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Kratom Extract Effects, Mitragyna speciosa by Wantana Reanmongkol

Effects of the extracts from Mitragyna speciosa Korth. Leaves on analgesic and behavioral activities in experimental animals.

Wantana Reanmongkol1, Niwat Keawpradub2 and Kitja Sawangjaroen3

Abstract

Reanmongkol, W., Keawpradub, N. and Sawangjaroen, K. Effects of the extracts from Mitragyna speciosa Korth. leaves on analgesic and behavioral activities in experimental animals
Songklanakarin J. Sci. Technol., March 2007, 29(Suppl. 1) : 39-48

The leaves of Mitragyna speciosa Korth. (M. speciosa) were extracted with methanol to give methanol extract. The methanol extract was made in acid and then in alkaline and extracted with chloroform to give alkaloid extract. The effects of the methanol and alkaloid extracts on analgesic activities in hot plate test in mice and tail flick test in rats and behavioral activities in locomotor activity and pentobarbital-induced sleep in mice, were examined. In acute toxicity test, the LD50 values of oral administration of the methanol and alkaloid extracts of M. speciosa leaves in mice were 4.90 g/kg and 173.20 mg/kg, respectively. Oral administrationm (50, 100 and 200 mg/kg) of the methanol extract of M. speciosa leaves significantly prolonged the latency of nociceptive response on hot plate test in mice. The alkaloid extract of M. speciosa also increased the pain response latency at the dose of 20 mg/kg but less potent than those of the methanol extract (100 mg/kg) in mice (comparing 5-10 mg/kg alkaloid extract with corresponding to approximately 200 mg/kg of

ORIGINAL ARTICLE

1Ph.D.(Pharmacology), Assoc. Prof., Department of Clinical Pharmacy, 2Ph.D.(Pharmacognosy), Asst. Prof., Department of Pharmacognosy and Pharmaceutical Botany, 3Ph.D.(Pharmacology), Asst. Prof., Department of Pharmacology, Faculty of Science, Prince of Songkla University, Hat Yai, Songkhla, 90112 Thailand. Corresponding e-mail: wantana.r@psu.ac.th Songklanakarin J. Sci. Technol. Vol.29 (Suppl. 1), March 2007 : Thai Herbs II 40

Effects of the extracts from M. speciosa
Reanmongkol, W., et al.
(methanol extract). The antinociceptive action of either methanol extract (100 mg/kg, p.o.) or alkaloid extract (20 mg/kg, p.o.) of M. speciosa leaves was blocked by naloxone (2 mg/kg, i.p.) in mice. Neither the methanol extract nor the alkaloid extract significantly prolonged latency of nociceptive response on tail flick test in rats. Both of the extracts had no significant change on spontaneous motor activity or pentobarbital-induced sleep in mice, respectively. These results suggest that the methanol and alkaloid extracts of M. speciosa leaves possess the analgesic activity which partly acted at opioid receptors in the supraspinal opioid system. Key words : Mitragyna speciosa leaves, extract, alkaloid, analgesic, behavioral

Mitragyna speciosa (M. speciosa) Korth. (Rubiaceae) is traditionally used in Thailand and known as Kratom. It is often used as a substitute for opium when opium is unavailable, or to moderate opium addiction. In folk medicine, it is often used to treat diarrhea. A small minority of users use kratom to prolong sexual intercourse. Users of kratom tend to be peasants, laborers and farmers who use the plant to overcome the burdens of their hard work. Heavy users may chew kratom between 3-10 times a day while new users may only need a few leaves to obtain the desired effects. Some users find with time they need to increase doses to 10-30 leaves or even more per day (Anon,2006).

