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N-type calcium channel potassium voltage-gated channel subfamily J Adenylate cyclase type 2 GABAA receptor Gamma- aminobutyric acid type B receptor Solute carrier organic anion transporter family member 1B3 Cholinesterase Mu-type opioid receptor Gβ Gγ γ-Aminobutyric acid Morphine 6-Acetylmorphine cAMP Morphine Morphine Heroin Heroin 6-Acetylmorphine 6-Acetylmorphine Ca+ Ca+ Na+ Na+ γ-Aminobutyric acid Heroin Heroin H2O Acetic acid H2O Acetic acid H2O Acetic acid ATP PPi GTP Cocaine esterase Liver carboxylesterase 1 Cocaine esterase Liver carboxylesterase 1 Pain Guanine nucleotide- binding protein G(i) subunit alpha-1 Magnesium Heroin and 6-Acetylmorphine (6-MAM) are lipid soluble which means they pass through membranes without transporters, including the blood-brain barrier. This leads to a faster uptake of heroin than other drugs Morphine is not lipid soluble, and therefore cannot pass through membranes as easily as heroin or 6-acetylmorphine (6-MAM). It takes slightly longer to activate mu-receptors than 6-MAM, but does contribute to the effects. Neural Axon Endoplasmic Reticulum Lumen The endoplasmic reticulum is present throughout axon of neurons where heroin is metabolized into 6-acetylmorphine and morphine which are the active drugs Less GABA leads to disinhibition of dopamine cell firing in the spinal chord pain transmission neurons. This leads to neuronal depression, including pain signalling Decreased calcium levels lead to decreased neurotransmitter release. Less GABA is released for synaptic vesicles. Morphine and 6-Acetylmorphine agonize to presynaptic mu opioid type receptors. The Gi subunit of the mu opioid receptor activates the inwardly rectifying potassium channel increasing K+ conductance. This causes membrane hyperpolarization decreasing the chances of neuronal firing/action potential. Post-Synaptic Neuron Pre-Synaptic Neuron Synapse Cytosol Synaptic Vesicle The mu opioid receptor through the gamma subunit inhibits voltage gated N-type calcium channels stopping the influx of calcium into the neuron. Blood-Brain Barrier Diffusion With the inhibition of adenylate cyclase, it is unable to synthesize cAMP which further prevents calcium from entering the neuron and depolarization of the neuron Heroin crosses the blood-brain barrier more readily than morphine
Endoplasmic Reticulum CACNB1 KCNJ9 ADCY2 GABRG2 GABBR1 SLCO1B3 BCHE OPRM1 GNB1 GNG2 γ-Aminobutyric acid Morphine 6- Acetylmorphine cAMP Morphine Morphine Heroin Heroin 6- Acetylmorphine 6- Acetylmorphine Calcium Calcium Sodium Sodium γ-Aminobutyric acid Heroin Heroin Water Acetic acid Water Acetic acid Water Acetic acid Adenosine triphosphate Pyrophosphate Guanosine triphosphate CES2 CES1 CES2 CES1 Pain GNAI1