Consequences of the 118A>G polymorphism in the OPRM1 gene: translation from bench to bedside?

Figures & data

Figure 1 Consequences of OPRM1 118A>G SNP.

Abbreviations: mRNA, messenger RNA; SNP, single nucleotide polymorphism.

Table 1 Molecular consequences of the 118A>G polymorphism (in vitro studies)

Author	Experimental setting	Opioid analyzed	Results
Bond et al^Citation16	• Radioligand-binding assay in AV-12 cells stably expressing the human μ-opioid receptor variants • Electrophysiological analysis in Xenopus oocytes injected with in vitro transcribed mRNAs for the 118A or the 118G alleles	β-endorphins, Met-enkephalin, Leu-enkephalin, endomorphin-1, endomorphin-2, DAMGO, dynorphin A morphine, fentanyl, methadone, naloxone	• Compared to the wild-type the variant receptor had 3-fold higher binding affinity for β-endorphins but it showed unaltered binding affinity for all the other opioid analyzed • β-endorphins are 3 times more potent in agonist-induced activation of G protein–coupled potassium channels at the variant receptor compared to the wild-type
Befort et al^Citation18	• Studies of ligand-binding and [^Citation35 S]GTPγS binding assay using COS cells • Study of receptor desensitization using HEK293 cells	β-endorphin, morphine, DAMGO, CTOP, heroin, Met-enkephalin, dynorphin A	• No differences in the agonist-binding property between the variant and the wild-type receptors • No differences in the agonist-induced stimulation between the variant and the wild-type receptors at the G protein level • No differences in receptor downregulation between the variant and the wild-type receptors
Beyer et al^Citation19	HEK293 cells stably expressing the human μ-opioid receptor variants	β-endorphin, morphine, morphine-6-glucuronide	• Lower cell-surface receptor binding site availability in cells expressing the 118G variant compared to cells expressing the 118A one • No differences in the opioids-binding property between the variant and the wild-type receptors • No differences in opioid-induced receptor response between the variant and the wild-type receptors • Wild-type and variant receptors do not differ in their time courses of agonist-induced desensitization and resensitization
Margas et al^Citation20	Evaluation of 118A>G SNP on intracellular signaling cascades downstream μ-opioid receptors using sympathetic neurons transfected with either 118G or 118A allele	Endomorphin-l, DAMGO, morphine, morphine-6-glucuronide	DAMGO and morphine were more potent in inhibiting calcium channel currents downstream variant μ-opioid receptor activation compared to the wild-type
Kroslak et al^Citation21	• AV-12 cells stably expressing the human μ-opioid receptor variants • HEK293 cells stably expressing the human μ-opioid receptor variants	β-endorphin, morphine, methadone, DAMGO	• Lower cell-surface receptor binding site availability in cells expressing the 118G variant compared to cells expressing the 118A one • Forskolin-induced cAMP-levels in 118G transfected cells were lower than in cells expressing the wild-type receptors • 118G variant was associated to a less potent agonist-mediated cAMP signaling for morphine, methadone and DAMGO, but not for β-endorphin
Oertel et al^Citation22	Analysis of μ-opioid receptor expression, binding affinity and signaling in human post-mortem brain tissue from both the secondary somatosensory area and the ventral posterior part of the lateral thalamus	DAMGO	In secondary somatosensory area DAMGO was less efficient in agonist-induced receptor signaling in 118G carriers than 118A homozygous
Deb et al^Citation30	Murine neuroblastoma Neuro 2A cells stably transfected with cDNA containing the 118G	Morphine	• No differences in pCREB levels upon both chronic and acute treatment are shown in both wild-type and mutants • 118G expressing cells exhibited lower basal level of pERK 1/2 and a higher level of PKA compared to the wild-type • Acute treatment causes inhibition of PKA and induction of pERK 1 activity for both the mutant and the wild-type (hence, both the variant and the wild-type triggered a similar response during acute treatment) • Differential regulation of PKA and pERK 1/2 occurs between the mutant and the wild-type cells during chronic treatment: PKA activity and pERK 1/2 level remained unaltered in cells expressing the mutant
Zhang et al^Citation31	• Human autopsy brain tissue • Transfected CHO cells		• 118A mRNA was 1.5–2.5 fold more abundant than the 118G mRNA in both human tissues and CHO cells. mRNA turnover was the same for 118A and 118G variants • The levels of the variant receptors were 10-fold lower than the wild-type in CHO cells
Huang et al^Citation13	• Ex vivo studies on tissue derived from the knock-in mouse model 112A>G • CHO cells stably expressing the human μ-opioid receptor		• The variant receptor had lower relative molecular mass than the wild-type one which was due to differences in N- glycosylation in both experimental settings • Pulse-chase studies in CHO cells revealed that the half life of the mature form of variant receptor was shorter than that of the wild-type

