Diacetylmorphine (Heroin)

Heroin (diacetylmorphine) is itself a lipophilic prodrug with low intrinsic affinity for opioid receptors. Its two acetyl groups make it far more lipid-soluble than morphine, so after injection or inhalation it crosses the blood–brain barrier much faster and more completely: the basis of its rapid, intense onset compared with morphine. Once in blood and brain it is rapidly deacetylated, first to 6-monoacetylmorphine (6-MAM) and then to morphine. 6-MAM and morphine are the pharmacologically active species: both are potent agonists at the μ-opioid receptor (MOR), with weaker activity at the δ- and κ-opioid receptors. Heroin's effects are therefore mediated almost entirely by these metabolites rather than by heroin's own receptor binding. The μ-opioid receptor is Gi/o-coupled: activation inhibits adenylyl cyclase (lowering cAMP), opens G-protein-gated inwardly rectifying K⁺ (GIRK) channels and closes voltage-gated Ca²⁺ channels. The resulting neuronal hyperpolarisation and reduced neurotransmitter release produce analgesia, euphoria and sedation. μ-agonism in the brainstem respiratory centres depresses the drive to breathe, the mechanism of fatal overdose, while further μ-mediated effects include miosis (pupillary constriction), reduced gastrointestinal motility (constipation) and, with repeated use, tolerance and physical dependence driven by receptor and second-messenger adaptation.