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Pathway Description
Diamorphine Action Pathway
Homo sapiens
Drug Action Pathway
Created: 2022-03-09
Last Updated: 2023-10-25
Diamorphine (heroin) is a narcotic analgesic used to manage pain and to induce feelings of eurphoria. It is illegal in most countries, but in the UK it is legal so long as prescribed under the name diamorphine instead of heroin. It is a pro-drug for morphine and 6-MAM which means diamorphine doesn't act on opioid receptors itself, and instead synthesizes morphine and 6-acetylmorphine (6-MAM) which act on mu-opioid receptors, as well as kappa-opioid receptors and delta-opioid receptors. These receptors all have similar effects, but the main target is mu-opioid receptors. Diamorphine is a highly addictive drug especially when taken intravenously where the onset of effect is quite fast because of diamorphine and 6-MAM's ability to pass through membranes due to it being lipid soluble. The effects are less if taken orally since the onset of effect is slower.
Diamorphine can be metabolized by first-pass metabolism in the liver if taken orally or in the central nervous sytem. In the central nervous system it is metabolized in the lumen of the endoplasmic reticulum in neurons. Diamorphine passes directly into the endoplasmic reticulum where it is metabolized by either liver carboxylesterase 1 or cocaine esterase into 6-MAM which is metabolized by the same enzymes into morphine. Diamorphine is also metabolized by cholinesterase directly into morphine. 6-MAM on its own, if it is not metabolized into morphine, diffuses through the membrane and binds to and activates a pre-synaptic mu-opioid receptor. Morphine is transported out of the endoplasmic reticulum lumen by solute carrier organic anion transporter family member 1B3 or a similar transporter. Morphine takes slightly longer to bind and activate the mu-opioid receptor whcih means 6-MAM attributes more to the immediate high caused by diamorphine.
The mu-opioid receptor is coupled with G-protein receptors. Binding of 6-MAM or morphine stimulates the exchange of GTP for GDP on the G-protein complex. The G-protein system inhibits adenylate cyclase which prevents ATP from being synthesized into cAMP which causes a decrease in intracellular cAMP. The activated G-proteins also close N-type voltage-operated calcium channels which prevents calcium from entering the neuron, and it opens calcium-dependent inwardly rectifying potassium channels which causes sodium to leave the neuron. This results in hyperpolarization and reduced neuronal excitability. Subsequently, this leads to the release of nociceptive neurotransmitters such as GABA. Less GABA leads to disinhibition of dopamine cell firing in the spinal cord and brain pain transmission neurons as well as the pleasure center of the brain. This leads to less pain signaling and analgesia, as well as increased pleasure and feelings of euphoria. There are a lot of side-effects caused by diamorphine.
References
Diamorphine Pathway References
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