The relationship between morphine and associated opioids and ginseng has proved both remarkable and unexpected. Opioids are widely used as legitimate, effective analgesics, especially in terminal afflictions such as cancers although continued use of morphine-type drugs is rapidly accompanied by the development of tolerance, the craving for ever-increasing doses, and by psychic and physical dependence. Seeking effective antagonists of the narcotic and addictive effects of opium and morphine, H.S.Kim and his colleagues in a long series of studies from 1985 onwards have demonstrated the effectiveness of ginseng versus morphine tolerance. The protopanaxadiol-type ginsenosides Rb1 and Rb2 and the protopanaxatriol-type ginsenosides Re and Rg1 inhibited the development of morphine-induced tolerance in mice and ginsenosides Rb1 and Rg1 also had an inhibitory effect on naloxone-induced withdrawal jumping response. In addition the ginsenosides inhibited body weight loss in physically dependent mice undergoing multiple injections of morphine (Kim et al., 1989a). Naloxone ((-)-N-allyl-7,8-dihydro-14-hydroxy-nor-morphinone hydrochloride), an opioid receptor antagonist, partially blocked the analgesic effect of a large dose of morphine and also completely inhibited the development of an acute type tolerance. Ginseng total saponin extract, on the other hand, did not oppose the analgesic effect of a large dose of morphine although partially inhibiting the development of both acute and delayed-type tolerance. Therefore it was concluded that the partial inhibition of the development of acute and delayed-type tolerance by ginseng total saponins was not mediated by the opioid receptors (Kim et al., 1989b).
The metabolism of morphine in the liver includes the partial conversion of morphine to the ketone morphinone, a reaction prompted by the enzyme morphine-6-dehydrogenase. Morphinone is considered nine times as toxic as morphine but demonstrates only half the analgesic effect. On conversion to morphinone-protein-sulphydryl conjugate by covalent bonding between morphinone and the sulphydryl groups, the opiate receptors become blocked irreversibly with diminishing analgesic action, so encouraging more and higher dosages of morphine to achieve the same analgesic effect. The subsequent development of tolerance and addiction can be detoxified by reaction with liver glutathione. Ginseng functions by blocking morphine-6-dehydrogenase and also by maintaining, or even increasing, the hepatic glutathione level so inhibiting reduction of non-protein sulphydryl levels. This has been proved in vitro using the standardised extract G115 and the protopanaxatriol-type ginsenosides, especially ginsenoside Rg1 (Kim and Jeong, 1994). Ginseng leaf saponins were also shewn to antagonise the analgesic action of morphine and to inhibit the development of morphine induced tolerance and physical dependence and also to inhibit the reduction in liver glutathione induced by repeated morphine injections (Kim et al., 1989e).
The effect of ginseng on the nociceptors, nerve ending sensory receptors detecting and transmitting the pain normally caused by chemical or physical damage to the tissues, is analgesic. In rats, ginseng at 200 mg/kg produced analgesia and hypothermia which was not reversed by naltrexone (17-(cyclopropylmethyl)-4,5a-epoxy3,14-dihydroxy-morphinan-6-one), a narcotic antagonist used to treat opioid dependency orally. Morphine at 8 mg/kg also produced analgesia and hypothermia but the analgesic response to morphine was antagonised by 25 mg/kg and 50 mg/kg doses of ginseng extract although not by 12.5, 100 and 200 mg/kg doses. The hypothermic effect induced by morphine was opposed by ginseng extract in doses of 12.5 to 500 mg/kg. The cataleptic (trance-like) effect of morphine in 50 mg/kg doses was antagonised by 25 mg/kg ginseng extract. From such results Ramarao and Bhargava (1990) concluded that the analgesia and hypothermia induced by ginseng extract was via a non-opiate mechanism and that ginseng opposed the acute pharmacological effects of morphine. Subsequent work (Bhargava and Ramarao, 1991) confirmed the inhibitory effect of ginseng extract in appropriate doses on the occurrence of tolerance to the pharmacological actions of morphine. The analgesic and hypothermic effects of red ginseng extract occur at relatively high doses and are not mediated via the endogenous opiates or opiate mediators as the effects are not antagonised by naltrexone. Ginseng produces partial analgesia in disorders of pain sensation, and hyperaesthesia (morbid sensitivity of the nerves) produced in animal pain models is not caused by chemical sympathectomy. Although the effect may be the result of depression of both dosal horn neurons in the spinal cord and the nociceptors sensitised by continuous impulse discharges at nerve injury sites, a non-opioid mechanism is probable (Kim and Kim, 1995). Current research based on the formalin test (injection of the hind paws of mice with 1 per cent formalin solution) suggests that the antinociceptive action of the ginsenosides (administered intrathecally) was due to blocking of peptide
SP-induced nociceptive information to post-synaptic site(s) at the spinal level. Normal reaction to formalin injection is biting or licking of the affected area but ginsenoside pretreatment inhibited the biting/licking reponse in a dose-dependent manner. The peptide compound substance P (SP), a probable neurotransmitter conveying information from pain receptors to the central nervous system, also prompted pain behaviour including licking, scratching and biting of the hind portion of the body. Co-administration of substance P (SP) with ginsenosides inhibited the SP-induced pain response. Therefore it was concluded that the ginsenosides were indeed probable nociceptive pain signal blockers (Yoon et al., 1998).
