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.
Dynorphins (Dyn) are a class of opioid peptides that arise from the precursor protein prodynorphin. When prodynorphin is cleaved during processing by proprotein convertase 2 (PC2), multiple active peptides are released: dynorphin A, dynorphin B, and α/β-neoendorphin. Depolarization of a neuron containing prodynorphin stimulates PC2 processing, which occurs within synaptic vesicles in the presynaptic terminal. Occasionally, prodynorphin is not fully processed, leading to the release of "big dynorphin". "Big dynorphin" is a 32-amino acid molecule consisting of both dynorphin A and dynorphin B.
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 as ligands 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.
Functional selectivity is the ligand-dependent selectivity for certain signal transduction pathways relative to a reference ligand at the same receptor. Functional selectivity can be present when a receptor has several possible signal transduction pathways. To which degree each pathway is activated thus depends on which ligand binds to the receptor. Functional selectivity, or biased signaling, is most extensively characterized at G protein coupled receptors (GPCRs). A number of biased agonists, such as those at muscarinic M2 receptors tested as analgesics or antiproliferative drugs, or those at opioid receptors that mediate pain, show potential at various receptor families to increase beneficial properties while reducing side effects. For example, pre-clinical studies with G protein biased agonists at the μ-opioid receptor show equivalent efficacy for treating pain with reduced risk for addictive potential and respiratory depression. Studies within the chemokine receptor system also suggest that GPCR biased agonism is physiologically relevant. For example, a beta-arrestin biased agonist of the chemokine receptor CXCR3 induced greater chemotaxis of T cells relative to a G protein biased agonist.
Opioid peptides or opiate peptides are peptides that bind to opioid receptors in the brain; opiates and opioids mimic the effect of these peptides. Such peptides may be produced by the body itself, for example endorphins. The effects of these peptides vary, but they all resemble those of opiates. Brain opioid peptide systems are known to play an important role in motivation, emotion, attachment behaviour, the response to stress and pain, control of food intake, and the rewarding effects of alcohol and nicotine.
The κ-opioid receptor or kappa opioid receptor, abbreviated KOR or KOP for its ligand ketazocine, is a G protein-coupled receptor that in humans is encoded by the OPRK1 gene. The KOR is coupled to the G protein Gi/G0 and is one of four related receptors that bind opioid-like compounds in the brain and are responsible for mediating the effects of these compounds. These effects include altering nociception, consciousness, motor control, and mood. Dysregulation of this receptor system has been implicated in alcohol and drug addiction.
Endomorphins are considered to be natural opioid neuropeptides 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 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.
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.
Atypical chemokine receptor 3 also known as C-X-C chemokine receptor type 7 (CXCR-7) and G-protein coupled receptor 159 (GPR159) is a protein that in humans is encoded by the ACKR3 gene.
RB-101 is a drug that acts as an enkephalinase inhibitor, which is used in scientific research.
Adrenorphin, also sometimes referred to as metorphamide, is an endogenous, C-terminally amidated, opioid octapeptide (Tyr-Gly-Gly-Phe-Met-Arg-Arg-Val-NH2, YGGFMRRV-NH2) that is produced from proteolytic cleavage of proenkephalin A and is widely distributed throughout the mammalian brain. It was named based on the fact that it was originally detected in human phaeochromocytoma tumour derived from the adrenal medulla, and was subsequently found in normal human and bovine adrenal medulla as well. Adrenorphin exhibits potent opioid activity, acting as a balanced μ- and κ-opioid receptor agonist while having no effects on δ-opioid receptors. It possesses analgesic and respiratory depressive properties.
Conolidine is an indole alkaloid. Preliminary reports suggest that it could provide analgesic effects with few of the detrimental side-effects associated with opioids such as morphine, though at present it has only been evaluated in mouse models.
Spinorphin is an endogenous, non-classical opioid peptide of the hemorphin family first isolated from the bovine spinal cord (hence the prefix spin-) and acts as a regulator of the enkephalinases, a class of enzymes that break down endogenous the enkephalin peptides. It does so by inhibiting the enzymes aminopeptidase N (APN), dipeptidyl peptidase III (DPP3), angiotensin-converting enzyme (ACE), and neutral endopeptidase (NEP). Spinorphin is a heptapeptide and has the amino acid sequence Leu-Val-Val-Tyr-Pro-Trp-Thr (LVVYPWT). It has been observed to possess antinociceptive, antiallodynic, and anti-inflammatory properties. The mechanism of action of spinorphin has not been fully elucidated (i.e., how it acts to inhibit the enkephalinases), but it has been found to act as an antagonist of the P2X3 receptor, and as a weak partial agonist/antagonist of the FP1 receptor.
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.
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 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.
RTI-5152-12, or WW-12, is a synthetic small-molecule agonist of the atypical chemokine receptor ACKR3 (CXCR7) that was derived from the naturally occurring alkaloid conolidine. RTI-5152-12 has 15-fold improved potency towards ACKR3 relative to conolidine.
