http://www.back-in-business-physiotherapy.com/images/files/DescendingControl.pdf

Descending control of pain.

http://yael-nissan.weebly.com/uploads/5/2/9/2/5292348/the_introduction_to_pain_an_integrative_review_-_millan.pdf

The induction of pain: an integrative review

Opium is one of the world's oldest drugs, and its derivatives morphine and codeine are among the most used clinical drugs to relieve severe pain. These prototypical opioids produce analgesia as well as many undesirable side effects (sedation, apnoea and dependence) by binding to and activating the G-protein-coupled µ-opioid receptor (µ-OR) in the central nervous system. Here we describe the 2.8 A crystal structure of the mouse µ-OR in complex with an irreversible morphinan antagonist. Compared to the buried binding pocket observed in most G-protein-coupled receptors published so far, the morphinan ligand binds deeply within a large solvent-exposed pocket. Of particular interest, the µ-OR crystallizes as a two-fold symmetrical dimer through a four-helix bundle motif formed by transmembrane segments 5 and 6. These high-resolution insights into opioid receptor structure will enable the application of structure-based approaches to develop better drugs for the management of pain and addiction.

/pdf/crystal-structure-of-the-u-opioid-receptor-bound-to-a-3114f9v1hs.pdf

Crystal structure of the µ-opioid receptor bound to a morphinan antagonist

Opioid drugs play important roles in the clinical management of pain, as well as in the development and treatment of drug abuse. The mu opioid receptor is the primary site of action for the most commonly used opioids, including morphine, heroin, fentanyl, and methadone. By sequencing DNA from 113 former heroin addicts in methadone maintenance and 39 individuals with no history of drug or alcohol abuse or dependence, we have identified five different single-nucleotide polymorphisms (SNPs) in the coding region of the mu opioid receptor gene. The most prevalent SNP is a nucleotide substitution at position 118 (A118G), predicting an amino acid change at a putative N-glycosylation site. This SNP displays an allelic frequency of approximately 10% in our study population. Significant differences in allele distribution were observed among ethnic groups studied. The variant receptor resulting from the A118G SNP did not show altered binding affinities for most opioid peptides and alkaloids tested. However, the A118G variant receptor binds β-endorphin, an endogenous opioid that activates the mu opioid receptor, approximately three times more tightly than the most common allelic form of the receptor. Furthermore, β-endorphin is approximately three times more potent at the A118G variant receptor than at the most common allelic form in agonist-induced activation of G protein-coupled potassium channels. These results show that SNPs in the mu opioid receptor gene can alter binding and signal transduction in the resulting receptor and may have implications for normal physiology, therapeutics, and vulnerability to develop or protection from diverse diseases including the addictive diseases.

https://www.pnas.org/content/pnas/95/16/9608.full.pdf

Single-nucleotide polymorphism in the human mu opioid receptor gene alters beta-endorphin binding and activity : possible implications for opiate addiction

Neuroscience of Addiction

Peptides have been identified in mammalian brain that are considered to be endogenous agonists for the delta (enkephalins) and kappa (dynorphins) opiate receptors, but none has been found to have any preference for the mu receptor. Because morphine and other compounds that are clinically useful and open to abuse act primarily at the mu receptor, it could be important to identify endogenous peptides specific for this site. Here we report the discovery and isolation from brain of such a peptide, endomorphin-1 (Tyr-Pro-Trp-Phe-NH2), which has a high affinity (Ki = 360 pM) and selectivity (4,000- and 15,000-fold preference over the delta and kappa receptors) for the mu receptor. This peptide is more effective than the mu-selective analogue DAMGO in vitro and it produces potent and prolonged analgesia in mice. A second peptide, endomorphin-2 (Tyr-Pro-Phe-Phe-NH2), which differs by one amino acid, was also isolated. The new peptides have the highest specificity and affinity for the mu receptor of any endogenous substance so far described and they may be natural ligands for this receptor.

Lin-Jun Ge

Papers

A potent and selective endogenous agonist for the mu-opiate receptor.

The Endogenous Mu-Opioid Receptor Agonists Endomorphins 1 and 2 Have Novel Hypotensive Activity in the Rabbit