Endogenous Opioid Peptides

Enkephalin, β-endorphin, and dynorphin were identified as endogenous agonists for the δ-, μ-, and κ-opioid receptors, respectively. Following purification of these peptides from mammalian tissues, cDNAs for the precursors of these peptides were cloned. cDNA cloning and amino acid determination of preproopiomelanocortin demonstrated that the cleavage of this precursor protein produces not only β-endorphin but also several other neuropeptides, including methionine enkephalin, adrenocorticotropic hormone, and α-melanocyte-stimulating hormone. The amino acid sequencing of preproenkephalin indicates that four methionine enkephalins and one leucine enkephalin are cleaved from this precursor. Furthermore, the primary structure of preprodynorphin, the precursor of dynorphin, was determined by cDNA cloning.

A novel endogenous opioid peptide with a significant sequence homology to dynorphin was isolated in 1995.^{[3] [4]} This peptide was called orphanin FQ, or nociceptin, because it lowered the pain threshold under certain conditions, in contrast to the other endogenous opioid peptides. Pharmacologic and physiologic studies have demonstrated that nociceptin/orphanin FQ has behavioral and pain modulatory properties distinct from those of the three classical opioid peptides.^[6] Studies of the effects of nociceptin/orphanin FQ on pain sensitivity have produced conflicting results, which may suggest

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The search for endogenous ligand binding with the μ receptor with high affinity and high selectivity led to the discovery of a class of novel endogenous opioids termed endomorphin-1 and 2,^[8] which are tetrapeptides with the sequence Tyr-Pro-Trp-Phe and Tyr-Pro-Phe-Phe, respectively. An endomorphin gene has yet to be cloned, and much remains to be learned about the anatomic distribution, mode of interaction with the opioid receptors, function in vivo, and potential existence of other related peptides that are highly selective for each of the opioid receptors.