7-hydroxymitragynine produces euphoric effects through opioid receptor binding

Interactive Effects of µ-Opioid and Adrenergic-α2 Receptor Agonists in Rats: Pharmacological Investigation of the Primary Kratom Alkaloid Mitragynine and Its Metabolite 7-Hydroxymitragynine. 2022. https://doi.org/10.1124/jpet.122.001192

The primary kratom alkaloid mitragynine is proposed to act through multiple mechanisms, including actions at µ-opioid receptors (MORs) and adrenergic-α2 receptors (Aα2Rs), as well as conversion in vivo to a MOR agonist metabolite (i.e., 7-hydroxymitragynine). Aα2R and MOR agonists can produce antinociceptive synergism. Here, contributions of both receptors to produce mitragynine-related effects were assessed by measuring receptor binding in cell membranes and, in rats, pharmacological behavioral effect antagonism studies. Mitragynine displayed binding affinity at both receptors, whereas 7-hydroxymitragynine only displayed MOR binding affinity. Compounds were tested for their capacity to decrease food-maintained responding and rectal temperature and to produce antinociception in a hotplate test. Prototypical MOR agonists and 7-hydroxymitragynine, but not mitragynine, produced antinociception. MOR agonist and 7-hydroxymitragynine rate-deceasing and antinociceptive effects were antagonized by the opioid antagonist naltrexone but not by the Aα2R antagonist yohimbine. Hypothermia only resulted from reference Aα2R agonists. The rate-deceasing and hypothermic effects of reference Aα2R agonists were antagonized by yohimbine but not naltrexone. Neither naltrexone nor yohimbine antagonized the rate-decreasing effects of mitragynine. Mitragynine and 7-hydroxymitragynine increased the potency of the antinociceptive effects of Aα2R but not MOR reference agonists. Only mitragynine produced hypothermic effects. Isobolographic analyses for the rate-decreasing effects of the reference Aα2R and MOR agonists were also conducted. These results suggest mitragynine and 7-hydroxymitragynine may produce antinociceptive synergism with Aα2R and MOR agonists. When combined with Aα2R agonists, mitragynine could also produce hypothermic synergism. SIGNIFICANCE STATEMENT Mitragynine is proposed to target the µ-opioid receptor (MOR) and adrenergic-α2 receptor (Aα2R) and to produce behavioral effects through conversion to its MOR agonist metabolite 7-hydroxymitragynine. Isobolographic analyses indicated supra-additivity in some dose ratio combinations. This study suggests mitragynine and 7-hydroxymitragynine may produce antinociceptive synergism with Aα2R and MOR agonists. When combined with Aα2R agonists, mitragynine could also produce hypothermic synergism.

IUPHAR themed review: Opioid efficacy, bias, and selectivity.. 2023. https://doi.org/10.1016/j.phrs.2023.106961

Drugs acting at the opioid receptor family are clinically used to treat chronic and acute pain, though they represent the second line of treatment behind GABA analogs, antidepressants and SSRI's. Within the opioid family mu and kappa opioid receptor are commonly targeted. However, activation of the mu opioid receptor has side effects of constipation, tolerance, dependence, euphoria, and respiratory depression; activation of the kappa opioid receptor leads to dysphoria and sedation. The side effects of mu opioid receptor activation have led to mu receptor drugs being widely abused with great overdose risk. For these reasons, newer safer opioid analgesics are in high demand. For many years a focus within the opioid field was finding drugs that activated the G protein pathway at mu opioid receptor, without activating the β-arrestin pathway, known as biased agonism. Recent advances have shown that this may not be the way forward to develop safer analgesics at mu opioid receptor, though there is still some promise at the kappa opioid receptor. Here we discuss recent novel approaches to develop safer opioid drugs including efficacy vs bias and fine-tuning receptor activation by targeting sub-pockets in the orthosteric site, we explore recent works on the structural basis of bias, and we put forward the suggestion that Gα subtype selectivity may be an exciting new area of interest.