Abbreviations: AV-12 cells, Syrian hamster adenovirus-12-induced tumor cell line; DAMGO, [D-ala2,MePhe4,Gly(ol)5]enkephalin; HEK293 cells, human 293 embryonic kidney cells; COS cells, cells being CV-1, simian, in Origin, and carrying the SV40 genetic material; CTOP, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH₂; pCREB, phosphorylated cAMP response element-binding protein; pERK, phosphorylated extracellular signal regulated kinase; PKA, protein kinase A; CHO, Chinese hamster ovary.

Table 2 Animal models for the 118A>G SNP

Author	Animal model	Phenotypes	Results of either ex vivo or in vitro-related analyses
Miller et al^Citation35	770G Rhesus macaque. These non-human primates show the substitution of a C with a G at position 77 resulting in a substitution of an arginine with a proline in the orthologue μ-opioid receptor	• 77G macaques showed lower basal and ACTH-stimulated plasma Cortisol levels • 77G macaques had higher aggressive threat scores than 77C macaques	The expression of 77G-containing rhesus monkey μ-opioid receptor clones in HEK293 cells was related to a ~3.5 fold increase of μ-opioid receptor affinity for β-endorphin but not for exogenous opioid ligands
Barr et al^Citation40	77C>G Rhesus macaque. These non-human primates show the substitution of a C with a G at position 77 resulting in a substitution of an arginine with a proline in the orthologue μ-opioid receptor	• 77G macaques had higher alcohol preference than 77C homozygous subjects • After naltrexone administration 77G carriers decreased their preference compared to vehicle and no longer differed from 77C homozygous subjects
Mague et al^Citation41	112A>G mice: knock-in mouse model in which a point mutation (substitution of a A with a G in position 112) has been inserted in the mouse μ-opioid receptor gene. The 112A>G leads to the substitution of an asparagine with aspartic acid at position 38 of the amino acid sequence of the mouse receptor protein and causes the elimination of a N- glycosylation site, similarly to human 118A>G SNP	• In contrast to 112AA mice, homozygous 112G mice did not exhibit hyperactivity following acute morphine administration. In contrast to 112AA mice, 112GG mice did not develop locomotor sensitization following repeated morphine administration • Hot-plate assay: 112GG mice showed lower analgesic effect of morphine than 112AA mice. At high temperatures 112GG mice showed both higher sensitivity to pain and lower analgesic effect of morphine than 112AA mice. Following 7 days of repeated morphine injections all animals showed the occurrence of tolerance • A sex x genotype interaction is evident in behavioral responses associated to hedonia, with female mice homozygous for the 112G allele showing a reduction in both the rewarding properties of morphine and in the aversive components of naloxone-precipitated morphine withdrawal	• Ex vivo analyses of μ-opioid receptor expression and levels: mRNA was reduced in 112GG mice in several brain regions related to pain, stress and reward (PAG, hypothalamus, VTA NAc and cortex). Receptor protein levels were reduced in 112GG animals compared to 112AA mice, particularly in the thalamus • Variant receptors showed binding affinity for β-endorphin, morphine and naloxone comparable to the wild-type
Ramchandani et al^Citation43	Humanized mouse genes for the μ-opioid receptor: in these mice the first exon of the mouse μ-opioid receptor gene has been replaced by the corresponding human sequence carrying either 118A or 118G allele	• Microdialysis on humanized mice: 118GG mice showed a 4-fold increase in DA release in striatum in response to alcohol compared to 118AA mice • PET study on humans using [^Citation11 C]-raclopride (an antagonist of D2 receptors): 118AG subjects showed greater DA release than 118AA individuals in striatum after an intravenous alcohol challenge • This mouse model shares a specific neurochemical pattern with humans	• Expression of humanized μ-opioid receptor mouse gene in CHO cells: variant receptors showed binding affinity for β-endorphin comparable to the wild-type • Electrophysiological analyses in isolated trigeminal ganglion neurons: there were no genotype differences in Ca^++ currents in response to the μ-opioid receptor agonists DAMGO and β-endorphin • [^Citation3 H]-DAMGO binding on mouse brain sections did not show genotype differences in receptor densities across a number of brain regions examined (ventral and dorsal striatum and VTA)
Mahmoud et al^Citation48	Humanized mouse genes for the μ-opioid receptor: in these mice the first exon of the mouse μ-opioid receptor gene has been replaced by the corresponding human sequence carrying either 118A or 118G allele	118AA mice had a greater analgesic response to morphine compared to 118GG mice	• Sensory neurons isolated from 118G homozygous humanized mice show a fivefold reduced potency of morphine, (but not of fentanyl) in inhibiting voltage-gated calcium channels downstream μ-opioid receptors compared with neurons isolated from 118A homozygous mice • Biophysical parameters (cell size, current density and peak current amplitude potential) were the same in both groups of neurons

