Kratom Alkaloids, Natural and Semi-Synthetic, Show Less Physical Dependence and Ameliorate Opioid Withdrawal.

Chronic administration of opioids produces physical dependence and opioid-induced hyperalgesia. Users claim the Thai traditional tea "kratom" and component alkaloid mitragynine ameliorate opioid withdrawal without increased sensitivity to pain. Testing these claims, we assessed the combined kratom alkaloid extract (KAE) and two individual alkaloids, mitragynine (MG) and the analog mitragynine pseudoindoxyl (MP), evaluating their ability to produce physical dependence and induce hyperalgesia after chronic administration, and as treatments for withdrawal in morphine-dependent subjects. C57BL/6J mice (n = 10/drug) were administered repeated saline, or graded, escalating doses of morphine (intraperitoneal; i.p.), kratom alkaloid extract (orally, p.o.), mitragynine (p.o.), or MP (subcutaneously, s.c.) for 5 days. Mice treated chronically with morphine, KAE, or mitragynine demonstrated significant drug-induced hyperalgesia by day 5 in a 48 °C warm-water tail-withdrawal test. Mice were then administered naloxone (10 mg/kg, s.c.) and tested for opioid withdrawal signs. Kratom alkaloid extract and the two individual alkaloids demonstrated significantly fewer naloxone-precipitated withdrawal signs than morphine-treated mice. Additional C57BL/6J mice made physically dependent on morphine were then used to test the therapeutic potential of combined KAE, mitragynine, or MP given twice daily over the next 3 days at either a fixed dose or in graded, tapering descending doses. When administered naloxone, mice treated with KAE, mitragynine, or MP under either regimen demonstrated significantly fewer signs of precipitated withdrawal than control mice that continued to receive morphine. In conclusion, while retaining some liabilities, kratom, mitragynine, and mitragynine pseudoindoxyl produced significantly less physical dependence and ameliorated precipitated withdrawal in morphine-dependent animals, suggesting some clinical value.

Prevention of morphine dependence and tolerance by Nepeta menthoides was accompanied by attenuation of Nitric oxide overproduction in male mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Repeated administration of morphine for chronic pain leads to dependence and tolerance that limits clinical usage. Nepeta menthoides is commonly known as Iranian Ustukhuddoos and are administered in traditional medicine for gastrodynia, bone pain, blood depurative and restlessness. AIMS OF STUDY: To investigate the effects of Nepeta menthoides on expression and acquisition of morphine dependence and tolerance in mice with regard to oxidative stress. MATERIALS AND METHODS: Morphine dependence in mice was developed by administration of gradually increasing doses of morphine twice daily for 7 consecutive days. In experimental groups, administration of Nepeta menthoides (200 and 400mg/kg), methadone and their combination were performed 60min prior to each morphine injection (for acquisition) or the last injection of morphine on test day (for expression). Morphine tolerance was measured by the tail-immersion test before and after the administration of a single dose of morphine (100mg/kg; i.p.) on the test day (8th day). Morphine dependence was also evaluated by counting the number of jumps after the injection of naloxone (5mg/kg; i.p.). RESULTS: Nepeta menthoides, similar to methadone, significantly prevented the development (but not the expression) of morphine dependence, tolerance, and potentiated morphine antinociception and also reduced (23.23±1.15) Nitric oxide (NO) overproduction (35.23±3.36) (in compared with naloxone group (6.3±0.52)). However, single and repeated application of the extract could not change high single-dose morphine analgesia. CONCLUSION: It appears that Nepeta menthoides and methadone prevented morphine dependence and tolerance, partly through inhibition of the NO overproduction.

Salvia officinalis L. attenuates morphine analgesic tolerance and dependence in rats: possible analgesic and sedative mechanisms.