Apart from the inhibitory effect on morphine tolerance and psychic dependence by ginseng extracts and particularly by the extract G115, there is also a marked preventative effect on addiction withdrawal symptoms. This has been demonstrated in morphine-dependent animal experiments but the precise mechanism of action is, as yet, not understood. Certainly the withdrawal symptoms are accompanied by an increase in the dopamine and cyclic adenosine monophosphate (cAMP) levels, a reduction in the acetylcholine level in the brain and decrease in serotonin (5-hydroxytryptamine) release from the brain stem. Dopamine (hydroxytyramine) is a normally inhibitory neurotransmitter produced in neurones in the substantia nigra of the basal ganglia of the brain stem and is involved in motor control; cAMP is an intracellular hormonal mediator arising within the cells and in its short life controls reactions such as promotion of enzyme activity, alteration of cell permeability, prompting of muscle contraction and relaxation, inciting synthesis of specific intracellular proteins, initiation of secretion, etc.; acetylcholine is another neurotransmitter occurring in the brain, spinal cord, nervous system ganglia, at the terminals of the motor neurones controlling skeletal muscle fibres and in the postganglionic fibres of the parasympathetic nervous system, and serotonin is a further neurotransmitter that is produced by nuclei originating in the median raphe of the brain stem and projecting into the dorsal horns of the spinal cord, the hypothalamus and other parts of the brain. Serotonin inhibits pain pathways in the spinal cord and is involved in control of mood, prolactin secretion, sleep and circadian rhythms.
More recent work by Kim et al. (1995) confirmed the potential value of ginseng total saponins at 200 mg/kg intraperitoneally in rodents in the prevention and therapy of the adverse reactions of morphine, ginseng total saponins being able to inhibit the development of sensitivity or reverse tolerance to the ambulatory-accelerating effect of morphine and to prevent the development of dopamine supersensitivity caused by chronic administration of morphine (10 mg/kg per day for 7 days). Similarly, in mice, ginseng total saponins blocked the development of reverse tolerance to the ambulation-accelerating effect induced by the CNS stimulant methamphetamine (2 mg/kg, subcutaneously) and also prevented the development of dopamine receptor supersensitivity induced by the chronic administration of methamphetamine. As ginseng saponins oppose the development of reverse tolerance to both morphine and methamphetamine as well as inhibiting dopamine supersensitivity, it was suggested that reverse tolerance may be related to enhanced dopamine receptor supersensitivity. Oh et al. (1997), observing that ginseng pretreatment reduced the magnitude of methamphetamine-induced dopamine (3,4-dihydroxy-phenylethylamine), 3,4-dihydroxy-phenylacetic acid and homovanillic acid depletions, suggested that ginseng total saponins could partially prevent methamphetamine-induced striatal dopaminergic depletions.
Because the ginseng (P. ginseng root) total saponins inhibit the hyperactivity and conditioned place-preference response induced by psychostimulants and opiates, it has been concluded that the mechanism is direct or indirect modulation of dopaminergic activity. As the protopanaxadiol-derived ginsenoside Rb1 and the protopanaxatriol-derived ginsenoside Rg1 are the major P. ginseng root saponins, Kim et al. (1998a) investigated their effects on morphine-induced hyperactivity and place-preference. Both ginsenosides inhibited morphine-induced hyperactivity but not apomorphine-induced climbing behaviour, thus agreeing with the hypothesis that ginsenosides modulate catecholaminergic activity preferentially at pre-synaptic sites. Morphine-induced conditioned place-preference for greater time in the dark compartment, however, was inhibited only by the protopanaxatriol-derived ginsenoside Rg1 with resulting test animal preference for more time in the white compartment. At low doses ginsenosides Rb1 and Rg1 were equally effective as inhibitors of catecholamine secretion at the pre-synaptic site but at higher doses ginsenoside Rg1 was the more effective inhibitor. This could explain why morphine-induced conditioned place-preference was inhibited by ginsenoside Rg1 only. Such results suggest that ginsenoside Rg1 has potential as an agent for the prevention and treatment of the adverse effects of morphine type drugs.
Researchers at the Medical and Pharmaceutical University at Toyama, Honshu, Japan investigated the effect of majonoside R2, the principal saponin from P. vietnamensis, Vietnamese ginseng, on morphine-induced antinociception. Majonoside R2, P. vietnamensis extract and P. vietnamensis total saponins inhibited or attenuated the ^.-opioid agonist morphine-induced antinociception as judged by the tail-pinch and hot-plate tests in mice and also reversed the tail-flick latency increased by conditioned fear stress in rats. Repeated administration of P. vietnamensis saponin or majonoside R2 suppressed the development of morphine tolerance as judged by the tail-pinch test (Huong et al., 1996, 1997a).
Clinical trials are necessary to clarify not only the potential use of ginsengs in the treatment of morphine tolerance in man but also the possible value in the prevention of adverse reactions of methamphetamine and cocaine.
Was this article helpful?