In any discussion regarding the ‘primary-secondary’ actions of homeopathic drug substances, the phenomenon of ‘opium causing excessive sleep and constipation, later followed by profound sleeplessness” is always cited as an example.

Opium contains two main groups of alkaloids. Phenanthrenes such as morphine, codeine, and thebaine are the main narcotic constituents. Isoquinolines such as papaverine and noscapine have no significant central nervous system effects

To understand the biochemistry of ‘primary- secondary’ actions of opium, we should learn the biochemical processes involving μ-opioid receptors.

Read from Wikipedia: “The μ-opioid receptors (MOR) are a class of opioid receptors with high affinity for enkephalins and beta-endorphin but low affinity for dynorphins. They are also referred to as μ opioid peptide (MOP) receptors. The prototypical μ receptor agonist is the opium alkaloid morphine; μ (mu) refers to morphin

MOR can mediate acute changes in neuronal excitability via “disinhibition” of presynaptic release of GABA. Activation of the MOR leads to different effects on dendritic spines depending upon the agonist, and may be an example of functional selectivity at the μ receptor. The physiological and pathological roles of these two distinct mechanisms remain to be clarified. Perhaps, both might be involved in opioid addiction and opioid-induced deficits in cognition.

Activation of the μ receptor by an agonist such as morphine causes analgesia, sedation, slightly reduced blood pressure, itching, nausea, euphoria, decreased respiration, miosis (constricted pupils) and decreased bowel motility often leading to constipation. Some of these side effects, such as sedation, euphoria and decreased respiration, tend to lessen with continued use as tolerance develops. Analgesia, miosis and reduced bowel motility tend to persist; little tolerance develops to these effects.

As with other G protein-coupled receptors, signalling by the mu opioid receptor is terminated through several different mechanisms, which are upregulated with chronic use, leading to rapid tachyphylaxis. The most important regulatory proteins for the mu opioid receptor are the β-arrestins Arrestin beta 1 and Arrestin beta 2, and the RGS proteins RGS4, RGS9-2, RGS14 and RGSZ2.

Long-term or high dose use of opioids may also lead to additional mechanisms of tolerance becoming involved. This includes downregulation of mu opioid receptor gene expression, so the number of receptors presented on the cell surface is actually reduced, as opposed to the more short-term desensitisation induced by β-arrestins or RGS proteins. Another long-term adaptation to opioid use can be upregulation of glutamate and other pathways in the brain which can exert an opioid-opposing effect and so reduce the effects of opioid drugs by altering downstream pathways, regardless of mu opioid receptor activation.

Opioid overdoses kill through apnea and fatal hypoxia, often aggravated by simultaneous use of alcohol, benzodiazepines or barbiturates. Substantial tolerance to respiratory depression develops quickly, and tolerant individuals can withstand larger doses. However tolerance to respiratory depression is lost just as quickly during withdrawal. Many overdoses occur in people who misuse their medication after being in withdrawal long enough to lose the tolerance to respiratory depression. Less commonly, massive overdoses have been known to cause circulatory collapse.

Opioid overdoses can be rapidly reversed with any of several opioid antagonists: naloxone, or naltrexone, differing primarily in their duration of action and potency. While commonly referred to as antagonists, and when used to treat an overdose they do appear to function as such, naloxone & naltrexone are inverse agonists”.

So-called secondary actions of opioid substances such as opium can be explained by the phenomenon up-regulation of glutamate and other pathways in the brain induced by the over-activation of opioid receptors, thereby exert an opioid-opposing effect and so reduce the effects of opioid drugs by altering downstream pathways, regardless of mu opioid receptor activation. In effect, the ‘primary-action’ of opioids finally lead to ‘secondary actions’, which are totally in reverse direction.

This is the biochemical mechanism underlying the ‘primary-secondary actions’ of ‘opioid’ substances.
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