Mode Of Action

Endogenous opioid peptides (endorphins, dynor-phins, enkephalins), have been termed 'the brain's own morphine'. Their discovery in 1972 explained why the brain has opioid receptors when there were no opioids in the body. These peptides attach to specific opioid receptors, mainly Li (mu), 5 (delta) or k (kappa) located at several spinal and multiple supraspinal sites in the CNS. Opioid receptors are part of the family of G-protein-coupled receptors (see p. 91) and act to open potassium channels and prevent the opening of voltage-gated calcium channels which reduces neuronal excitability and inhibits the release of pain neurotransmitters, including substance P.

The most important is the ja-receptor, of which two subtypes are recognised, the li,-receptor, associated with analgesia, euphoria and dependence, and the (i2-receptor with respiratory depression and inhibition of gut motility. The K-receptor is responsible for analgesia at the level of the spinal cord and is also associated with dysphoria. The role of the 8-receptor in humans is less clear.

Pure morphine-like opioid agonists in general act on p- and k-receptors.

27 In classical mythology Morpheus was son of Somnus, the infernal deity who presided over sleep. He was generally represented as a corpulent, winged boy holding opium poppies in is hand. His principal function seems to have been to stand by his sleeping father's black-curtained bed of feathers, on watch to prevent his being awakened by noise.

Mixed agonist-antagonists and partial agonists.

Opioid drugs may be agonist to one class of opioid receptor, and antagonist to another, which explains the differing patterns of action seen. A single opioid may also have dual agonist/antagonist effect on a single receptor; these are known as partial agonists. Buprenorphine is a partial agonist at the |i- and an antagonist at the k-receptor. Pentazocine produces analgesia and also dysphoria by activating spinal k-receptors, and is a weak antagonist of p-receptors. Partial agonists have a limited ceiling of therapeutic efficacy and by antagonism will precipitate a withdrawal syndrome if given to subjects dependent on morphine or heroin (high-efficacy agonists). In addition, a weak (low-efficacy) agonist (codeine) will compete with a high-efficacy opioid for receptors and so reduce the receptor occupancy, and therefore the therapeutic efficacy of the latter. Thus a weak agonist partially antagonises a strong agonist. It is no surprise that there are differences between opioids in both emphasis and the pattern of their many actions.

Pure competitive opioid antagonists, e.g. naloxone, naltrexone, block all opioid receptors while exerting no activating effect.

Some of the endorphins, dynorphin and enkephalins are about as active as morphine and some have higher efficacy. The discovery of the function of natural opioid mechanisms in physiology and pathology opens up possibilities for major developments in pain management, and indeed, wider, for endogenous opioid mechanisms may play a role, e.g. in shock.

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