Opioid Receptors

Given the diversity of opioid effects, William R. Martin hypothesized that multiple opioid receptors existed. Recently, a number of previously hypothesized opioid receptors have been cloned (¡, 8, and K).The a-receptor, once thought to be an opioid receptor, is a nonopioid receptor that mediates some of the dysphoric effects of the opioids. The cloned opioid receptors are members of the large superfamily of G protein-coupled receptors. Subtypes of the receptors have been proposed. It has been shown that ^-receptors mediate the analgesic and euphoric effects of the opioids and physical dependence on them, whereas ^-receptors mediate the bradycardiac and respiratory depressant effects. 8-Receptors, of which at least two subtypes have been identified pharmacologically, mediate spinal analgesic effects and have been implicated in the modulation of tolerance to ¡-opioids. Three K-opioid receptors have been identified and are thought to mediate spinal analgesia, miosis, sedation, and diuresis. The existence of the e-receptor is hypothetical pending cloning of the receptor.

Opioid receptors and their precursor mRNAs are distributed throughout the brain and spinal cord. High levels of opioid binding have been found in the ascending pathways for nociceptive transmission, including the dorsal horn of the spinal cord and in particular the sub-stantia gelatinosa lamina II. Other ascending tracts with high levels of binding include the spinothalamic tracts to the subcortical regions and limbic areas of the brain responsible for the discriminative and sensory aspects of pain and the euphoric effects of the drugs. Limbic areas, including cortical sites and the amygdala, are involved in the anxiolytic effects of the drugs. Binding in the thalamus and hypothalamus is also very high. Binding in the hypothalamus is linked to the modulation of hormone release and to thermoregulation by the opioids and opioid peptides. Some descending pathways possess high levels of opioid receptors believed to be linked to the analgesic effects of the drugs. In addition, the receptor binding in medullary pathways has been linked to inhibitory neurotransmitter release in the dorsal horn.

Opioid binding at medullary sites is consistent with the respiratory depressant effects of the drugs. Binding in the nucleus accumbens and the resultant release of dopamine by the and 8-opioids is linked to the development of physical dependence. However, the k-opioids, which also bind extensively in the nucleus accumbens, are linked to a decrease in dopamine release, possibly explaining their lower abuse liability. The localization of different receptor subtypes within different-size fiber pathways has been established. The and 8-receptors appear associated with the large-diameter fibers, while the K-receptors appear to be located in the small to medium-size fiber bundles of the dorsal root ganglia. Such differences may explain the modulation of specific types of nociceptive stimuli by the different opioid agonists and opioid peptides.

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