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

Abstract

Background The most common functional single nucleotide polymorphism of the human OPRM1 gene, A118G, has been shown to be associated with inter-individual differences in opioid analgesic requirements, particularly with morphine, in patients with acute postoperative pain. The purpose of the present 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. Methods The coupling of wild-type and mutant mu opioid receptors to voltage-gated Ca2+ 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. Results 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 5-fold 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 to the 118AA mice. Conclusions 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. Additionally, the impaired analgesic response with morphine may explain why carriers of this receptor variant have an increased susceptibility to become addicted to opioids.

Receptor Reserve Moderates Mesolimbic Responses to Opioids in a Humanized Mouse Model of the OPRM1 A118G Polymorphism

“…Naive h/mOPRM1-118AA and 118GG mice are equally sensitive to fentanyl, supporting previous findings using this model (Mahmoud et al, 2011). As a highly potent, efficacious, and brain-penetrant agonist, fentanyl has a large receptor reserve in vivo that appears to override differences in tissue receptor content.…”

Structural Consequences of the Polymorphism Q223r in the Human Leptin Receptor: A Molecular Dynamics Study

“…Also, some reports have evidenced that the polymorphisms could affect the protein's functionality such as its interaction with ligands, the dimerization, or signalling. As for LEPR, fluctuations of the alpha carbons support the hypothesis that the change of a single amino acid could modify the LEP-LEPR interaction or LEPR function (Basu et al, 2011;Mahmoud et al, 2011;Marie et al, 2012;Yates and Sternberg, 2013).…”

Impact of A118G Polymorphism on the Mu Opioid Receptor Function in Pain

“…However, one study has reported the opposite result in humanized mice expressing human MOR-N or MOR-D. This study found that Ca V currents from trigeminal ganglion neurons are inhibited at lower morphine doses when the neurons are injected with human MOR-D mRNA as compared with the inhibition observed in neurons injected with MOR-N mRNA [11]. The discrepancy between this report and the previously mentioned studies could be due to the fact that trigeminal ganglia have several Ca V types contributing to the voltage gated calcium currents [28,29] while Lopez Soto et al [8] analyzed Ca V 2.2 transfected in HEK293 cells and Margas et al [7] studied SGC neurons where the Ca V 2.2 are the predominant voltage gated channels.…”

“…At molecular level, we and others have reported differences in the agonist affinity and potency, intracellular cascades and effectors involved in MOR effects [4][5][6][7][8][9][10][11]. On the other hand, clinical studies have demonstrated changes in pain sensation and morphine requirements under different pain conditions [12][13][14][15][16].…”