Endogenous Opioid Peptides

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Chapter: Essential pharmacology : Opioid Analgesics And Antagonists

In the mid 1970s, with herculean efforts, a number of peptides having morphinelike actions were isolated from mammalian brain, pituitary, spinal cord and g.i.t.



In the mid 1970s, with herculean efforts, a number of peptides having morphinelike actions were isolated from mammalian brain, pituitary, spinal cord and g.i.t. These are active in very small amounts, their actions are blocked by naloxone, and they bind with high affinity to the opioid receptors. There are 3 distinct families of opioid peptides. Each is derived from a specific large precursor polypeptide.




β-endorphin (βEND) having amino acids is the most important of the endorphins. It is derived from Proopiomelanocortin (POMC) which also gives rise to γ-MSH, ACTH and two lipotropins. βEND is primarily μ agonist, but also has δ action.




Methionine-enkephalin (met-ENK) and leucine-enkephalin (leu-ENK) are the most important. Both are pentapeptides. The large precursor peptide proenkephalin has 4 met-ENK and 1 leu-ENK residues. The two ENKs have a slightly different spectrum of activity; while met-ENK has equal affinity for μ and δ sites, leu-ENK prefers δ receptors.




Dynorphin A and B (DYNA, DYNB) are 8–17 amino acid peptides derived from prodynorphin which contains 3 leu-ENK residues also. DYNs are more potent on κ receptors, but also activate μ and δ receptors.


Distribution of the 3 families of peptides is summarized below:



The opioid peptides constitute an endogenous opioid system which normally modulates pain perception, mood, hedonic (pleasure related) and motor behaviour, emesis, pituitary hormone release and g.i.t. motility, etc.


β-END injected directly into the brain is 20– 40 times more potent analgesic than morphine. Its primary localization in hypothalamus and pituitary and its long t½ ascribes it a neurohormone function which modulates the release of other hormones. It decreases LH, FSH release and increases GH and prolactin release. Naloxone has opposite effects on the levels of these hormones—suggesting that the system is constitutively active.


The wide distribution of ENKs and DYNs and their short t½ suggests function as neuromodulator or neurotransmitter. They appear to regulate pain responsiveness at spinal and supraspinal levels. Naloxone blocks placebo, acupuncture and stress-induced analgesias, suggesting the involvement of opioid peptides in these responses. Opioid peptides also appear to participate in regulation of affective behaviour and autonomic function.


Recently a novel opioid peptide Nociceptin/orphanin FQ (N/OFQ) has been isolated from mammalian brain. It is localized in cortex, hippocampus, spinal cord and certain sensory sites; is believed to play a role in stress response, reward and reinforcing actions, learning and memory. The N/OFQ receptor, also labelled ‘Opioid-receptor-like1’ (ORL1) receptor, is thus the 4th opioid receptor to be identified. At certain sites, N/OFQ can act as an ‘antiopioid’ through the ORL1 receptor. In the pain control mechanisms, N/OFQ appears to play both opioidlike as well as antagonistic roles, depending on the site and the basal state of pain.


Morphine and other opioids act as exogenous agonists on some of the receptors for these peptides. This has given an explanation for the existence of specific receptors in the body for exogenous substances like morphine. Morphine itself has now been detected in mammalian brain.

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