve neuropathic pain in mice neuropathic models and a potentiation of morphine antinociception in thermal pain. The potentiating effect shown by SJW was not secondary to its antinociceptive activity as the increase of the morphine antinociceptive effect was produced at a dose (1mg/kg o.s.) devoid of any capability to modulate the pain threshold in neuropathic pain mice. Further examinations of the SJW main components revealed that hypericin was responsible for the potentiating properties whereas flavonoids were ineffective. Conclusions. These results show that SJW has notable antinociceptive activity for both neuropathic pain models and could be used in neuropathic pain relief alone or in combination with morphine. These data support the utility of combination SJW/opioid therapy in pain management for antinociceptive efficacy by enhancing opioid analgesia. Key Words. Morphine; St. John s Wort; Neuropathic Pain; Hypericin; PKCc Introduction Neuropathic pain is defined as pain arising as a direct consequence of a lesion or disease affecting the somatosensory system [1]. Peripheral neuropathic pain is frequently observed in patients with cancer, AIDS, longstanding diabetes, traumatic injury, and as side effect of many chemotherapeutic and antiretroviral drugs [2,3]. Under the International Association for the Study of Pain (IASP), the Neuropathic Pain Special Interest Group (NeuPSIG) has developed evidence-based guidelines for the pharmacologic management of neuropathic pain that take into account efficacy, adverse effects, impact on health-related quality of life, convenience, and costs. Antidepressants, calcium channel a 2 -d ligands, and topical lidocaine are recommended as a first line of neuropathic pain treatment. The use of opioids such as morphine to treat neuropathic pain is controversial due to the mixed results of clinical studies and is considered to be a second or third tier of treatment at best [4 7]. Preclinical evidence indeed supports the observation that the analgesic effects of morphine are greatly diminished in the setting of neuropathic pain and quite often necessitate greater concentrations of morphine to provide pain relief. The guidelines acknowledge that a combination of medications with efficacy for neuropathic pain may provide greater analgesia than use of individual medications as monotherapy, although such combination therapy is often associated with increased side effects, inconvenience, risk of drug interactions, and cost. Nevertheless, Downloaded from by guest on 15 November 18 VC 16 American Academy of Pain Medicine. All rights reserved. For permissions, please journals.permissions@oup.com 1334

2 because less than 5% of patients in neuropathic pain trials of efficacious medications typically achieve satisfactory pain relief, many patients in clinical practice require treatment with a combination of medications [8]. Hypericum species (Hypericaceae) are used around the world for their medicinal properties, particularly Hypericum perforatum L. (popularly called St. John s wort [SJW]), for the treatment of several disorders such as skin wounds and gastrointestinal and psychological disorders, among others [9,1]. In recent years, the antidepressant activity of alcoholic extracts prepared from the flowering aerial parts of this plant has been demonstrated in several experimental and clinical studies, and SJW has been used successfully in the treatment of mild to moderate depressive disorders [11,12]. Numerous studies proved that SJW is endowed with many other bioactivities such as anti-inflammatory [13,14] and analgesic effects [15,16]. The antinociceptive property of SJW has been demonstrated in two different models of neuropathic pain and has been shown to be related to the modulation of two different intracellular pathways: the activation of the opioid system mediated by the presence of hyperforin and a protein kinase (PKC) mediated mechanism through the PKC-blocking properties of hypericin [15]. We have been previously demonstrated that protein kinase block acts as analgesic potentiation in morphine analgesia [17,18]. In order to identify adjuvants of morphine analgesia to improve opioid efficacy in the clinical management of neuropathic pain syndromes, the aim of this study was to examine the potentiating effect of SJW dried extract and its active constituents on morphine