BACKGROUND: Salvia officinalis L. (SO) has effects on the central nervous system, including anti-addiction properties that may involve an opioid mechanism. OBJECTIVE: Effects of a hydroalcoholic extract of SO on nociception and on morphine-induced tolerance and dependence were evaluated in rats. METHODS: Tolerance and dependence were induced by injection of morphine (10 mg/kg, s.c.) or escalating doses of morphine (2.5, 2.5, 5, 10, 20, 40 and 50 mg/kg, s.c.) twice daily for 7 days. SO (400, 600 and 800 mg/kg, i.g.) was administered before morphine. The tail-flick and naloxone precipitation withdrawal tests were used to evaluate tolerance and dependence. Sedative effects as well as total polyphenolic and flavonoid were also measured. RESULTS: The morphine-treated group showed significant decrements in the percentage maximum possible effect (%MPE) on days 5 and 7 compared to the first day, illustrating morphine tolerance. Higher doses decreased morphine tolerance. Furthermore, SO (600 and 800 mg/kg) attenuated almost all of the withdrawal signs including weight loss, jumping, penis licking, teeth chattering, wet dog shakes, rearing, standing, sniffing, face grooming and paw tremor and increased sleep duration (64.5 ± 9.7, 100.3 ± 4.7, respectively). Total polyphenolic and flavonoid content of SO was 138 and 69 mg per g of dried extract, respectively. CONCLUSION: SO has antinociceptive effects and may decrease tolerance and dependence induced by repeated morphine administration. However, to determine whether treatment with SO blocks tolerance by interfering with neurobiological mechanisms that mediate the development of morphine tolerance will require further studies.

A Scutellaria baicalensis radix water extract inhibits morphine-induced conditioned place preference.

CONTEXT: Scutellaria baicalensis Georgi (Lamiaceae) has been used as a traditional herbal preparation for the treatment of neuropsychiatric disorders in Asian countries for centuries. OBJECTIVE: To evaluate the effects of S. baicalensis on morphine-induced drug dependence in rats. MATERIALS AND METHODS: In order to evaluate the effect of S. baicalensis and baicalin on morphine-induced dependence-like behavior, a water extract of S. baicalensis [500 mg/kg, intraperitoneally (i.p.)] or baicalin (50 mg/kg, i.p., a flavonoid found in S. baicalensis) was administered prior to morphine injection [5 and 2.5 mg/kg, respectively, subcutaneously (s.c.)] to rats for 8 and 4 d, respectively. Morphine-induced conditioned place preference was assessed by measuring the time spent in a drug-paired chamber. The effect of S. baicalensis on dopamine receptor supersensitivity (locomotor activity) and dopamine agonist-induced climbing behavior due to a single apomorphine treatment (2 mg/kg, s.c.) was also measured. RESULTS: At 50 mg/kg, a water extract of S. baicalensis decreased morphine (5 mg/kg)-induced conditioned place preference by 86% in rats. Apomorphine (2 mg/kg)-induced locomotor activity (dopamine receptor supersensitivity) in rats and climbing behavior in mice were attenuated after pretreatment with 500 mg/kg of S. baicalensis water extract by 41% and 56%, respectively. In addition, baicalin-reduced morphine-induced conditioned places preference by 86% in rats at 50 mg/kg. DISCUSSION AND CONCLUSION: These results suggest that S. baicalensis can ameliorate drug addiction-related behavior through functional regulation of dopamine receptors.

Acupuncture at HT7 suppresses morphine self-administration at high dose through GABA system.

In the previous study, acupuncture at HT7 has shown to attenuate the self-administration of morphine at a low dose (0.1mg/kg). In this study, it was further investigated whether acupuncture at HT7 could attenuate the morphine self-administration at a high dose (0.5mg/kg). Male Sprague-Dawley rats weighing 270-300g were used. After surgery of catheterization, animals were trained to self-administer morphine solution (0.5mg/kg) using daily 1h session under fixed ratio 1 schedule for 3 weeks. Animals that had shown stable morphine-taking (establish baseline: variation less than 20% of the mean of three consecutive days) were subjected to the acupuncture treatment. Bicuculline and SCH 50911 were used to investigate the possible relation between the effect of acupuncture and the GABA receptor system. Acupuncture at HT7, but not at control acupoint, LI5, suppressed spontaneous morphine-taking behavior significantly. In addition, the effect of acupuncture was blocked by both GABA receptor antagonists. The results of this study suggest that acupuncture at HT7 suppresses morphine-taking behavior through the mediation of GABA receptor system.

Withania somnifera prevents acquisition and expression of morphine-elicited conditioned place preference.

