Endorphins are peptides produced in the brain that block the perception of pain and increase feelings of wellbeing. They are produced and stored in the pituitary gland of the brain. Endorphins are endogenous painkillers often produced in the brain and adrenal medulla during physical exercise or orgasm and inhibit pain, muscle cramps, and relieve stress.
Pro-opiomelanocortin (POMC) is a precursor polypeptide with 241 amino acid residues. POMC is synthesized in corticotrophs of the anterior pituitary from the 267-amino-acid-long polypeptide precursor pre-pro-opiomelanocortin (pre-POMC), by the removal of a 26-amino-acid-long signal peptide sequence during translation. POMC is part of the central melanocortin system.
Opioid receptors are a group of inhibitory G protein-coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are ~40% identical to somatostatin receptors (SSTRs). Opioid receptors are distributed widely in the brain, in the spinal cord, on peripheral neurons, and digestive tract.
An enkephalin is a pentapeptide involved in regulating nociception in the body. The enkephalins are termed endogenous ligands, as they are internally derived and bind to the body's opioid receptors. Discovered in 1975, two forms of enkephalin have been found, one containing leucine ("leu"), and the other containing methionine ("met"). Both are products of the proenkephalin gene.
β-Endorphin (beta-endorphin) is an endogenous opioid neuropeptide and peptide hormone that is produced in certain neurons within the central nervous system and peripheral nervous system. It is one of three endorphins that are produced in humans, the others of which include α-endorphin and γ-endorphin.
Lipotropin is the name for two hormones produced by the cleavage of pro-opiomelanocortin (POMC). The anterior pituitary gland produces the pro-hormone POMC, which is then cleaved again to form adrenocorticotropin (ACTH) and β-lipotropin (β-LPH).
Endomorphins are considered to be natural opioid neurotransmitters central to pain relief. The two known endomorphins, endomorphin-1 and endomorphin-2, are tetrapeptides, consisting of Tyr-Pro-Trp-Phe and Tyr-Pro-Phe-Phe amino acid sequences respectively. These sequences fold into tertiary structures with high specificity and affinity for the μ-opioid receptor, binding it exclusively and strongly. Bound μ-opioid receptors typically induce inhibitory effects on neuronal activity. Endomorphin-like immunoreactivity exists within the central and peripheral nervous systems, where endomorphin-1 appears to be concentrated in the brain and upper brainstem, and endomorphin-2 in the spinal cord and lower brainstem. Because endomorphins activate the μ-opioid receptor, which is the target receptor of morphine and its derivatives, endomorphins possess significant potential as analgesics with reduced side effects and risk of addiction.
The μ-opioid receptors (MOR) are a class of opioid receptors with a high affinity for enkephalins and beta-endorphin, but a low affinity for dynorphins. They are also referred to as μ(mu)-opioid peptide (MOP) receptors. The prototypical μ-opioid receptor agonist is morphine, the primary psychoactive alkaloid in opium and for which the receptor was named, with mu being the first letter of Morpheus, the compound's namesake in the original Greek. It is an inhibitory G-protein coupled receptor that activates the Gi alpha subunit, inhibiting adenylate cyclase activity, lowering cAMP levels.
The nociceptin opioid peptide receptor (NOP), also known as the nociceptin/orphanin FQ (N/OFQ) receptor or kappa-type 3 opioid receptor, is a protein that in humans is encoded by the OPRL1 gene. The nociceptin receptor is a member of the opioid subfamily of G protein-coupled receptors whose natural ligand is the 17 amino acid neuropeptide known as nociceptin (N/OFQ). This receptor is involved in the regulation of numerous brain activities, particularly instinctive and emotional behaviors. Antagonists targeting NOP are under investigation for their role as treatments for depression and Parkinson's disease, whereas NOP agonists have been shown to act as powerful, non-addictive painkillers in non-human primates.
The δ-opioid receptor, also known as delta opioid receptor or simply delta receptor, abbreviated DOR or DOP, is an inhibitory 7-transmembrane G-protein coupled receptor coupled to the G protein Gi/G0 and has enkephalins as its endogenous ligands. The regions of the brain where the δ-opioid receptor is largely expressed vary from species model to species model. In humans, the δ-opioid receptor is most heavily expressed in the basal ganglia and neocortical regions of the brain.
Dynorphin A is a dynorphin, an endogenous opioid peptide that activates the κ-opioid receptor. Its amino acid sequence is Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys.
Leu-enkephalin is an endogenous opioid peptide neurotransmitter with the amino acid sequence Tyr-Gly-Gly-Phe-Leu that is found naturally in the brains of many animals, including humans. It is one of the two forms of enkephalin; the other is met-enkephalin. The tyrosine residue at position 1 is thought to be analogous to the 3-hydroxyl group on morphine. Leu-enkephalin has agonistic actions at both the μ- and δ-opioid receptors, with significantly greater preference for the latter. It has little to no effect on the κ-opioid receptor.