Phytochemical studies of the constituents Songklanakarin J. Sci. Technol. Vol.29 (Suppl. 1), March 2007 : Thai Herbs II

Effects of the extracts from M. speciosa 41 Reanmongkol, W., et al. of M. speciosa have been reported. Several 9-methoxy-corynanthe-type monoterpenoid indole alkaloids were isolated from M. speciosa leaves (Takayama et al., 2000). The pharmacological activities of the compounds from M. speciosa leaves have been studied. Mitragynine, a major indole-alkaloid, isolated from M. speciosa leaves, exerts inhibitory effect on electrically stimulated contraction of isolated guinea-pig ileum (Watanabe et al., 1997); on forskolin-stimulated cAMP formation in NG108-15 cells (Tohda et al., 1997) and on 5-methoxy-N, N-dimethyltryptamine-induced headtwitch response in mice (Matsumoto et al., 1997) and has morphine-like action on gastric acid secretion in anesthetized rats and inhibits the vas deferens contraction of guinea-pig elicited by nerve stimulation (Tsuchiya et al., 2002; Matsumoto et al., 2005a). Mitragynine pseudoindoxyl, oxidative derivative of mitragynine possesses opioid agonist, leading to a potent inhibition of electrically stimulated contraction in guinea pig ileum through mu-receptors and in mouse vas deferens through delta-receptors (Yamamoto et al., 1999; Takayama et al., 2002). 7-hydroxymitragynine, a minor alkaloid constituent of M. speciosa, exhibited a potent opioid effect on the electrically-stimulated contraction in guinea-pig ileum and orally active analgesic effect based on activation of mu-opioid receptors (Horie et al., 2005; Takayama, 2004; Matsumoto, 2004; Matsumoto et al., 2005b). 9-hyhroxycorynantheidine, synthesized from mitragynine, has partial agonist properties on mu-opioid receptors in the guinea-pig ileum (Matsumoto et al., 2005c). Although some active compounds, isolated from M. speciosa leaves have been reported to show antinociceptive activity, no evaluation of the analgesic activity of the methanol and alkaloid extracts of M. speciosa leaves has been clearly reported. In the present study, we investigated the potential analgesic activities of the methanol and alkaloid extracts obtained from M. speciosa leaves by using hot plate test in mice and tail flick test in rats. The general behaviors using locomotor activity measurement and pentobarbital-induced sleep in mice were also observed.