A Critical Review of the Neuropharmacological Effects of Kratom: An Insight from the Functional Array of Identified Natural Compounds.. 2023. https://doi.org/10.3390/molecules28217372

Kratom (<i>Mitragyna speciosa</i> Korth. Havil) has been considered a narcotic drug for years, barred by the law in many parts of the world, while extensive research over the past few decades proves its several beneficial effects, some of which are still in ambiguity. In many countries, including Thailand, the indiscriminate use and abuse of kratom have led to the loss of life. Nonetheless, researchers have isolated almost fifty pure compounds from kratom, most of which are alkaloids. The most prevalent compounds, mitragynine and 7-hydroxy mitragynine, are reported to display agonist morphine-like effects on human μ-opioid receptors and antagonists at κ- and δ-opioid receptors with multimodal effects at other central receptors. Mitragynine is also credited to be one of the modulatory molecules for the Keap1-Nrf2 pathway and SOD, CAT, GST, and associated genes' upregulatory cascades, leading it to play a pivotal role in neuroprotective actions while evidently causing neuronal disorders at high doses. Additionally, its anti-inflammatory, antioxidative, antibacterial, and gastroprotective effects are well-cited. In this context, this review focuses on the research gap to resolve ambiguities about the neuronal effects of kratom and demonstrate its prospects as a therapeutic target for neurological disorders associated with other pharmacological effects. In many countries, including Thailand, the indiscriminate use and abuse of kratom have led to the loss of life. Nonetheless, researchers have isolated almost fifty pure compounds from kratom, most of which are alkaloids. The most prevalent compounds, mitragynine and 7-hydroxy mitragynine, are reported to display agonist morphine-like effects on human μ-opioid receptors and antagonists at κ- and δ-opioid receptors with multimodal effects at other central receptors. The primary alkaloid in kratom, mitragynine, a corynanthine-like indole alkaloid, was initially isolated by Field in 1921 and has subsequently shown opioid receptor affinity and partial agonist activity. It makes up roughly 1−2% of the dried leaf material [ 76 ]. The structure of mitragynine, a white amorphous powder, was first fully determined in 1965 through X-ray crystallography [ 77 ] and was found to be soluble in alcohol, chloroform, and acetic acid. Toxicology and Toxicokinetics of Kratom As of yet, nothing is known about the toxicokinetics of kratom in humans, including the metabolic half-life, protein binding characteristics, and elimination rates [ 90 , 91 ]. On the other hand, moderate to high dosages (5 to 15 g) produce opioid-like effects. It has been demonstrated experimentally that low to moderate dosages (1 to 5 g) provide modest stimulant effects to aid employees in overcoming weariness [ 9 ]. High dosages (>15 g) are associated with reports of anxiety, irritation, and increased aggression, which have been linked to several unusual consequences [ 9 , 38 , 51 ]. The ability of 7-HMG to penetrate the blood–brain barrier (BBB) and exert a more rapid effect than morphine has been attributed to its higher potency and rapid effect [ 68 , 122 ]. 7-HMG was also confirmed to have a high level of potency in opioid receptors. The analgesic properties of mitragynine are 13 times greater than those of 7-HMG, while 3–4 times higher for mitragynine [ 23 , 127 ]. There was also evidence that 7-HMG, a minor constituent of kratom, was 46 times more potent as an analgesic than mitragynine in another study [ 122 ]. In humans, it exerts sedative and Due to this characteristic of the plant, drug addicts have been highly tempted to abuse it [ 128 ]. In the tail-flick test in mice, intracerebroventricular administration of mitragynine and mitragynine pseudoindoxyl had an antinociceptive effect with an ED 50 estimate of 60.22 nM and 6.51 nM, respectively. The antinociceptive effects of mitragynine and mitragynine pseudoindoxyl were blocked by naloxone, indicating that they are mediated by opioid receptors [ 78 , 121 ]. By blocking 1-opioid receptors, the antinociceptive effect of 7-HMG was eliminated in both tail-flick and hot-plate tests since its antinociceptive action is dose-dependent and predominantly mediated through these receptors [ 129 ]. It has been shown that mitragynine binds strongly to the μ-opioid receptors and has analgesic, respiratory depression, and euphoric effects [ 130 , 131 ]. A part of the antinociceptive activity of 7-HMG has also been attributed to the supraspinal-μ and δ-opioid receptors [ 6 , 130 , 131 ]. In addition to alleviating withdrawal symptoms, kratom can be used to diminish the effects of opium addiction. However, it has a lower affinity for the κ-receptor [ 131 ]. Through presynaptic dopamine actions, the κ-receptor exhibited analgesic and depressive effects on locomotor activity [ 132 ]. 7-HMG’s supportive actions are partially mediated by μ and δ-opiate receptors [ 133 ]. In contrast, a study revealed that kratom powder has less affinity for the μ-opioid receptor than morphine [ 134 ]. In mice, the head-twitch reaction brought on by activating postsynaptic 2-adrenoceptors can be reduced by mitragynine and the 5-HT2A receptor antagonist ritanserine. Mitragynine and 7-hydroxymitragynine may produce antinociceptive synergism with adrenergic-α2 (Aα2R) and μ-opioid receptor agonists, according to Obeng, S [ 135 ]. Mitragynine administration into the fourth ventricle of anesthetized rats caused a dose-dependent inhibition of 2-deoxy - d - glucose-stimulated gastric acid secretion, though its effects were reversed by naloxone, indicating the involvement of opioid receptors. Mitragynine administration centrally did not affect the basal gastric acid secretion into the lateral ventricle. In addition to having an impact on anorexia and weight loss, mitragynine also has a direct inhibitory effect on neurons in the lateral hypothalamus [ 166 ]. In addition, subcutaneous administration of 7-HMG to mice inhibited their gastrointestinal transit [ 68 ].

