Opium and its alkaloids

American Journal of Pharmaceutical Education, Summer 2002 by Schiff, Paul L Jr

Endogenous opioids are peptides found in mammalian tissue, with three distinct families of classical endogenous opioid peptides having been characterized. Each of these families contain unique polypeptide precursors that are encoded by three corresponding genes, with each family having a (characteristic distinct) anatomical distribution. These families include the endorphins, the enkephalins, and the dynorphins. betaEndorphin is the major opioid peptide derived from proopiomelanocortin (POMC). Met-enkephalin and leu-enkephalin are derived from proenkephalin, while dynorphin A, dynorphin B, and neoendorphin are all derived from prodynorphin. The pro-opioid proteins are synthesized in the nucleus and transported to nerve cell terminals prior to their release. Active peptides are subsequently hydrolyzed from large proteins via processing proteases that recognize double basic amino acid sequences positioned directly before and after the opioid peptide sequences. Each precursor undergoes cleavage and posttranslational modifications resulting in the production of numerous active peptides. These peptides, having been designated as the "opioid motif," are known to share a common pentapeptide amino-terminal sequence of Tyr-Gly-Gly-Phe- (Met or Leu). C-terminal extensions of this motif occur affording peptides of differing chain length (5-31 residual amino acids)(21-23).

The mode of action of opioids involves an increase in K conductance (opening of K channels) with most neurons responding via hyperpolarization. This results in a decrease of Ca^sup ^ influx into nerve termini (closing of voltage-gated Cae channels) and subsequent inhibition in the release of excitatory neurotransmitters and in synaptic activity. The resulting synaptic inhibition is characterized by either a depressant or an excitant effect, depending on the population of cells involved(23).

Morphine and like narcotic agonists have agonistic actions at the mu (mu), kappa (kappa), and delta (delta) receptors. Nociceptive effects result from actions at the level of both the brain and the spinal cord, the former being resposible for the attenuation of impulse spread and the inhibition of pain perception, while the latter is responsible for inhibition of transmission of nociceptive impulses(23). Major features of morphine and morphine-like narcotic agonists in the central nervous system include: analgesia, drowsiness, euphoria, a sense of detachment, respiratory depression (reduced sensitivity of medullary chemoreceptors to carbon dioxide), nausea and vomiting (direct stimulation of medullary emetic chemoreceptors in the area postrema), depressed cough reflex (partially via direct action on the medullary cough center), and hypothermia. A stimulant action on the parasympathetic portion of the oculomotor nucleus (third cranial nerve) is responsible for pupillary miosis. Orthostatic hypotension results from peripheral vasodilation, reduced peripheral resistance, and inhibition of baroreceptors. Distinct effects on the gastrointestinal tract include decreased motility and secretion, increased resting tone and spasm, and increased anal sphincter tone, all of which combine to produce a classical spastic constipation. Decreased biliary secretions and spasm of the Sphincter of Oddi may occur due to increased biliary tract pressure. Histamine release produces increased bronchial tone in the lungs and vasodilation in the skin. There is a distinct increase in detrusor (urinary bladder wall) tone and vesical (bladder) sphincter tone resulting in urinary retention. Tolerance and physical dependence occur on repeated administration of the drug. Morphine is used therapeutically in the relief of moderate to severe acute and chronic pain, as well as both preoperatively and intraoperatively in various anesthesia protocols. It is also useful in the therapy of acute pulmonary edema, both for its hemodynamic actions and as a calmative. The drug may be given orally, parenterally (intramuscular, intravenous), or rectally in addition to epidurally and intrathecally(21,22,24).