Materials and methods
Plant material The fresh leaves of M. speciosa Korth. (Rubiaceae) were collected from natural sources in Songkhla and Satun Provinces during 2004-2005. Authentication of plant material was carried out at the Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Songkhla, Thailand, where the herbarium vouchers (No.
PCOG/MS001-002) have been kept. Preparation of the methanol and alkaloid extracts from the leaves of M. speciosa The fresh leaves of M. speciosa (5 kg) were dried in hot air oven at 45-50OC, powdered and macerated with methanol for 72 hours. Then filtered and evaporated under reduced pressure at 40-45OC to obtain a syrupy mass. The marc was remacerated with methanol twice, filtered and evaporated. All syrupy masses were combined to give crude methanol extract 396 g. An aliquot (300g) of the methanol extract was dissolved in 10% acetic acid, well shaken and left to stand for 24 hours, then filtered to give the acidic filtrate, which was washed with petroleum ether, made alkaline (pH 9) with 25% ammonia solution and extracted with portions of chloroform. The combined chloroform extract was washed with distilled water, dried over anhydrous sodium sulfate and evaporated under reduced pressure at 40OC to give crude alkaloid extract 9.38 g (approximately 0.25% yield of the fresh leaves weight). The methanol and alkaloid extracts were used as the test extract. All doses were expressed in terms of the extract (mg/kg body weight). All animals used in this study were obtained from the Animal House, Faculty of Science, Prince of Songkla University, Hat Yai, Songkhla, Thailand. Male Swiss mice and Wistar rats with the weight ranging from 30-39 g and 150-230 g, respectively, Songklanakarin J. Sci. Technol. Vol.29 (Suppl. 1), March 2007 : Thai Herbs II 42 Effects of the extracts from M. speciosa Reanmongkol, W., et al. were used. The rats were handled for 5-10 min daily for several days before experiments. The animals were housed for at least one week in the laboratory animal room prior to testing. Food and water were given ad libitum unless otherwise specified. All procedures described were reviewed and approved by the Institutional Committee for Ethical Use of Animals, Prince of Songkla University, Thailand. Acute toxicity The 50% lethal dose of the methanol and alkaloid extracts of M. speciosa leaves were estimated by the up-and-down method in mice (Bruce, 1985). Doses were adjusted by a constant multiplicative factor; viz. 1.5, for this experiment. The dose for each successive animal was adjusted up or down depending on the previous outcome. Antinociceptive activity
1. Hot plate test
The hot plate test was carried out according to the method described by Woolfe & MacDonald (1944). Mice were placed on a hot plate maintained at 55OC ± 1OC. Latency of nociceptive response such as licking of a hind limb or jumping was measured. Starting thirty minutes after p.o. administration of the test agents except morphine (15 min after administration), the nociceptive response was measured every 15 min over a 60 min period. Morphine sulfate was injected subcutaneously. The cut-off time was 45 sec. Only the mice that showed nociceptive responses within 15
sec were used for the experiments.
2. Tail flick test
The tail flick test was performed according to a previously described procedure (D'Amour & Smith, 1941). The tail-flick reflex latency (sec) was measured every 15 min for 1 hr period starting 30 min after oral administration of the methanol extract (50, 100, 200 mg/kg), the alkaloid extract (5, 10, 20 mg/kg) of M. speciosa leaves or cosolvent except morphine was subcutaneously administered 15 min (10 mg/kg). The rats whose basal responses were more than 3 sec, were discarded and a cut-off time of 10 sec was maintained throughout the experiment. Antagonism of the antinociceptive activity of the extracts by pre-treatment with naloxone Mice were administered with naloxone at a dose of 2 mg/kg ( i.p.). After 10 min the test agents were given. The assessments were conducted by
hot plate test.
General behaviors
Locomotor activity Locomotor activity was recorded in an activity cage (Basile, Milan) using a modification of the method previously reported (Capasso et al., 1996). The mice were placed in the cage for at least 10 min for acclimatization before oral administration of drugs. Temperature, sound and light conditions were maintained uniform during the course of the experiments. Measurements were performed at 5 min intervals and cumulative counts were recorded for a 1 h period. Experiments were carried out from 9 a.m. to 5 p.m. Pentobarbital-induced sleep Mice were injected with pentobarbital (50 mg/kg) intraperitoneally to induce sleep. The duration of sleep was measured as the period between the loss and the recovery of the righting reflex. The methanol extract (50, 100, 200 mg/kg), alkaloid extract of M. speciosa (5, 10 and 20 mg/ kg), or cosolvent vehicle was administered orally
30 min before pentobarbital (Ferrini et al., 1974).
Chemicals
The following drugs were used: morphine sulfate, pentobarbital sodium and methamphetamine hydrochloride (AR grade, Sigma Chem. Co., St. Louis, U.S.A.); methanol, petroleum ether, chloroform (AR grade, Merck, Germany); sodium chloride, sodium sulfate, ammonia (AR grade, Carlo Erba, Germanny). The methanol and alkaloid extracts of M. speciosa leaves were dissolved in cosolvent solution (propylene glycol : tween 80 : water = 4:1:4) and administered orally in a constant volume (10 ml/kg for mice and 5 ml/kg for rats) 30 min before the experiments. Morphine sulfate was dissolved in 0.9% sodium chloride solution Songklanakarin J. Sci. Technol.
Vol.29 (Suppl. 1), March 2007 : Thai Herbs II
Effects of the extracts from M. speciosa 43 Reanmongkol, W., et al. and administered subcutaneously. All drug solutions were prepared immediately before starting the
experiments.
Statistical Analysis
Data are expressed as mean ± SEM and were analyzed statistically by one-way ANOVA procedures, followed by Dunnett's test. A difference was considered significant at p<0.05.
Results
Acute toxicity
In acute toxicity test, the signs of toxicity included lethargy, tremor, fatigue, paralysis, loss of righting reflex, apnea, tonic-clonic convulsion and death. The LD50 values of orally administration of the methanol and alkaloid extracts of M. speciosa leaves in mice were 4.90 g/kg and 173.20
mg/kg, respectively.