Opioid overdose. https://en.wikipedia.org/wiki/Opioid_overdose

increased drug usage. Opioids bind with neural opioid receptors to provoke analgesic, sedative, and euphoric effects. Opioids function by stimulating An opioid overdose is toxicity due to excessive consumption of opioids, such as morphine, codeine, heroin, fentanyl, tramadol, Oxycodone, and methadone. This preventable pathology can be fatal if it leads to respiratory depression, a lethal condition that can cause hypoxia from slow and shallow breathing. Other symptoms include small pupils and unconsciousness; however, its onset can depend on the Opioids bind with neural opioid receptors to provoke analgesic, sedative, and euphoric effects. Opioids function by stimulating specific G-protein coupled receptors distributed throughout the body—including the brain, skin and spinal cord. Three of the major opioid receptors include mu, kappa, delta, and nociception, each playing a role in eliciting the effects associated with opioids. An opioid overdose results from over-activation of these receptors, which can cause permanent brain damage from cerebral hypoxia or neurotoxicity. Mu receptors have an analgesic effect on the brain, and are found in various parts of the nervous system including the cerebral cortex and thalamus. They can be found in the nucleus accumbens, the pleasure centre of the brain, as well as the amygdala. Kappa receptors, in the hypothalamus, produce a similar analgesic effect. They bind with dynorphins to stimulate anti-reward effects (dysphoria) and other negative effects of withdrawal. While mu receptors are the source of addiction, kappa receptors contribute to continued use. They generate dysphoria in response to increasing stress levels via corticotropin-releasing factor (CRF). This increases erratic shifts in mood during the withdrawal period and can prompt relapse. Delta receptors, found in the basal ganglia of the limbic system, have been shown to reduce anxiety by binding with enkephalins, although this requires further research. The most recent addition to these receptors are nociception opioid receptors. Although they have been determined to be receptors to certain ligands from opioids, their role is not yet fully understood. When opioids are ingested, the ligand binds to these constitutively active receptors to reduce neural activity. This is accomplished by inhibiting adenylyl cyclase and cyclic AMP, which are necessary for communication within the central nervous system. There is research indicating that opioids reduce pain by disrupting ion channels and vesicle fusion. Prolonged exposure to opioids can cause these receptors to become internalized, leading to increased tolerance and increased opioid use.