34 research outputs found
7‑hydroxymitragynine is an active metabolite of mitragynine and a key mediator of its analgesic effects
Mitragynina speciosa, more commonly known as kratom, is a
plant native to Southeast Asia, the leaves of which have been used
traditionally as a stimulant, analgesic, and treatment for opioid addiction. Recently,
growing use of the plant in the United States and concerns that kratom
represents an uncontrolled drug with potential abuse liability, have
highlighted the need for more careful study of its pharmacological activity. The
major active alkaloid found in kratom, mitragynine, has been reported to have
opioid agonist and analgesic activity in vitro
and in animal models, consistent with the purported effects of kratom leaf in
humans. However, preliminary research has provided some evidence that
mitragynine and related compounds may act as atypical opioid agonists, inducing
therapeutic effects such as analgesia, while limiting the negative side effects
typical of classical opioids. Here we report evidence that an active metabolite
plays an important role in mediating the analgesic effects of mitragynine. We
find that mitragynine is converted in
vitro in both mouse and human liver preparations to the much more potent
mu-opioid receptor agonist 7-hydroxymitragynine, and that this conversion is
mediated by cytochrome P450 3A isoforms. Further, we show that 7-hydroxymitragynine
is formed from mitragynine in mice and that brain concentrations of this
metabolite are sufficient to explain most or all of the opioid-receptor-mediated
analgesic activity of mitragynine. At the same time, mitragynine is found in the
brains of mice at very high concentrations relative to its opioid receptor
binding affinity, suggesting that it does not directly activate opioid
receptors. The results presented here provide a metabolism-dependent mechanism
for the analgesic effects of mitragynine and clarify the importance of route of
administration for determining the activity of this compound. Further, they
raise important questions about the interpretation of existing data on
mitragynine and highlight critical areas for further research in animals and
humans.</p
Lack of Genotype Effect on D1, D2 Receptors and Dopamine Transporter Binding in Triple MOP-, DOP-, and KOP-Opioid Receptor Knockout Mice of Three Different Genetic Backgrounds
Lack of Genotype Effect on D1, D2 Receptors and Dopamine Transporter Binding in Triple MOP-, DOP-, and KOP-Opioid Receptor Knockout Mice of Three Different Genetic Backgrounds
The biology of Nociceptin/Orphanin FQ (N/OFQ) related to obesity, stress, anxiety, mood, and drug dependence.
ociceptin/Orphanin FQ (N/OFQ) is a 17 amino acid peptide that was deorphanized in 1995. The generation of specific agonists, antagonists and receptor deficient mice and rats has enabled progress in elucidating the biological functions of N/OFQ. Additionally, radio-imaging technologies have been advanced for investigation of this system in animals and humans. Together with traditional neurobehavioral techniques, these tools have been utilized to identify the biological significance of the N/OFQ system and its interacting partners. The present review focuses on the role of N/OFQ in the regulation of feeding, body weight homeostasis, stress, the stress-related psychiatric disorders of depression and anxiety, and in drug and alcohol dependence. Critical evaluation of the current scientific preclinical literature suggests that small molecule modulators of nociceptin opioid peptide receptors (NOP) might be useful in the treatment of diseases related to these biological functions. In particular, the literature data suggest that antagonism of NOP receptors will produce anti-obesity and antidepressant activities in humans. However, there are also contradictory data discussed. The current literature on the role of N/OFQ in anxiety and addiction, on the other hand points primarily to a role of agonist modulation being potentially therapeutic. Some drug-like molecules that function either as agonists or antagonists of NOP receptors have been optimized for human clinical study to test some of these hypotheses. The discovery of PET ligands for NOP receptors, combined with the pharmacological tools and burgeoning preclinical data set discussed here bodes well for a rapid advancement of clinical understanding and potential therapeutic benefit
Mechanisms of Ovarian Steroid Regulation of Norepinephrine Receptor-Mediated Signal Transduction in the Hypothalamus: Implications for Female Reproductive Physiology
7-Hydroxymitragynine is an Active Metabolite of Mitragynine and a Key Mediator of its Analgesic Effects
Mitragynina speciosa, more commonly known as kratom, is a
plant native to Southeast Asia, the leaves of which have been used
traditionally as a stimulant, analgesic, and treatment for opioid addiction. Recently,
growing use of the plant in the United States and concerns that kratom
represents an uncontrolled drug with potential abuse liability, have
highlighted the need for more careful study of its pharmacological activity. The
major active alkaloid found in kratom, mitragynine, has been reported to have
opioid agonist and analgesic activity in vitro
and in animal models, consistent with the purported effects of kratom leaf in
humans. However, preliminary research has provided some evidence that
mitragynine and related compounds may act as atypical opioid agonists, inducing
therapeutic effects such as analgesia, while limiting the negative side effects
typical of classical opioids. Here we report evidence that an active metabolite
plays an important role in mediating the analgesic effects of mitragynine. We
find that mitragynine is converted in
vitro in both mouse and human liver preparations to the much more potent
mu-opioid receptor agonist 7-hydroxymitragynine, and that this conversion is
mediated by cytochrome P450 3A isoforms. Further, we show that 7-hydroxymitragynine
is formed from mitragynine in mice and that brain concentrations of this
metabolite are sufficient to explain most or all of the opioid-receptor-mediated
analgesic activity of mitragynine. At the same time, mitragynine is found in the
brains of mice at very high concentrations relative to its opioid receptor
binding affinity, suggesting that it does not directly activate opioid
receptors. The results presented here provide a metabolism-dependent mechanism
for the analgesic effects of mitragynine and clarify the importance of route of
administration for determining the activity of this compound. Further, they
raise important questions about the interpretation of existing data on
mitragynine and highlight critical areas for further research in animals and
humans.</p
Truncated G protein-coupled mu opioid receptor MOR-1 splice variants are targets for highly potent opioid analgesics lacking side effects
Pain remains a pervasive problem throughout medicine, transcending all specialty boundaries. Despite the extraordinary insights into pain and its mechanisms over the past few decades, few advances have been made with analgesics. Most pain remains treated by opiates, which have significant side effects that limit their utility. We now describe a potent opiate analgesic lacking the traditional side effects associated with classical opiates, including respiratory depression, significant constipation, physical dependence, and, perhaps most important, reinforcing behavior, demonstrating that it is possible to dissociate side effects from analgesia. Evidence indicates that this agent acts through a truncated, six-transmembrane variant of the G protein-coupled mu opioid receptor MOR-1. Although truncated splice variants have been reported for a number of G protein-coupled receptors, their functional relevance has been unclear. Our evidence now suggests that truncated variants can be physiologically important through heterodimerization, even when inactive alone, and can comprise new therapeutic targets, as illustrated by our unique opioid analgesics with a vastly improved pharmacological profile