Clinical pharmacology of opioids: basic pharmacology
Nigel Sykes, Michael I Bennett, Chun-Su Yuan in Clinical Pain Management, 2008
Opioid peptides are endogenously produced predominantly in the central nervous system and the spinal cord.37 The three distinct families of peptides, endorphins, enkephalins, and dynorphins, are natural agonist ligands for opioid receptors mu, delta, and kappa, respectively (Table 12.1).35 Each family of opioid peptides is derived from a distinct precursor molecule, with proopiomelanocortin, proenkephalin, and prodynorphin being precursors of endorphins, enkephalins, and dynorphins, respectively. Of the relatively newly discovered endogenous opioid-related peptides, endomorphin-1 and -2 are selective, potent mu-receptor agonists that demonstrate a significant degree of analgesic activity.42, 43 Endomorphin-1 at equianalgesic doses appears to cause less severe respiratory depression compared with other mu agonists,43 suggesting that it may act on specific mu receptor subtypes.44 Another notable endogenous peptide orphanin NQ/nociceptin, a ligand to receptor ORL-1, plays a complex role in producing analgesia and is being investigated.45
Neurotransmitters and pharmacology
Mark J. Ashley, David A. Hovda in Traumatic Brain Injury, 2017
The first discovered opioid peptides were the pentapeptides (containing five amino acids), leucine-enkephalin, and methionine-enkephalin, which were isolated by Hughes et al.202 Although there may be other families of opioid peptides, current interest is focused on three separate families of opioid peptides, each derived from a separate gene family.203 These include 1) the enkephalins (pentapeptides derived from a proenkephalin precursor), 2) the endorphins (e.g., β-endorphin, a 31 amino acid-containing peptide derived from proopiomelanocortin or POMC), and 3) the dynorphins (8 to 13 amino acid-containing peptides derived from a prodynorphin precursor). Three other endogenous opioid peptides have more recently been discovered and are known as orphanin FQ, endomorphin-1, and endomorphin-2. Orphanin FQ, also known as nociceptin, has effects opposite those of morphine and is referred to as pronociceptive (see section on opioid receptors). Much current research is focused on whether the endormorphins are selective mu agonists, but because there is relatively little known about the edomorphin peptides, we focus our discussion on the enkephalins, endorphins, and dynorphins.
Clinical pharmacology: opioids
Pamela E Macintyre, Suellen M Walker, David J Rowbotham in Clinical Pain Management, 2008
Endogenous ligands acting at opioid receptors include enkephalins (δ receptor), dynorphins (κ receptor), endorphins (high affinity, but poor selectivity for μ receptors),41 and nociceptin/orphanin FQ (NOP receptor, see below under Nociceptin/orphanin FQ receptor). The endogenous selective ligands for the μ receptor (endomorphins) were first identified in 1997.29 Both endomorphin 1 and endomorphin 2 are peptides of four amino acids and intimately involved in nociceptive pathways.42 Unlike the other recognized peptides, precursors for endomorphin 1 and 2 have not been identified.
Neuropharmacological basis for multimodal analgesia in chronic pain
Published in Postgraduate Medicine, 2022
Ryan Patel, Anthony H Dickenson
The pain-relieving properties of naturally occurring opioids have been utilized for centuries, and today opioids remain the mainstay of treating acute and chronic pain. Morphine has become the gold standard analgesic to which all others are compared. The classical opioid receptors μ, δ and κ are G-protein coupled, and later a fourth opioid-like receptor (ORL1) was described and renamed the nociceptin receptor. Soon after, a series of endogenous peptide ligands were described. Most of these bind to multiple receptors through endomorphin-1/2 and β-endorphin have highest affinity for μ-opioid receptors, met- and leu-enkephalin have highest affinity δ-opioid receptors, dynorphin A/B have highest affinity κ-opioid receptors, and nociceptin/orphanin FQ has highest affinity for the nociceptin receptor [69]. Upon receptor activation neuronal excitability or action potential propagation is inhibited by several mechanisms including opening of G protein–coupled inwardly rectifying potassium channels [70], inhibition of sodium [71] and calcium channels [72], and inhibition of Ih currents [73].
The potential interplay between opioid and the toll-like receptor 4 (TLR-4)
Published in Immunopharmacology and Immunotoxicology, 2023
Nasrin Zare, Marjan Pourhadi, Golnaz Vaseghi, Shaghayegh Haghjooy Javanmard
Opioids are classified base on the type of opioid receptors. These receptors are located on neuronal cell membranes and all the receptors (the delta receptor or DOP, the kappa receptor or KOP, the mu receptor or MOP, and nociceptin receptor or NOP) are a member of the large family of G-protein-coupled receptors. Pharmacological investigations demonstrate that enkephalins interact with delta receptors or DOP, dynorphin with k receptors or KOP and β-endorphin and endomorphin 1 and 2 with m receptors or MOP and nociceptin receptor or NOP with nociceptin/orphanin FQ (N/OFQ). As well, most clinical drugs such as morphine (a potent alkaloid in opium), Fentanyl/remifentanil, buprenorphine, codeine, and methadone bind to MOP receptors. Furthermore, the opioid antagonist (naloxone and naltrexone) could inhibit all opioid receptors; however, they have the most affinity for m receptors [3–6].
Preclinical discovery and development of oliceridine (Olinvyk®) for the treatment of post-operative pain
Published in Expert Opinion on Drug Discovery, 2022
Ammar A.H. Azzam, David G. Lambert
There is extensive preclinical in vitro evaluation of TRV-130/Oliceridine, Table 2 [11,15,28–36]. Oliceridine binds to MOP with relatively high affinity; 6 nM [28] – 25 nM [32]. In addition, in our own lab, we have reported some binding (no functional data) to NOP. At the time of writing, we were unable to find any other full MOP/DOP/KOP/NOP receptor binding screen. Based on a possible binding profile of ‘Opioid-NOP’ there are similarities with the novel mixed ‘Opioid-NOP’ ligand cebranopadol [7]. We can also infer relative MOP selectivity from the cAMP data in [36]; NOP was not included. In GTPγ[35S] binding studies (G-protein pathway) TRV-130/oliceridine is a full agonist relative to DAMGO; we have reported partial agonist activity at MOP relative to Endomorphin-1. In a second assay for G-protein pathway activation cAMP production is inhibited with relatively high affinity (~10 nM) and efficacy (>70%) relative to DAMGO. For β-arrestin-2 signaling there was a range from predominantly no signal detected to low efficacy. The study of Gillis et al. shows efficacy for β-arrestin-2 of ~50% [29]. Collectively these data describe a relatively high affinity, high selectivity MOP agonist with full or partial agonist activity for G-protein signaling and either no or low efficacy at Arrestin signaling. There is one paper from Lee et al. [37] that appears to show some weak activity at DOP in the cAMP assay. The issue of partial agonism is considered further below.
Related Knowledge Centers
- Endomorphin
- Ligand
- Morphine
- Pain Management
- Agonist
- Protein Primary Structure
- Opioid Peptide
- Μ-Opioid Receptor
- Endomorphin-2
- Gene