analgesia in two different animal models of neuropathic pain induced by single administration of zalcitabine (2,3-dideoxycitidine [ddc]), or by the repeated administration of the chemotherapeutic agent oxaliplatin. Methods Animals Male CD (clusters of differentiation)-1 mice (-22 g) from the Harlan Laboratories (Bresso, Italy) breeding farm were used. Mice were randomly assigned to standard cages, with four to five animals per cage. The cages were placed in the experimental room 24 hours before behavioral test for acclimatization. The animals were fed a standard laboratory diet and tap water ad libitum and kept at C with a 12-hour light/dark cycle, lights on at 7 a.m. The experimental protocol was carried out after approval by the Animal Care and Research Ethics Committee of the University of Florence, Italy, under license from the Italian Department of Health and in compliance with the European Communities Council directive of November 24, 1986 (86/69/EEC). All studies involving animals are reported in accordance with the Animals in Research: Reporting In Vivo Experiments (ARRIVE) guidelines for experiments involving animals [19]. Experiments were performed during the light cycle in the experimental room for a total of St. John s Wort Potentiates anti-nociceptive Effects three weeks. Animals were randomly assigned to the treatment groups. In order to reduce as much as possible the number of animals used, sample size criteria with regard to statistical significance were followed as set out in Feinstein []. Animals were investigated by observers kept unaware of the treatment of the animals. Behavioral Testing Animals were habituated to the experimental room and randomly assigned to each treatment group. A total of 1 animals were used in order to have the probability of 86% that the study detects a treatment difference at a two-sided.5 significance level. Sample size was calculated by G Power software [21]. Mice were investigated by observers blinded to the treatment of the animals. Animals were divided into the following groups: Group 1: ddc administered on day 1, and behavioral tests detected from day 1 to day 1. Group 2: Oxaliplatin administered for five consecutive days per week for three consecutive weeks and behavioral test detected from day 1 to day 28. Group 3: Morphine (1 and 5 mg/kg i.p.) administered at day 7 after ddc treatment and at 21 day after oxaliplatin treatment. Behavioral tests were detected from 15 to 6 minutes. Group 4: SJW (1 and 5 mg/kg i.p.) administered at day 7 after ddc treatment and at 21 day after oxaliplatin treatment. Behavioral tests were detected from 15 to 6 minutes. Hot Plate Test The hot plate test was performed with hot plate apparatus (Ugo Basile Biological Research Apparatus, Varese, Italy), which was set thermostatically at 46 C, 48 C, 5 C, or 52.5 C 6.1 C. Reaction times (s) were measured with a stopwatch. The endpoint used was the licking of the fore or hind paws. Mice were removed from the hot plate immediately after the first response. Data was recorded as raw latencies in seconds. Cold Plate Test Mice were placed on the ice surface maintained at 4 C. The time between placements of a mouse on the plate and licking of a paw or jumping was measured with a stopwatch. Mice were removed from the cold plate immediately after the first response. Data was recorded as raw latencies in seconds. Drug Administration Oxaliplatin (Sequoia Research Product Ltd, USA) was dissolved in a 5% glucose solution at a concentration of Downloaded from by guest on 15 November

3 Domenica Sanna et al. 2.4 mg kg 1. Oxaliplatin was administered intraperitoneally (i.p.) for five consecutive days per week for three consecutive weeks according to a previous established protocol [22]. The control group received a 5% glucose solution. 