Previous studies have reported that some of the central effects of morphine are counteracted by the administration of the methanolic extract of the root of Indian ginseng, Withania somnifera Dunal (WSE). The present study sought to determine whether WSE affects acquisition and expression of morphine-elicited conditioned place preference (CPP) in CD-1 mice. In CPP acquisition experiments, WSE (0, 25, 50, and 100 mg/kg) was administered, during conditioning, 30 min before morphine (10 mg/kg), whereas in expression experiments, WSE (0, 25, 50, and 100 mg/kg) was administered 30 min before the postconditioning test. The results demonstrate (i) that WSE was devoid of motivational properties; (ii) that WSE (100 mg/kg) was devoid of effects on spontaneous and morphine-stimulated motor activity and on spatial memory; and (iii) that WSE (50 and 100 mg/kg) significantly prevented the acquisition and expression of CPP. Further, to characterize the receptor(s) involved in these effects, we studied, by receptor-binding assay, the affinity of WSE for µ-opioid and γ-aminobutyric acid B receptors. These experiments revealed a higher affinity of WSE for γ-aminobutyric acid B than for µ-opioid receptors. Overall, these results point to WSE as an interesting alternative tool, worthy of further investigation, to study opiate addiction.

Acupuncture at SI5 attenuates morphine seeking behavior after extinction.

Our previous studies have shown that acupuncture attenuates morphine self-administration and sensitization behavior as well as withdrawal signs. The present study was designed to investigate the role of acupuncture in the reinstatement of morphine seeking. Male Sprague-Dawley rats weighing 270-300 g were subjected to intravenous catheterization after food training. The animals were trained to self-administer morphine (1.0mg/kg, 3 weeks), followed by extinction (1 week). Extinction conditions were introduced by substituting saline for morphine. The rats were then tested for reinstatement of morphine self-administration by a priming injection of morphine (0.25mg/kg). To see whether acupuncture can reduce morphine reinstatement, acupuncture was performed at SI5 or LI5 for 1 min immediately before a morphine injection. To further test the involvement of gamma aminobutyric acid (GABA) receptors in acupuncture effects, GABA receptor antagonists were injected before acupuncture. In the present results, acupuncture at SI5, but not at control acupoint LI5 attenuated the reinstatement of morphine seeking behavior, which was blocked by the GABA receptor antagonists. It suggests that acupuncture can reduce the reinstatement of morphine seeking, possibly due to the mediation of GABA receptor system.

Effects of a Rhodiola rosea L. extract on acquisition and expression of morphine tolerance and dependence in mice.

This study investigated the effect of Rhodiola rosea L. extract on acquisition and expression of morphine tolerance and dependence in mice. Therefore animals were injected with repeated administration of morphine (10 mg/kg, subcutaneous) twice daily for five or six days, in order to make them tolerant or dependent. Rhodiola rosea L. extract (0, 10, 15 and 20 mg/kg) was administered by the intragastric route 60 min prior to each morphine injection (for acquisition) or prior the last injection of morphine or naloxone on test day (for tolerance or dependence expression, respectively). Morphine tolerance was evaluated by testing its analgesic effect in the tail flick test at the 1st and 5th days. Morphine dependence was evaluated by counting the number of withdrawal signs (jumping, rearing, forepaw tremor, teeth chatter) after naloxone injection (5 mg/kg; intraperitoneal) on the test day (day 6). Results showed that Rhodiola rosea L. extract significantly reduced the expression of morphine tolerance, while it was ineffective in modulating its acquisition. Conversely, Rhodiola rosea L. extract significantly and dose-dependently attenuated both development and expression of morphine dependence after chronic or acute administration. These data suggest that Rhodiola rosea L. may have human therapeutic potential for treatment of opioid addiction.

Ginger (Zingiber officinale Roscoe) elicits antinociceptive properties and potentiates morphine-induced analgesia in the rat radiant heat tail-flick test.

