Opioid-induced respiratory depression
Opioid-induced respiratory depression is a potentially fatal side effect in the classical mu-opioid receptor agonists used for pain management especially at high doses.
Opioid receptors are located in respiratory center in the brain stem. Mechanosensory units located in the smooth muscles, submucosa, and the epithelium lining the respiratory tract. These units control the lung mechanics and express opioid receptors. Opioids cause slow and irregular respiration (hypoventilation) leading to hypercapnia (excess CO2) and hypoxia (lack of O2).
Partial mu- agonist opioids like Kratom’s alkaloids are less likely to cause severe respiratory depression, as the full mu-agonist opioids like morphine.
Kratom showed less respiratory depression:
Mitragynine and 7-hydroxymitragynine; the main active constituents in kratom, are selective partial mu-receptor agonist and according to a new study, they showed competitive antagonists activity at kappa and delta- opioid receptors. Affinity of mitragynine to δ – and κ- opioid receptors is higher than that of morphine. The opioid agonist effect of Mitragynine have found to be antagonized by the opioid receptor antagonist naloxone.
Mitragynine and 7-OHMG showed G protein biased signaling over β-arrestin signaling at mu-opioid receptor (MOR). Some evidence indicates that this biased MOR agonists provides less respiratory depression, tolerance development, and constipation, with keeping potent analgesic effect.
Mitragynine has been found to have some affinity to other non-opioid CNS receptors, including α2 adrenergic receptor, ADORA2A, D2R, and the (5-HT2C and 5-HT7) serotonin receptors, but the strength of affinities to these receptors has not been reported.
Kratom and antidepressive action:
Kappa-receptor antagonist activity of both Mitragynine and 7-hydroxymitragynine suggests that kratom alkaloids or even its synthetic derivatives may offer novel antidepressants.
The other alkaloids in the plant as speciogynine, speciociliatine, and paynatheine have shown some effects on intestinal function and behavioral response in animals that were not inhibited by the opioid receptor antagonist naloxone. A new study reported that they showed competitive mu-receptor antagonist activity.