Effects of the methanol and alkaloid extracts of M. speciosa leaves and morphine on nociceptive response induced by heat in hot plate test As shown in Table 1, oral administration (50, 100, 200 mg/kg) of the methanol extract of M. speciosa leaves significantly prolonged the latency of nociceptive response but less potent than those of the morphine group (10 mg/kg, s.c.) in mice. The alkaloid extract of M. speciosa leaves also increased the pain response latency at the dose of 20 mg/kg but had weaker analgesic activity than
the methanol extract (100 mg/kg) in mice.
Effects of the naloxone on methanol and alkaloid extracts of M. speciosa leaves and morphine in hot plate test The antinociceptive action of the methanol extract (100 mg/kg, p.o.) and the alkaloid extract (20 mg/kg, p.o.) of M. speciosa leaves was blocked by pure opioid antagonist, naloxone (2 mg/kg, i.p.). Morphine sulfate (10 mg/kg, s.c.), a centrally acting analgesic drug, was also antagonized by naloxone,
as shown in Table 2.

Effects of the methanol and alkaloid extracts of M. speciosa leaves and morphine on nociceptive response in tail-flick test Neither the methanol extract (50, 100, 200 mg/kg, p.o.) nor the alkaloid extract (5, 10, 20 mg/ kg, p.o.) of M. speciosa leaves significantly prolonged the rat tail's time that subjected to heat Table 1. Effects of the methanol and alkaloid extracts of M. speciosa leaves and morphine on nociceptive response in hot plate test.
Latency of nociceptive response (sec)
Drug
15 30 45 60 min Cosolvent - 9.7±0.6 11.4±1.0 10.4±1.3 11.7±1.5 Morphine 10 24.0±3.8* 28.4±3.9* 23.1±4.2* 21.9±4.0* M. speciosa 50 13.2±2.2 11.5±0.7 17.2±3.4* 14.3±1. (methanol) 100 13.6±1.2 17.4±3.2* 18.5±3.4* 16.3±3.3* 200 14.0±1.0 12.9±1.1 16.4±2.8* 13.9±1.2 Cosolvent - 10.0±0.7 10.0±1.2 9.3±0.9 9.2±1.4 Morphine 10 17.5±2.3* 21.6±3.0* 19.7±3.2* 17.8±3.3* M. speciosa 5 10.1±0.6 9.3±0.6 8.5±0.6 8.7±0.6 (alkaloid) 10 11.5±0.6 9.7±0.8 9.6±1.0 9.4±0.9
20 13.5±1.1* 13.1±1.4* 12.3±1.1 10.3±0.9
Beginning 30 min after oral administration of test agents (or 15 min after morphine injection, s.c.), the nociceptive response was measured every 15 min over a 60-min period. Each datum represents the
latency of nociceptive responses (sec) ± S.E.M. (n=10). * p< 0.05 compared with the control group
(Dunnett's test).
Dose (mg/kg, p.o.) Songklanakarin J. Sci. Technol. Vol.29 (Suppl. 1), March 2007 : Thai Herbs II 44 Effects of the extracts from M. speciosa Reanmongkol, W., et al. generated by the tail flick apparatus while morphine (10 mg/kg, s.c.) significantly increased the latency of nociceptive response (Table 3). Effects of the methanol and alkaloid extracts of M. speciosa leaves and methamphetamine on locomotor activity in mice Neither the methanol extract (50, 100, 200 mg/kg, p.o.) nor the alkaloid extract (5, 10, 20 mg/kg, p.o.) of M. speciosa leaves significantly changed spontaneous motor activity in mice while methamphetamine, a CNS stimulant, significantly increased the motor activity, compared with the
cosolvent group (Table 4). Effect of the methanol and alkaloid extracts of M. speciosa leaves on pentobarbital-induced sleep in mice Neither the methanol extract (50, 100, 200 mg/kg, p.o.) nor the alkaloid extract (5, 10, 20 mg/kg, p.o.) of M. speciosa leaves had a significant effect on pentobarbital-induced sleep in mice (Table 5).
Discussion