2,3-dideoxycitidine (Sigma, Milan, Italy) solution was freshly prepared in saline (.9% NaCl) on the day of the experiment. ddc- and -treated groups were given a one-time intraperitoneal injection of ddc ( mg/ kg) or saline, respectively [23]. Morphine hydrochloride (SALARS, Como, Italy) was dissolved in isotonic (NaCl.9%). Morphine and -treated groups were given a one time i.p. (1 and 5 mg/kg), and animals were tested 15, 3, and 45 minutes after the administration. The SJW components hypericin, hyperoside, and quercetin (Sigma, Milan, Italy) were orally administered 9 minutes before the test. The doses of hypericin (.1 mg/kg), quercetin (.415 mg/kg), and hyperoside (.3175 mg/kg) correspond to the amount of each component present in a 5 mg/kg preparation of SJW dried extract (Table 1) [15]. Statistical Analysis GraphPad Software (LaJolla, CA) was used to determine the statistical significance. Results were expressed as mean 6 s.e.m. When only two groups were compared, the Student s t test was used. Multiple comparisons were evaluated by Tukey s multiple comparison tests after one-way analysis of variance. A P value of.5 was considered to be statistically significant. Table 1 Results Composition of the SJW dried extract, CHL, and MET fractions Effect of ddc and Oxaliplatin on Thermal Nociceptive Threshold To explore possible behavioral changes to cold and hot stimuli, mouse cold and hot plate tests were performed after drug administration. A single administration of the antiretroviral ddc induced a short-term cold allodynia that appeared three days after injection, persisted up to five days, and disappeared on day 7 postinjection (P <.5) (Figure 1A). During the first weeks of oxaliplatin treatment, the reaction times to a cold stimulus were progressively reduced. The hypersensitivity to the cold stimulus reached statistical significance 16 days after the beginning of the treatment (P <.5) (Figure 1B). Conversely, ddc did not induce heat thermal hyperalgesia at four different temperatures tested (from 46 Cto 52.5 C) (Figure 1, E and F). We found instead that repeated administration of oxaliplatin reduced the thermal nociceptive threshold at every temperature tested (46 C, 48 C, 5 C: P <.1; 52.5 C: P <.5) (Figure 1C). Time course experiments performed at 46 C showed that, starting 14 days after the beginning of the treatment, a statistically significant heat hyperalgesia was produced (14, 16, 21 days: P <.1; 18, 23 days: P <.5) (Figure 1D). Combination of Morphine and SJW Extract Reverses ddc-induced Cold Allodynia at Day 7 It is known that administration of morphine reverses mechanical hypersensitivity by ddc [24]. Here, we Content % (mg/1 mg) Constituent SJW CHL MET Flavonoids Rutin 4.28 Hyperoside 6.35 Isoquercitrin.61 Rutin, hyperoside, isoquercitrin n.d Quercitrin.65 n.d..69 Quercetin.83 n.d..42 I3,II8-biapigenin Total flavonoids Phloroglucinols Oxihyperforin 1.16 n.d. Furohyperforin 1.21 n.d. Hyperforin n.d. Adhyperforin 1.34 n.d. Total phloroglucinols 4.23 Naphtodianthrones Pseudohypericin.4.11 Hypericin.1. Total naphtodianthrones.32 Downloaded from by guest on 15 November 18 The content of each constituent is expressed as percentage (mg/1 mg). CHL ¼ chloroform fraction; MET ¼ methanol fraction; SJW ¼ St. John s Wort. 1336

4 St. John s Wort Potentiates anti-nociceptive Effects A C E saline ddc before days after ddc treatment confirmed the analgesic effect of morphine on ddcinduced cold allodynia at the effective dose of 5 mg/kg i.p. (P <.5) (Figure 2A). To first determine whether SJW extract alone is effective for ddc-induced tactile allodynia, we administered SJW 1 and 5 mg/kg o.s. to ddc mice at day 7. The dose of 1 mg/kg was devoid of any effect, while the higher dose reversed thermal allodynia, with an effect lasting 3 minutes (P <.5) (Figure 2B). The drug combination study revealed that there was increased efficacy with the combination pharmacotherapy of 5 mg/kg morphine and 1 mg/kg SJW (P <.5) (Figure 2D). Conversely, no effect has been C ddc OXA B D 5 saline OXA 3 1 F pretest observed following co-administration of 1 mg/kg of both drugs (Figure 2C). Effect of Combination of Morphine and SJW Extract on Oxaliplatin-Induced Cold Allodynia The dose response effect of morphine and SJW on oxaliplatin-induced cold allodynia was determined at 21 days. Systemic administration of low-dose morphine (1 mg/kg i.p.) had no effect on cold allodynia. In contrast, i.p. injection of morphine at 5 mg/kg significantly increased reaction time 15 minutes after injection days of treatment 15 before days of treatment 15 C before days after ddc treatment OXA ddc Figure 1 Induction of thermal hypersensitivity by 2,3-dideoxycitidine (ddc) and oxaliplatin administration. (A and B) Time course of cold allodynia by ddc and oxaliplatin treament in the mouse cold plate test. (C and E) Behavioral response in the hot plate test with different plate temperatures. (D and F) Time course of thermal hyperalgesia detected at 46 C. Hypersensitivity to a thermal stimulus was restored at 28 day (D). P <.5 and P <.1 in comparison with saline-treated animals. ddc ¼ 2,3-dideoxycitidine; OXA ¼ oxaliplatin. Downloaded from by guest on 15 November

