Pharmacological Consequence of the A118G μ Opioid Receptor Polymorphism on Morphine- and Fentanyl-mediated Modulation of Ca2+ Channels in Humanized Mouse Sensory Neurons

The most common functional single nucleotide polymorphism of the human OPRM1 gene, A118G, has been shown to be associated with interindividual differences in opioid analgesic requirements, particularly with morphine, in patients with acute postoperative pain. The purpose of this study was to examine...

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Published in:	Anesthesiology (Philadelphia) Vol. 115; no. 5; pp. 1054 - 1062
Main Authors:	MAHMOUD, Saifeldin, THORSELL, Annika, SOMMER, Wolfgang H, HEILIG, Markus, HOLGATE, Joan K, BARTLETT, Selena E, RUIZ-VELASCO, Victor
Format:	Journal Article
Language:	English
Published:	Hagerstown, MD Lippincott Williams & Wilkins 01-11-2011
Subjects:	Analgesia Analgesics Analgesics, Opioid - pharmacology Anesthesia Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy Animal models Animals Biological and medical sciences Calcium channels Calcium channels (voltage-gated) Calcium Channels - drug effects Calcium Channels - physiology Cell size Cells, Cultured Dose-Response Relationship, Drug Female fentanyl Fentanyl - pharmacology Humans Male Medical sciences Mice Mice, Inbred C57BL Morphine Morphine - pharmacology Opioid receptors Pain perception Pharmacology Polymorphism, Single Nucleotide Receptors, Opioid, mu - genetics Sensory neurons Sensory Receptor Cells - drug effects Sensory Receptor Cells - physiology Single-nucleotide polymorphism Trigeminal ganglion Trigeminal Ganglion - drug effects Trigeminal Ganglion - physiology Agonist Rodentia μ Opioid receptor Fentanyl Opiates Morphine Narcotic analgesic Vertebrata Mammalia Mouse Animal Anesthesia Phenylpiperidine derivatives Polymorphism
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Summary:	The most common functional single nucleotide polymorphism of the human OPRM1 gene, A118G, has been shown to be associated with interindividual differences in opioid analgesic requirements, particularly with morphine, in patients with acute postoperative pain. The purpose of this study was to examine whether this polymorphism would modulate the morphine and fentanyl pharmacological profile of sensory neurons isolated from a humanized mouse model homozygous for either the 118A or 118G allele. The coupling of wild-type and mutant μ opioid receptors to voltage-gated Ca channels after exposure to either ligand was examined by employing the whole cell variant of the patch-clamp technique in acutely dissociated trigeminal ganglion neurons. Morphine-mediated antinociception was measured in mice carrying either the 118AA or 118GG allele. The biophysical parameters (cell size, current density, and peak current amplitude potential) measured from both groups of sensory neurons were not significantly different. In 118GG neurons, morphine was approximately fivefold less potent and 26% less efficacious than that observed in 118AA neurons. On the other hand, the potency and efficacy of fentanyl were similar for both groups of neurons. Morphine-mediated analgesia in 118GG mice was significantly reduced compared with the 118AA mice. This study provides evidence to suggest that the diminished clinical effect observed with morphine in 118G carriers results from an alteration of the receptor's pharmacology in sensory neurons. In addition, the impaired analgesic response with morphine may explain why carriers of this receptor variant have an increased susceptibility to become addicted to opioids.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23
ISSN:	0003-3022 1528-1175 1528-1175
DOI:	10.1097/ALN.0b013e318231fc11