The results demonstrate that the methanol and alkaloid extracts obtained from the leaves of M. speciosa exerted the antinociceptive response to heat-induced pain in hot plate test in mice. The methanol extract of M. speciosa leaves prolonged the latency of nociceptive response on heat-induced pain in hot plate test in mice. The alkaloid extract also increased the pain latency time in hot plate test but was less potent than the methanol extract. It is possible that not only the alkaloids but also some other active compounds included in the methanol extract possessed the analgesic action. Neither the methanol extract nor alkaloid extract significantly affected the pain response in tail flick test in rats. Since the analgesic action in hot plate and tail flick tests involves supraspinal (Yaksh and Rubi, 1976) and spinal components, respectively (Mayer & Liebeskind, 1974). The antinociceptive activity of the methanol and alkaloid extracts is due to action at the supraspinal system. In addition, the analgesic action of the methanol extract (100 mg/kg, p.o.) and alkaloid extract (20 mg/kg, p.o.) was also blocked by naloxone (2 mg/kg, i.p.), a pure opioid antagonist (Gutstein and Akil, 2001). These results suggest that the antinociceptive activity of the extracts partly acts at opioid receptors in the supraspinal opioid system. Furthermore, it has been reported that mitragynine, the active alkaloid in M. speciosa leaves, exhibited antinociceptive Table 2. Effects of the naloxone on methanol and alkaloid extracts of M. speciosa and
morphine in nociceptive response in Hot plate test.
Latency of nociceptive response (sec)
Drug 15 30 45 60 min Naloxone + Cosolvent - 9.4±0.7 10.9±0.9 11.9±0.8 10.8±0.8 Naloxone + Morphine 10 10.8±1.2 11.5±1.2 12.8±1.3 17.3±1.7* Naloxone + M. speciosa 100 12.3±1.2 15.4±1.2 13.5±1.1 15.6±1.9 (methanol) Naloxone + Cosolvent - 9.2±0.7 9.2±0.6 8.4±0.6 7.7±0.7 Naloxone + Morphine 10 10.0±0.5 9.0±0.7 10.7±1.2 10.9±1.3 Naloxone + M. speciosa 20 9.9±0.7 9.7±0.8 8.8±0.7 8.4±0.6 (alkaloid) Naloxone (2 mg/kg) was intraperitoneally injected 10 min before test agents administration in mice. The nociceptive response was measured every 15 min over a 60-min period. Each datum represents the
latency of nociceptive responses (sec) ± S.E.M. (n=10). *p< 0.05 compared with the control group
(Dunnett's test).
Dose (mg/kg, p.o.) Songklanakarin J. Sci. Technol. Vol.29 (Suppl. 1), March 2007 : Thai Herbs II Effects of the extracts from M. speciosa 45 Reanmongkol, W., et al. actions by involving the descending noradrenergic and serotonergic systems of the supraspinal opioid system on the mechanical noxious stimulation (Matsumoto et al., 1996a, b), which is dominantly mediated by mu- and delta-oipoid receptor subtypes in mice (Thongpradichote et al., 1998). In this study, the animals were orally administered the methanol extract of M. speciosa leaves at doses of 50, 100 and 200 mg/kg p.o., that are comparable to the peasants orally administered 10-30 leaves per day (Anon, 2006). The effective dose of the methanol extract obtained from M. Table 3. Effects of the methanol and alkaloid extracts of M. speciosa leaves and morphine
on nociceptive response in the tail-flick test.
Latency of nociceptive response (sec)
Drug 15 30 45 60 min Cosolvent - 2.8±0.6 2.1±0.3 1.9±0.1 2.2±0.3 Morphine 10 9.5±0.4* 9.6±0.4* 9.8±0.2* 8.1±0.8*M. speciosa 50 3.4±0.6 2.5±0.3 2.2±0.2 2.4±0.3 (methanol) 100 4.2±1.0 2.9±0.3 2.5±0.5 3.5±0.5 200 2.6±0.4 3.0±0.3 2.2±0.3 2.9±0.6 Cosolvent - 3.8±1.2 4.0±1.2 3.4±1.5 2.6±0.3 Morphine 10 9.5±0.3* 9.8±0.2* 10.0±0.0* 9.7±0.3* M. speciosa 5 3.7±1.3 2.9±0.8 3.9±0.5 4.8±1.3 (alkaloid) 10 3.2±1.1 4.1±1.0 2.8±0.7 2.1±0.2 20 4.1±1.5 4.2±1.5 2.8±0.3 3.1±0.6 Beginning 30 min after oral administration of test agents (or 15 min after morphine injection, s.c.), the nociceptive response was measured every 15 min over a 60-min period. Each datum represents