5 Domenica Sanna et al. A C pretest min after admin pretest ddc + morph1 saline ddc + saline ddc + morph 1 ddc + morph 5 min ddc + morph1 + SJW1 (P <.1) (Figure 3A). Otherwise a single oral administration of SJW dose-dependently reversed cold allodynia. The dose of 1 mg/kg was devoid of any effect, while at 5 mg/kg SJW significantly increased the mice s reaction time (P <.1) (Figure 3B). Additional analysis revealed that there was increased efficacy with the combination pharmacotherapy of 5 mg/kg morphine and 1 mg/kg SJW (P <.5) (Figure 3D), without any effect following co-administration of 1 mg/kg of both drugs (Figure 3C). Anti-Hyperalgesic Effect of Morphine in Combination with SJW Extract in Oxaliplatin-Induced Neuropathy In the hot plate test, obtained data clearly demonstrated a significant decrease in the thermal pain threshold of oxaliplatin-treated mice, indicating the occurrence of hyperalgesia. A single administration of morphine reversed thermal hyperalgesia in oxaliplatin-induced B D pretest saline ddc + saline ddc + SJW 1 ddc + SJW 5 neuropathic pain. The antihyperalgesic effect appeared at the dose of 1 mg/kg and significantly increased at concentrations higher than 5 mg/kg. Co-administration of SJW at the inactive dose (1 mg/kg) enhanced thermal antinociception induced by morphine at antinociceptive doses of 1 mg/kg and 5 mg/kg (P <.5, P <.1) (Figure 4A). Time course experiments showed that the antihyperalgesic effects exerted at two different doses of morphine co-administered with SJW did not share the same profile: The morphine dose of 1 mg/kg became statistically significant 3 minutes after administration and persisted up to 6 minutes only in the presence of SJW. Conversely, at the dose of 5 mg/kg, the antihyperalgesic effect became significant at 15 minutes and disappeared at 3 minutes. The coinjection of morphine with SJW potentiated morphine antinociceptive activity up to 6 minutes, showing a long-lasting effect (P <.5, P <.1, P <.1) (Figure 4B). min after admin pretest ddc + morph5 min ddc + morph5 + SJW1 Figure 2 Antinociceptive activity of morphine and St. John s Wort (SJW) alone and in combination in 2,3-dideoxycitidine-induced cold allodynia. (A and B) Time course effect induced by morphine at inactive dose (1 mg/kg) or at the active dose (5 mg/kg), alone or in combination with SJW (1, 5 mg/kg). (C and D) Time course of morphine (1, 5 mg/kg) with inactive dose of SJW (1 mg/kg). P <.5 in comparison with saline-treated animals; P <.5 in comparison with morphine-treated animals. ddc ¼ 2,3-dideoxycitidine; SJW ¼ St. John s Wort. Downloaded from by guest on 15 November

6 St. John s Wort Potentiates anti-nociceptive Effects A 35 B 35 C Antinociceptive profile of St. John s Wort Components in the Potentiation of Morphine Efficacy We investigated the effects produced by some of the main components of the SJW dried extract on morphine antinociception in ddc (P <.5) (Figure 5A) and ddcinduced (P <.5) (Figure 5B) thermal allodynia. In the cold plate test, hypericin showed a potentiating profile in combination with the active morphine dose (5 mg/ Kg). Conversely, other components were devoid of any effect. Discussion OXA OXA + morph 1 pretest min after morphine admin pretest OXA + morph 1 OXA + morph 5 min OXA + morph 1 + SJW1 Opioid analgesics have been found to be efficacious in patients with various types of neuropathic pain, and when compared with tricyclic antidepressants (TCAs) and gabapentin, they have produced at least as much analgesia []. However, owing to concerns over their D pretest min after SJW admin pretest OXA + morph 5 OXA + SJW 5 OXA + SJW 1 long-term safety, they are recommended principally for patients who have not responded to the first-line medications due to multiple adverse effects including incomplete efficacy [26], respiratory depression, and induction of sedation, constipation, nausea, vomiting, addiction, and tolerance [27]. It has also been reported both experimentally and clinically that exposure to morphine can elicit hyperalgesia, a paradoxical pain in regions of the body unrelated to the initial pain complaint, aggravating