Ginger (Zingiber officinale Roscoe), a well-known spice plant, has been used traditionally in the treatment of a wide variety of ailments. It has been shown that ginger is a calcium channel blocker; however, its influence on morphine analgesic effects has not been elucidated. We examined the effect of ginger root extract on nociceptive threshold and morphine-induced analgesia in male Wistar rats. To determine the effect of ginger on morphine analgesia, ginger extract (200, 400, and 600 mg/kg i.p.) was injected before a subeffective dose of morphine (2.5 mg/kg i.p.). The radiant heat tail-flick test was used to assess the nociceptive threshold before and at different times after drug administration. Our results showed that ginger extract elicited a significant antinociceptive effect. In addition, in groups that received both morphine and ginger, the observed analgesia was higher than that in groups treated with either morphine or ginger extract alone. Thus, the data indicate that ginger extract has a beneficial influence on morphine analgesia and can be an efficacious adjunct for pain management.

Effects of capsazepine, a transient receptor potential vanilloid type 1 antagonist, on morphine-induced antinociception, tolerance, and dependence in mice.

BACKGROUND: Repeated morphine treatment has been shown to induce transient receptor potential vanilloid type 1 (TRPV1) expression in the spinal cord, dorsal root ganglion (DRG), and sciatic nerve of a rat model. Increased TRPV1 expression may therefore play a role in morphine tolerance. In this study, we evaluated the hypothesis that blockage of TRPV1 may be useful as an adjunctive pain management therapy. We investigated whether blockage of TRPV1 by capsazepine, a TRPV1 antagonist, affected antinociception, development of tolerance, and physical dependence on morphine in mice. METHODS: Institute of Cancer Research mice were pretreated with capsazepine and post-treated with morphine acutely and repeatedly. Antinociception and its tolerance were assessed using the hot-plate test. Morphine dependence was examined through the manifestation of withdrawal symptoms induced by naloxone in morphine-dependent mice. RESULTS: Acute capsazepine treatment (5 mg kg⁻¹, i.p.) potentiated the antinociceptive effects of morphine, as measured by the hot-plate test. Repeated co-treatment of capsazepine (2.5 mg kg⁻¹ i.p.) with morphine attenuated the development of tolerance to the antinociceptive effect of morphine. The development of morphine dependence was also reduced by capsazepine (1.25 or 2.5 mg kg⁻¹ i.p.). CONCLUSIONS: Our results suggest that TRPV1 antagonists can be used adjunctively to morphine treatment because they strengthen morphine antinociception and prevent the development of tolerance, and also physical dependence, on morphine.

[Anti-alcoholic and anti-narcotic action of Methylobacteriim extorquens UCM B-3368].

The paper deals with action efficiency of microbial biomass on characteristic indicators at alcohol and morphine organism intoxication. The investigated microbial biomass affects the regulatory biochemical and physiological systems in experimental animals, normalizes activity of alcohol dehydrogenase and aldehide dehydrogenase, as well as the content of dophamine, disturbed under the effect of alcohol and morphine. Thus, the organism intoxication decreases. Except for the specific action, the above microbial biomass can be a source of protein, aminoacids, vitamins, microelements. So, the microbial preparation, made on its basis, can be used for the treatment of alcohol and morphine dependence in a form of biologically active dope. Thus the microbial drug intended for treatment of alcohol and opium dependence has been developed. One of its action mechanisms is based on the microorganisms capacity to transform alcohols and aldehides, owing to availability of alcohol and aldehide dehydrogenase, other its action mechanisms are at the stage of investigation.

The effect of L-stepholidine, a novel extract of Chinese herb, on the acquisition, expression, maintenance, and re-acquisition of morphine conditioned place preference in rats.

The effect of L-stepholidine (SPD), a novel alkaloid extract of the Chinese herb Stephania with partial dopamine D1 receptor agonistic and D2 receptor antagonistic dual actions, on morphine conditioned place preference (CPP) was studied. Daily injection of morphine (10 mg/kg, i.p.) for 6 days induced CPP in rats, and daily treatment with SPD at 10 or 20 mg/kg before morphine injection dose-dependently attenuated morphine-induced CPP. On the day following acquisition of morphine CPP, a single administration of SPD at 10 or 20 mg/kg failed to block the expression of CPP. However, daily administration of SPD at 20 mg/kg for 7 days attenuated the maintenance of CPP. Morphine-induced CPP extinguished after a 21-day saline training and then a single injection of morphine (3 mg/kg, i.p.) induced re-acquisition of morphine CPP; however, pretreatment with SPD at 10 or 20 mg/kg 30 min before morphine injection dose-dependently blocked morphine (3 mg/kg, i.p.)-induced re-acquisition of morphine CPP. Furthermore, our data indicate that SPD had no effect on food-induced CPP or state-dependent learning, suggesting that the observed effect of SPD does not result from an inhibition of general learning ability. These results demonstrate that SPD can inhibit acquisition, maintenance, and re-acquisition of morphine conditioned place preference and suggest its potential for treatment of opioid addiction.

