Pharmacological consequence of the A118G μ opioid receptor polymorphism on morphine- and fentanyl-mediated modulation of Ca²⁺ channels in humanized mouse sensory neurons.
- Authors
- Mahmoud, Saifeldin; Thorsell, Annika; Sommer, Wolfgang H; Heilig, Markus; Holgate, Joan K; Bartlett, Selena E; Ruiz-Velasco, Victor
- Year
- 2011
- Journal
- Anesthesiology
- PMID
- 21926562
- DOI
- 10.1097/ALN.0b013e318231fc11
- PMCID
- PMC3203255
BACKGROUND: 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. METHODS: 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. 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 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. 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. 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.
Summary scatter plots of mean membrane capacitance (picoFarads, pF) and Ca2+ current density (picoAmperes/picoFarads, pA/pF) in 118AA and 118GG carrier mice. Membrane capacitance (A) was determined from the numerical integration of a transient elicited with a depolarizing pulse from -80 mV to -70 mV before electronic compensation. Current density (B) was calculated from the peak Ca2+ current amplitude at a test pulse of -15 mV normalized to membrane capacitance. The lines on the plots represent the median with the interquartile range. No significant differences between groups were found employing the two-tailed, unpaired t test for A (P = 0.92) and B (P = 0.32). Numbers in parenthesis indicate the number of neurons tested.
Normalized current-voltage (I-V) curves of Ca2+ currents evoked with a 70 ms pulse from a holding potential of -80 mV to test potentials between -80 and +60 mV in mice carrying the 118AA (A) and 118GG (C) alleles. The current amplitude was measured 10 ms after the onset of the test pulse and normalized to the amplitude at -15 mV. The data in A and C represent the mean (± s.e.m.) Ca2+ current amplitude for each test potential. The number of neurons depicted in A is 58 for test potentials from -80 to -40 mV, 36 for -35 mV, 57 for +45 to +55 mV and 55 for +60 mV. In C, the number of neurons shown is 56 for all test potentials, except for -35 mV where 42 recordings were acquired. The Ca2+ current traces in B and D correspond to a sensory neuron isolated from 118AA and 118GG allele carriers, respectively. The currents were elicited from a holding potential of -80 mV to the indicated test potentials applied every 3 s.
Morphine concentration-response relationships of acutely dissociated TG neurons isolated from humanized mice expressing the MOR 118AA (A) or 118GG (C) allele. Time courses of Ca2+ current inhibition acquired during morphine (10 μM) application in a sensory neuron from 118AA (A) and 118GG (C) mice. The currents were evoked every 10 s by a single 70 ms test pulse to -15 mV from a holding potential of -80 mV (shown in 3B). Peak current amplitudes were determined isochronally 10 ms after depolarization. The filled bars indicate application of 10 μM morphine. B and D show the superimposed Ca2+ currents before (black, 1) and during (grey, 2) morphine application shown in A and C. The concentration-response relationships of 118AA and 118GG sensory neurons exposed to morphine are illustrated in E. Each point represents the mean (± s.e.m.) of the morphine-mediated Ca2+ current inhibition. The numbers in parenthesis indicate the number of neurons that were tested. The smooth curves were obtained by fitting the points to the Hill equation and the IC50 (nM) values for 118AA (●) and 118GG (▲) are shown in the inset. The curve fits for each group were significantly (P < 0.0001) different from each other. MOR = mu opioid receptors; TG = trigeminal ganglion.
Fentanyl concentration-response relationships of acutely dissociated TG neurons isolated from humanized mice expressing the MOR 118AA (A) or 118GG (C) allele. Time courses of Ca2+ current inhibition acquired during fentanyl (10 μM) application in a sensory neuron from 118AA (A) and 118GG (C) mice. The currents were evoked every 10 s by a single 70 ms test pulse to -15 mV from a holding potential of -80 mV (shown in 4B). Peak current amplitudes were determined isochronally 10 ms after depolarization. The filled bars indicate application of 10 μM fentanyl. B and D show the superimposed Ca2+ currents before (black, 1) and during (grey, 2) fentanyl application shown in A and C. The concentration-response relationships of 118AA and 118GG sensory neurons exposed to fentanyl are depicted in E. Each point represents the mean (± s.e.m.) of the fentanyl-mediated Ca2+ current inhibition, except 0.03 μM fentanyl (▲) where n = 2. The numbers in parenthesis indicate the number of neurons that were tested. The smooth curves were obtained by fitting the points to the Hill equation and the IC50 (nM) values for 118AA (●) and 118GG (▲) are shown in the inset. The curve fits for each group were not significantly different from each other (P = 0.63). MOR = mu opioid receptors; TG = trigeminal ganglion.
Morphine-mediated antinociceptive responses employing the hotplate assay in humanized mice expressing the MOR 118AA (●) or 118GG (▲) allele. Humanized 118AA (n = 13) and 118GG (n = 7) mice were administered morphine (3 mg/kg) subcutaneously and the antinociceptive response was determined employing the hotplate apparatus. Thereafter, the % maximal possible effect (MPE) (5A) and %MPE area under the curve (AUC) (5B) were determined. All data are presented as the mean (± s.e.m.); * indicates P < 0.05 employing the Student’s t test. MOR = mu opioid receptors.
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