Abbreviations: ACTH, adrenocorticotropic hormone; HEK293, human 293 embryonic kidney cells; PAG, periaqueductal gray; VTA, ventral tegmental area; NAc, nucleus accumbens; DA, dopamine; PET, positron emission tomography; CHO, Chinese hamster ovary; DAMGO, [D-ala2,MePhe4,Gly(ol)5]enkephalin.

Table 3 Clinical trials evaluating the 118A>G SNP

Author	Type of pain	Drug	Routes of administration	No of patients	Ethnicity	Effect of 118A>G SNP on individual sensitivity to pain	Effect of 118A>G SNP on the analgesic effect of the drug	Effect of 118A>G SNP on the occurrence/ severity of drug-related side effects
Fillingim et al^Citation45	EP: response to thermal, mechanical and ischemic pain	–	–	167 healthy subjects	Mixed	• 118G carriers showed higher pressure pain threshold than 118AA individuals• The 118G allele was associated with lower pain ratings among man but higher pain ratings among women for heat pain
Lötsch et al^Citation51	EP: evaluation of pain related cortical potential following a nociceptive stimulus (CO2) applied to the nasal mucosa	–	–	45 healthy subjects	Caucasian	Amplitudes of nociceptive event-related potentials in carriers of 118G allele were half as high as dose of non-carriers
Huang et al^Citation52	EP: pressor-induced pain test	–	–	72 healthy women	Taiwanese	No differences due to genotype
Fukuda et al^Citation53	• EP before surgery: cold pressor-induced pain test before and after opioid administration • AP due to orofacial surgery	F	• EP: Bolus iv injection • AP: iv (PCA)	280	Japanese	118G carriers showed a tendency (P = 0.064) for a lower EP threshold than 118AA individuals	• Carriers of 118G allele showed a lower analgesic effect of F during experimental pain • The 118A allele had no significant association with 24 h post-operative, perioperative, total perioperative F use and VAS at 3 and 24 h
Fukuda et al^Citation54	• EP before surgery: cold pressor-induced pain test before and after opioid administration • AP due to orofacial surgery	F	• EP: Bolus iv injection • AP: iv (PCA)	60	Japanese	118G carriers are more sensitive to EP than 118AA	• Carriers of 118G allele showed a lower analgesic effect of F during EP• Homozygous 118G patients showed higher drug consumption in the first post-operative 24 hours
Chou et al^Citation55	AP due to total knee arthroplasty	Mo	iv (PCA)	120	Taiwanese		• No differences in perceived pain (VAS) during opioid treatment at any assessment throughout the first post-operative 24 h• Homozygous 118G consumed more drug than 118AG and 118AA in the first post-operative 48 hours • Homozygous 118G demanded more doses than 1118AG and 118AA in the first post-operative 48 hours	• Patients were evaluated for: nausea (on a 4-point scale), pruritus (using the pain-track method), vomiting (assessed as events occurring in the first 24 h), sedation (Ramsey sedation score), respiratory rate and level of consciousness • There were no cases of respiratory depression • No influence of genotypes for adverse effects
Chou et al^Citation56	AP due to total hysterectomy	Mo	iv (PCA)	80 women	Taiwanese		• No differences in perceived pain (VAS) during opioid treatment at any assessment throughout the first postoperative 48 h • Homozygous 118G consumed more drug than 118AA in the first postoperative 24 hours • Homozygous 118G demanded more doses than 118AG and 118AA in the first post-operative 48 hours	• Patients were evaluated for: nausea (on a 4-point scale), vomiting (assessed as events occurring in the first 24 h), sedation (Ramsey sedation score), respiratory rate and level of consciousness • There was a tendency for the 118A carriers for more vomiting episodes than 118G carriers • No influence of genotypes for other adverse effects