the latency of nociceptive responses (sec) ± S.E.M. (n=6) * p<0.05 compared with the control group
(Dunnett's test)
Dose (mg/kg, p.o.) Table 4. Effects of the methanol and alkaloid extracts of M. speciosa leaves and methamphetamine on locomotor activity in mice. Drug Dose Locomotor activity (mg/kg, p.o.) (counts/30 min) Cosolvent - 343.6±48.5Methamphetamine (i.p.) 1 1315.9±135.7* M. speciosa 50 233.3±93.7 (methanol) 100 163.5±63.8200 159.2±34.4 Cosolvent - 507.5±179.9 Methamphetamine (i.p.) 1 1343.5±279.5* M. speciosa 5 252.9±87.2 (alkaloid) 10 269.4±101.220 258.9±93.9 Thirty min after oral administration of test agents except methamphetamine was injected intraperitoneally in mice, changes in spontaneous motor activity were measured over a 30-min period. Each datum represents the mean ± S.E.M. from 10 mice. *p< 0.05, compared with the control group (Dunnett's test). Songklanakarin J. Sci. Technol. Vol.29 (Suppl. 1), March 2007 : Thai Herbs II 46 Effects of the extracts from M. speciosa Reanmongkol, W., et al. Table 5. Effects of the methanol and alkaloid extracts of M. speciosa leaves on pentobarbital- induced sleep in mice. Drug Dose Duration of pentobarbital- (mg/kg, p.o.) induced sleep (min)Cosolvent - 62.2±4.1 M. speciosa 50 70.1±3.3 (methanol) 100 73.0±3.6200 75.5±4.9Cosolvent -91.6±7.8M. speciosa 5 86.8±6.6 (alkaloid) 10 90.0±5.320 86.1±5.8 The methanol and alkaloid extracts of M. speciosa leaves were orally administered. After 30 min, pentobarbital (50 mg/kg, i.p.) was injected, and sleeping time was measured. Each datum represents the mean ± S.E.M. (n = 10). speciosa leaves is 100 mg/kg, p.o. for antinociceptive activity. Although the alkaloid extract is expected to include more active compounds, however, it had weak analgesic activity. Taking into account the yield of 5-10 mg/kg alkaloid extract which corresponds to approximately 200 mg/kg of methanol extract of M. speciosa leaves, showed no significant antinociceptive effect. Furthermore, it exhibited higher toxicity than the methanol extract - the LD50 values of orally administration of alkaloid and methanol extracts were 173.20 mg/kg and 4.90 g/kg, respectively, in mice. It is possible that some active compounds included in the methanol extract have synergistic effects on the analgesic action. Thus the preparation of M. speciosa leaves or kratom in the methanol extract form has more analgesic efficacy and is less toxic than the alkaloid extract. In general behavioral study, the methanol and alkaloid extracts of M. speciosa leaves had no significant effect on pentobarbital-induced sleep in mice, so a sedative effect could be excluded from their antinociceptive responses in the tests used in this study. Neither of the extracts of M. speciosa leaves caused any significant changes in locomotor activity. In conclusion, these results suggest that the methanol and alkaloid extracts of M. speciosa leaves possess analgesic activity which partly acted
at opioid receptors in the supraspinal opioid system.
Acknowledgments
The authors are very grateful to the Thailand
Research Fund for financial support of this work.
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This article was published on Friday 18 May, 2007.
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