A neuroactive steroid, dehydroepiandrosterone sulfate, prevents the development of morphine dependence and tolerance via c-fos expression linked to the extracellular signal-regulated protein kinase.

In the present study, we investigated how the neurosteroid, dehydroepiandrosterone sulfate (DHEAS) affects the development of morphine dependence and tolerance in mice. Mice administered morphine (10 mg/kg) twice a day for 5 days developed tolerance to the analgesic effect and dependence as shown by a severe withdrawal syndrome induced by naloxone. Co-administration of DHEAS (10 mg/kg) with morphine significantly inhibited the development, but not the expression, of tolerance to morphine-induced analgesia and the naloxone-precipitated withdrawal. The expression of c-fos mRNA was observed in the frontal cortex and thalamus of mice showing signs of naloxone-precipitated withdrawal, while the expression of c-fos mRNA was significantly diminished by co-administration of DHEAS with morphine. On the naloxone-precipitated withdrawal, mice showed a significant elevation of cyclic AMP (cAMP) levels in the thalamus, whereas chronic administration of DHEAS with morphine did not affect the increase in cAMP. Interestingly, repeated co-administration of DHEAS with morphine prevented the withdrawal-induced phosphorylation of extracellular signal-regulated protein kinase (ERK) 2 in the frontal cortex. These results showed that DHEAS prevented the development of morphine tolerance and dependence and suggested that the attenuating effects of DHEAS might result from the regulation of c-fos mRNA expression, which is possibly involved the signaling activation of ERK, but not of cAMP pathway.

Alkaloids from Brugmansia arborea (L.) Lagerhein reduce morphine withdrawal in vitro.

Traditional medicine is a primary source for the study of medicinal plants. In some countries, knowledge about the therapeutic use of medicinal plants is very deep and very often 'magical' plants also are used to diagnose and treat illnesses. The study of these plants can help in the research of metabolites active on the central and peripheral nervous system. Brugmansia arborea (L.) Lagerheim (Solanaceae) is used in the northern Peruvian Andes for magic-therapeutic purposes and the present study examined the effect of three pure tropane alkaloids from Brugmansia arborea (L.) Lagerhein (Solanaceae) on morphine withdrawal in vitro. All the tropane alkaloids isolated from Brugmansia arborea (L.) (10(-7), 5 x 10(-7), 10(-6) m) significantly and in a concentration dependent manner reduced morphine withdrawal. The results of the present study suggest that these alkaloids may be a potential anti-additive agent.

Matricaria chamomilla extract inhibits both development of morphine dependence and expression of abstinence syndrome in rats.

The effect of Matricaria chamomilla (M. chamomilla) on the development of morphine dependence and expression of abstinence was investigated in rats. The frequencies of withdrawal behavioral signs (paw tremor, rearing, teeth chattering, body shakes, ptosis, diarrhea, and urination) and weight loss induced by naloxone challenge were demonstrated in morphine-dependent rats receiving M. chamomilla extract or saline. The withdrawal behavioral manifestations and weight loss were inhibited significantly by chronic co-administration of M. chamomilla extract with morphine. Administration of a single dose of M. chamomilla before the naloxone challenge in morphine-dependent animals abolished the withdrawal behavioral manifestations. The dramatic increase of plasma cAMP induced by naloxone-precipitated abstinence was prevented by chronic co-administration of M. chamomilla extract with morphine. These results suggest that M. chamomilla extract inhibits the development of morphine dependence and expression of abstinence syndrome.

Benefits of external qigong therapy on morphine-abstinent mice and rats.