Big dynorphin is an endogenous opioid peptide of the dynorphin family that is composed of both dynorphin A and dynorphin B. Big dynorphin has the amino acid sequence: Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys-Trp-Asp-Asn-Gln-Lys-Arg-Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Gln-Phe-Lys-Val-Val-Thr. It has nociceptive and anxiolytic-like properties, as well as effects on memory in mice.
DAMGO is a synthetic opioid peptide with high μ-opioid receptor specificity. It was synthesized as a biologically stable analog of δ-opioid receptor-preferring endogenous opioids, leu- and met-enkephalin. Structures of DAMGO bound to the µ opioid receptor reveal a very similar binding pose to morphinans.
Neoendorphins are a group of endogenous opioid peptides derived from the proteolytic cleavage of prodynorphin. They include α-neoendorphin and β-neoendorphin. The α-neoendorphin is present in greater amounts in the brain than β-neoendorphin. Both are products of the dynorphin gene, which also expresses dynorphin A, dynorphin A-(1-8), and dynorphin B. These opioid neurotransmitters are especially active in Central Nervous System receptors, whose primary function is pain sensation. These peptides all have the consensus amino acid sequence of Try-Gly-Gly-Phe-Met (met-enkephalin) or Tyr-Gly-Gly-Phe-Leu ( leu-enkephalin). Binding of neoendorphins to opioid receptors (OPR), in the dorsal root ganglion (DRG) neurons results in the reduction of time of calcium-dependent action potential. The α-neoendorphins bind OPRD1(delta), OPRK1(kappa), and OPRM1 (mu) and β-neoendorphin bind OPRK1.
Proenkephalin (PENK), formerly known as proenkephalin A, is an endogenous opioid polypeptide hormone which, via proteolyic cleavage, produces the enkephalin peptides [Met]enkephalin, and to a lesser extent, [Leu]enkephalin. Upon cleavage, each proenkephalin peptide results in the generation of four copies of [Met]enkephalin, two extended copies of [Met]enkephalin, and one copy of [Leu]enkephalin. Contrarily, [Leu]enkephalin] is predominantly synthesized from prodynorphin, which produces three copies of it per cleavage, and no copies of [Met]enkephalin. Other endogenous opioid peptides produced by proenkephalin include adrenorphin, amidorphin, BAM-18, BAM-20P, BAM-22P, peptide B, peptide E, and peptide F.
Leumorphin, also known as dynorphin B1–29, is a naturally occurring endogenous opioid peptide. Derived as a proteolytic cleavage product of residues 226-254 of prodynorphin, leumorphin is a nonacosapeptide and has the sequence Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Gln-Phe-Lys-Val-Val-Thr-Arg-Ser-Gln-Glu-Asp-Pro-Asn-Ala-Tyr-Ser-Gly-Glu-Leu-Phe-Asp-Ala. It can be further reduced to dynorphin B and dynorphin B-14 by pitrilysin metallopeptidase 1, an enzyme of the endopeptidase family. Leumorphin behaves as a potent and selective κ-opioid receptor agonist, similarly to other endogenous opioid peptide derivatives of prodynorphin.
Deltorphin, also known as deltorphin A and dermenkephalin, is a naturally occurring, exogenous opioid heptapeptide and thus, exorphin, with the amino acid sequence Tyr-D-Met-Phe-His-Leu-Met-Asp-NH2. Along with the other deltorphins (such as deltorphin I and deltorphin II) and the dermorphins, deltorphin is endogenous to frogs of the genus Phyllomedusa such as P. bicolor and P. sauvagei where it is produced in their skin, and is not known to occur naturally in any other species. Deltorphin is one of the highest affinity and most selective naturally occurring opioid peptides known, acting as a very potent and highly specific agonist of the δ-opioid receptor.
Endomorphin-2 (EM-2) is an endogenous opioid peptide and one of the two endomorphins. It has the amino acid sequence Tyr-Pro-Phe-Phe-NH2. It is a high affinity, highly selective agonist of the μ-opioid receptor, and along with endomorphin-1 (EM-1), has been proposed to be the actual endogenous ligand of this receptor (that is, rather than the endorphins). Like EM-1, EM-2 produces analgesia in animals, but whereas EM-1 is more prevalent in the brain, EM-2 is more prevalent in the spinal cord. In addition, the action of EM-2 differs from that of EM-1 somewhat, because EM-2 additionally induces the release of dynorphin A and [Met]enkephalin in the spinal cord and brain by an unknown mechanism, which in turn go on to activate the κ- and δ-opioid receptors, respectively, and a portion of the analgesic effects of EM-2 is dependent on this action. Moreover, while EM-1 produces conditioned place preference, a measure of drug reward, EM-2 produces conditioned place aversion, an effect which is dynorphin A-dependent. Similarly to the case of EM-1, the gene encoding for EM-2 has not yet been identified.
John Hughes is a British neuroscientist who shared the 1978 Albert Lasker Award for Basic Medical Research for the discovery of met-enkephalin and leu-enkephalin. This discovery demonstrated that opiate drugs exert their effects on the human brain by mimicking endogenous neurotransmitters, the opioid peptides.
