Relevance of frequent mu-opioid receptor polymorphisms for opioid activity in healthy volunteers
by
Lotsch J, Geisslinger G.
pharmazentrum frankfurt/ZAFES,
Institute of Clinical Pharmacology,
Johann Wolfgang Goethe-University,
Frankfurt am Main, Germany.
j.loetsch@em.uni-frankfurt.de
Pharmacogenomics J. 2006 May-Jun;6(3):200-10.

ABSTRACT

Polymorphisms in the mu-opioid receptor gene (OPRM1) are primary candidate sources of clinical variability in opioid therapy. Apart from the 118A>G single nucleotide polymorphism, nothing is known about the role of OPRM1 mutations in opioid therapy. The influence of the OPRM1 mutations on opioid pharmacodynamics was assessed in pooled data from 31 healthy volunteers obtained in previous studies with available plasma concentrations and pupil diameters after intravenous administration of morphine or morphine-6-glucuronide (M6G). A total of 24 candidate ORPM1 mutations were screened for and those found at an allelic frequency of at least 5% in the 31 subjects were analyzed for functional consequences, using population pharmacokinetic-pharmacodynamic modeling of the miotic effects of the opioids as a reliable and sensitive surrogate parameter of the central nervous opioid effects. Polymorphisms at an allelic frequency of > or =5% (n=310) were 118A>G in exon 1 (11.5%), the IVS2-31G>A (8.9%) and IVS2-691C>G (44.5%) SNPs in intron 2. The 118A>G SNP significantly increased the values of EC50 by a factor of more than 2 (non-mutated: EC50,morphine=30 nmol/l, EC50,M6G=750 nmol/l, 118G carriers: EC50,morphine=66 nmol/l, EC50,M6G=1650 nmol/l), whereas the IVS2-691C>G SNP had no effect. Based on morphine and M6G, the present analysis encourages focusing on the 118A>G SNP when investigating the role of OPRM1 mutations for the activity of opioid analgesics. Other OPRM1 mutations are probably less important either owing to low allelic frequency or due to poor indications for functional consequences. This applies to opioid potency in the context of opioid therapy but not to pain processing or substance addiction, in which opioid receptors are involved but other or additional OPRM1 mutations may be important.

Mu3
SOD Mu
Naloxonazine
Endomorphins
Dihydroetorphine
Receptor subtypes
Mu : gender and age
Morphine/verapamil
Fentanyl and ketamine
Dynorphin and dopamine
Genes, pharmacology and mu
Depression, opioids and the HPA
Kappa upregulation and addiction
Mice without mu don't miss their moms
Mu-opioid receptors, drugs and reward
Opioids, depression and learned helplessness

Refs
and further reading

HOME
HedWeb
Nootropics
cocaine.wiki
Future Opioids
BLTC Research
MDMA/Ecstasy
Superhapiness?
Utopian Surgery?
The Abolitionist Project
The Hedonistic Imperative
The Reproductive Revolution
Critique of Huxley's Brave New World

The Good Drug Guide
The Responsible Parent's Guide
To Healthy Mood Boosters For All The Family