OBJECTIVE: To exclude possible psychological effects of qigong therapy in the treatment of addiction effectively, morphine-dependence models need to be established in mice and rats. METHOD: The effects of external qi on withdrawal syndrome were examined in naloxone-precipitated mice and rats in three randomized control experiments: naloxone-precipitated test in morphine-dependent mice (n = 100 in 5 groups, 20 mice each group); conditioned position preference test in morphine-abstinent mice (n = 30 for 3 groups, 10 each); and naloxone-precipitated test with paired box in morphine-dependent rats (n = 40 for 4 groups, 10 each). RESULTS: These experiments showed that morphine-dependent mice, after external qigong (EQ) therapy, had decreased incidence of jumping and lower jumping frequencies, and attenuated loss of body weight. After EQ therapy, morphine-dependent rats had reduced withdrawal scores and body weight loss was inhibited. In the conditioned place preference test, the time spent in the drug-paired box was significantly shorter for the qigong group than for the morphine group. CONCLUSION: These results suggest that qigong might have an inhibitory effect on withdrawal syndrome, and reduce the dependence potential in mice. Three different designs confirm that the impact of qigong therapy on morphine-abstinent mice and rats is reliable and substantial. Further research on the effectiveness and the mechanism of qigong therapy on addiction is warranted.

Preliminary study of fresh juice of Benincasa hispida on morphine addiction in mice.

The juice of Benincasa hispida (BH) showed significant activity against symptoms of morphine withdrawal, such as jumping response and diarrhoea, in mice. These results seem to indicate that BH may prevent the development of morphine addiction and also suppress symptoms of opioid withdrawal in animals.

Pharmacological and physiological effects of ginseng on actions induced by opioids and psychostimulants.

Pharmacological and physiological effects of ginseng on actions induced by opioids and psychostimulants are summarized. Analgesic effects of opioids, such as morphine and U-50, 488H, were blocked by ginseng in a nonopioid dependent manner. Furthermore, ginseng inhibited the tolerance to and dependence on morphine, and eliminated the suppressive effect of the development of morphine tolerance by coexposure to footshock stress, but not psychological stress. On the other hand, behavior sensitization (reverse tolerance to their ambulation-accelerating effect) to morphine, methamphetamine and cocaine was also inhibited by ginseng. Interestingly, ginseng also inhibited the appearance of the recurrent phenomenon (reappearance of the sensitized state was observed at the time of readministration of methamphetamine and cocaine even after a 30-day discontinuation of drug administration) of the effect of methamphetamine and cocaine. The conditioned place preference of methamphetamine and cocaine was completely blocked by ginseng. These findings provide evidence that ginseng may be useful clinically for the prevention of abuse and dependence of opioids and psychostimulants.

Effect of yohimbine on the development of morphine dependence in the rat: lack of involvement of cortical beta-adrenoceptor modifications.

The alpha-2 receptor antagonist yohimbine has been previously shown to prevent the development of morphine dependence in a rat behavioral model. This study was directed to clarify the mechanism of this interaction, which is presently unknown. Since upregulation of cortical beta-adrenoceptors has been suggested to be involved in morphine withdrawal, we have tested the possible correlation between receptor density and withdrawal behaviors in the presence of yohimbine. Sprague-Dawley male rats received a s.c. suspension of morphine (300 mg/kg) or the vehicle. Animals received saline or yohimbine (4 mg/kg, IP) 24, 28, 48 and 52 h after morphine and finally naloxone (1 mg/kg i.p) at 72 h; the subsequent signs of withdrawal (mainly wet-dog shakes and escape attempts) were recorded and the cerebral cortex dissected to study [3H]-CGP 12177 binding. Morphine-treated animals displayed a marked withdrawal behavior together with beta-adrenoceptor upregulation; nevertheless, these effects were not correlated. As expected, yohimbine prevented morphine withdrawal behavior but did not reverse the beta-adrenoceptor upregulation induced by the opiate. These results confirm previous evidence against the involvement of beta-adrenoceptor upregulation on morphine withdrawal behaviors and also permit to discard beta-adrenoceptor regulation as the neurochemical basis of the antiwithdrawal effect of yohimbine. The possible contribution of some other neurochemical effects of yohimbine are discussed to explain the inhibition of morphine dependence by that drug.