preexisting pain [28]. Opioids, however, are unique among neuropathic pain medications in having the potential to provide immediate pain relief. For this reason, they can be considered for first-line use in certain clinical situations [29]. Thus, several approaches combining other drugs with opioids to increase their potency, and thus reduce opioid doses, have been proposed [3]. Our findings show that SJW increases the antinociceptive effect of morphine in ddc- and oxaliplatin-induced neuropathic pain. Morphine showed OXA min OXA + morph 5 + SJW1 Figure 3 Antinociceptive activity of morphine and St. John s Wort (SJW) alone and in combination in oxaliplatininduced cold allodynia. (A and B) Time course effect induced by morphine at inactive dose (1 mg/kg) at the active dose (5 mg/kg) alone or in combination with SJW (1, 5 mg/kg). (C and D) Time course of morphine (1, 5 mg/kg) with inactive dose of SJW (1 mg/kg). P <.5 in comparison with saline-treated animals; P <.5 in comparison with morphine-treated animals; ;. OXA ¼ oxaliplatin; SJW ¼ St. John s Wort. Downloaded from by guest on 15 November

7 Domenica Sanna et al. A 8 B before admin before admin anti-allodynic properties in a mouse cold plate test after ddc and oxaliplatin administration, starting from the dose of 5 mg/kg, whereas a lower dose was ineffective. Likewise, antihyperalgesic effect was observed after oxaliplatin administration at the same dose. It has already been demonstrated that blockade of protein kinase C c (PKCc) potentiates morphine analgesia [15]. A series of studies suggest that l-opioid receptor activation induced by morphine treatment may initiate G protein-mediated PKC translocation and activation and 15 min 3 min 45 min 6 min after morph admin 15 min 3 min 45 min 6 min after morph admin morph1 OXA + morph1 OXA + morph1 + SJW1 morph5 OXA + morph5 + S JW1 OXA + morph5 Figure 4 Time course of morphine and St. John s Wort (SJW) alone and in combination in oxaliplatin-induced thermal hyperalgesia. (A and B) Time course of morphine (1, 5 mg/kg) with inactive dose of SJW (1 mg/kg). P <.5, P <.1, and P <.1 in comparison with saline-treated animals; P <.1 in comparison with morphinetreated animals. OXA ¼ oxaliplatin; SJW ¼ St. John s Wort. cause a removal of the Mg 2þ blockade from the NMDA receptor that allows for an increased influx of Ca 2þ [31]. Activation of PKC can modulate l-opioid receptor responsiveness, resulting in desensitization of the l-opioid receptors [32]. Pharmacological studies on Hypericum perforatum, commonly called St. John s Wort, have documented that the compound can act as PKC blocker [33], competitively binding to the regulatory domain of PKC [34]. SJW produces a prolonged and tolerable antinociception in mice in a condition of acute thermal and chemical pain [15] and relieves nerve Downloaded from by guest on 15 November 18 13

8 St. John s Wort Potentiates anti-nociceptive Effects A 6 B 6 SALINE MORPH 1 MORPH 5 ddc injury and chemotherapy-induced neuropathic pain [16]. SJW increases the pain threshold through the selective modulation of two different intracellular pathways: The presence of hypericin is fundamental to induce both thermal and chemical antinociception through the inhibition of the PKC activity, whereas hyperforin selectively produces a thermal opioid antinociception [15]. We found that a single oral administration of SJW reversed thermal hypersensitivity in both models of neuropathic pain, producing an increase of the pain threshold. A potentiation of thermal antinociceptive effect was observed after morphine co-administration with SJW. When SJW inactive dose was co-administered with morphine, the SALINE MORPH 1 MORPH 5 OXA CMC hypericin.2 quercetin.83 hyperoside.6 hypericin+hyperoside CMC hypericin.2 quercetin.83 hyperoside.6 hypericin+hyperoside Figure 5 Effect of oral administration of St. John s Wort (SJW) components on morphine antinociception. In the cold plate test, hypericin (HYP) showed a potentiating profile similar to SJW. Conversely, quercetin (QUER) and hyperoside (HYS) were devoid of any effect. Nociceptive testing was performed 3 minutes after morphine injection. P <.5 in comparison with saline-treated animals; P <.5 in comparison with morphine-treated animals. CMC ¼ ; ddc ¼ 2,3-dideoxycitidine; OXA ¼ oxaliplatin. antinociceptive response to morphine was increased, establishing