Sia et al^Citation57	AP due to cesarean	Mo	iv (PCA)	588 women	Chinese Singaporean		• Carriers of 118G allele self-administered more iv Mo (PCA) in the first postoperative 24 hours: each additional copy of the G allele increased total Mo intake of 1.87 mg • Carriers of 118G allele had a worse control of pain (VAS): each additional copy of the G allele increased pain scores by 0.51 units• Total Mo consumption was also influenced by patient’s age and paying status	• Patients were evaluated for: nausea (on a 4-point scale), vomiting (assessed as events occurring in the first 24 h), CNS depression, respiratory depression and pruritus (on a 4-point scale) • No cases of respiratory and CNS depression • 118AA subjects were associated with the highest incidence of nausea than 118G carriers • No influence of genotypes for other adverse effects
Tan et al^Citation58	AP due to cesarean	Mo	(PCA)	994 women	Chinese, Malays, Indians		• 118GG subjects reported higher pain scores (VAS) and thus consumed more Mo than 118A carriers during the first post-operative 24 hrs • Pain score and Mo usage was also influenced by ethnicity, age and paying class • The 118G allelic frequency in the main ethnic groups considered were: 0.339 for Chinese, 0.49 for Malays and 0.441 for Indians. Separate analysis performed for each the 3 ethnic groups revealed that there was a statistically significant association between 118A>G SNP and Mo usage only for Chinese: every additional copy of the G allele results in an average increase in Mo usage by 0.025 mg	• Patients were evaluated for: nausea (on a 3-point scale), vomiting (assessed as events occurring in the first 24 h), respiratory depression and pruritus (on a 3-point scale) • 118GG subjects reported both the lowest nausea scores and the lowest number of vomiting episodes
Coulbault et al^Citation55	AP due to colorectal surgery	Mo	iv (PCA)	74	Mixed (black and white)		• The cumulative 24-hrs post-operative dose of Mo was influenced by age and regular use of psychotropic drugs before surgery • There was a trend for higher doses of Mo to be associated with 118G allele but it did not reach the statistic significance because of the low allele frequency of the 118G allelic variant	• Patients were evaluated for: nausea (on a 4-point verbal scale), vomiting (assessed as events occurring in the first 24 h), respiratory depression and drowsiness • No cases of respiratory depression and drowsiness. • No association between 118A>G SNP and nausea and vomiting
Wong et al^Citation60	Labor pain and AP due to cesarean	F (labor pain) Mo (postcesarean pain)	Intrathecal	190 (labor pain) and 103 women (post-cesarean pain)	Mixed		• There was no difference in the median duration of intrathecal F labor analgesia between 118AA subjects and subjects carrying the 118G allele • 118A>G SNP did not influence either the supplemental analgesic requirements required to treat breakthrough pain within 72 h after intrathecal Mo analgesia or the duration of intrathecal Mo analgesia following cesarean delivery	• In both studies patients were evaluated for: nausea (on a 4-point scale), vomiting and pruritus (on a 4-point scale) • Labor pain study: no association between the SNP and side effects • Post-cesarean study: the incidence of pruritus was lower for carriers of the 118G allele compare to 118AA subjects
Zhang et al^Citation50	• EP before surgery: pain threshold and pain tolerance threshold following electric stimulation • AP due to hysterectomy or myomectomy	F	(PCA)	174 women	Chinese	• Carriers of the 118G allele had lower pain tolerance threshold following electrical stimulation than others • No differences in postoperative VAS pain scores	118GG patients consumed significantly more F than other patients during the first 24-hrs post operatively. F consumption increased in accordance with the number of G alleles in the additive model	• Patients were evaluated for: nausea, vomiting (assessed as events occurring in the first 24 h) and sedation (Ramsay sedation score) • No association between 118A>G SNP and side effects