that SJW could increase the pain threshold through the selective inhibition of the PKC activity and not as result of combination of antinociceptive effects. The main components of the SJW dried extract are phloroglucinols, naphthodiantrones, and flavonoids [16]. The effects produced by these constituents were investigated in order to identify the component responsible for the potentiation of morphine antinociception. The doses used were estimated based on the percentage of each single constituent present in the SJW dried extract dose administered in our experiments. Among the numerous SJW components, only purified hypericin Downloaded from by guest on 15 November

9 Domenica Sanna et al. increased morphine antinociception in both animal models of neuropathic pain. Even though hyperforin showed antinociceptive activity, this effect was not detectable at the low SJW doses investigated [15,16], ruling out any possible involvement of this component in morphinepotentiating activity. As already established [18], we here support and confirm the morphine-potentiating activity of hypericin as a component of SJW that underlies the morphine-antinociceptive potentiation effect by extending this property to neuropathic pain, a pain condition that is difficult to treat and less sensitive to opioid therapy. Enzyme assays performed on rat brains demonstrated that hypericin and pseudohypericin are potent and selective inhibitors of the protein kinase C (PKC) [33,35]. PKC is a family of enzymes involved in numerous important cellular events, including pain modulation. PKC integrates numerous receptor pathways into final effectors that increase excitatory signaling and decrease inhibitory signaling, thus inducing pain. The activation of PKC has been related to the induction of a painful condition, whereas PKC blockers decrease nociception [35]. Increased activation of PKC has been shown in a number of pain models, and a specific upregulation of PKCc was detected in the ddc and oxaliplatin model of neuropathic pain [36,37]. SJW oral administration produced a complete reversal of the phosphorylation of both PKCc in neuropathic rats, suggesting the hypothesis of a PKC-inhibiting mechanism in SJW for antinociception and indicating the isoform c of PKC as potential target for this antinociceptive effect [16]. Furthermore, when SJW was administered with morphine, PKCc phosphorylation was prevented and the thermal antinociceptive response was enhanced, further supporting that PKCc inhibition is directly implicated in SJWinduced morphine potentiation [16]. Collectively these findings suggest that SJW could potentiate morphine antinociception in neuropathic pain mice through inhibition of the PKCc isoform. Recently, interactions of SJW with prescription drugs have been reported. SJW, at the dose recommended for the treatment of mild to moderate depression, is a potent inducer of cytochrome P45 enzymes, resulting in decreased plasma concentration of a number of drugs used in comedication (i.e., digoxin, warfarin, oral contraceptives, etc.) [38]. Recent studies have shown that the degree of enzyme induction by SJW correlates strongly with the amount of hyperforin found in the product [39]. We observed that SJW potentiated morphine antinociception at very low doses containing an amount of hyperforin unable to produce clinically significant interactions [38,39]. In summary, the results of this study demonstrate that oral administration of SJW (at doses that did not produce any toxic effects), in addition to being analgesic when administrated alone, can enhance morphine antinociception in conditions of neuropathic pain. Combining different analgesic drugs for the improvement of morphine efficacy is a recommended strategy, intended to achieve optimal therapeutic effects. These strategies that are commonly used in almost all clinical settings are aimed to facilitate compliance in patients, simplify drug prescription, and decrease side effects, concomitant with increasing their efficacy. In this context, we suggest that SJW should be used as an adjuvant to morphine for the treatment of chronic neuropathic pain, a pain condition that is usually less sensitive to opioid therapy, and as a safer therapeutic perspective for decreasing opioid requirement. References 1 Treede RD, et al. 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