Zhang et al^Citation61	AP due to hysterectomy or myomectomy	F	iv (PCA)	165 women	Chinese		118GG patients consumed significantly more F than other patients during the first 24-hrs post operatively	Patients were evaluated for nausea and vomiting (on a 4-point scale): no association between 118A>G SNP and side effects
Wu et al^Citation62	AP due to laparoscopic abdominal surgery	F	iv bolus injection	189	Chinese		Carriers of the 118G allele had significantly worse control of pain (VAS) 15 and 30 minutes after a bolus injection of F	• Patients were evaluated for respiratory depression (minute expiratory volume, end-tidal carbon dioxide concentration and respiratory rate) • No effect of the 118A>G SNP on the incidence of respiratory depression
Landau et al^Citation63	Labor pain	F	Intrathecal	223 women	Caucasian and Asians		118AA women required significantly more F than carriers of the 118G allele	Patients were evaluated for pruritus (on a 4-point scale): no association
Zwisler et al^Citation64	EP: electrical nerve stimulation and cold pressure test before and after drug administration	O	Oral	33 healthy subjects			• No volunteers had the genotype 118GG • 118AG subjects required a higher dose of O to show adequate pain control during the single electrical stimulation but not during the cold pressor test	Patients were evaluated for dizziness, tiredness/drowsiness, nausea/vomiting, itching, reduced ability to keep focus: carriers of the 118G allele had a reduced ability to keep focus compared with the wild-type carriers
Zwisler et al^Citation65	AP due to thyroidectomy or mastectomy or hysterectomy	O	iv (PCA)	266	Caucasian		No association between 118A>G SNP and the nonresponder rate, the need for rescue medication, O consumption, any of the pain measurement (NRS)	Patients were evaluated for sedation, tiredness/drowsiness, nausea/vomiting, skin itching: no association
Klepstad et al^Citation66	CCP	Mo	Oral	207	Caucasian		• 118AG patients had lower control of pain (BPI) than others • 118GG patients received significantly higher daily Mo doses compared to wild-type patients • The serum concentrations of Mo, M6G and M3G were significantly higher in 18GG patients	Patients were evaluated for nausea/vomiting, constipation, fatigue, dyspnea, sleep disturbances, loss of appetite and cognitive function: no association
Ross et al^Citation69	CCP	Mo		162	Caucasian		• This study evaluated the contribution of 118A>G SNP to variability in responses to Mo treatment (good control of pain or need to switch to O): there were no significant differences in allelic and genotype frequencies for the SNP between responders and nonresponders • Also 6 haplotypes containing the 118A>G SNP were evaluated: no differences were observed in haplotype frequencies between switchers and responders	One of the reasons for switch to O was the occurrence of drowsiness, hallucinations/confusion, nightmares, nausea/vomiting, myoclonus, pruritus: no significant differences in allelic and genotype frequencies for the 118A>G SNP between responders and nonresponders
Janicki et al^Citation70	• AP due to abdominal surgery • CNCP	AP: Mo CNCP: O, Mo, Me and F	CNCP: oral or transdermal or intrathecal	• AP: 101 • CNCP: 127	Mixed		• AP: no association between the118A>G SNP and total administered dose of Mo during the post-operative stay. No association between the SNP and average postoperative pain scores (11-point verbal NRS) • CNCP: no association between the SNP and opioid usage (expressed in Mo equivalents) • Comparison of the cohort of patients affected by chronic pain with the cohort comprising of AP patients: 118G allele is less common in chronic pain patients, particularly in those requiring higher doses of analgesics (thus, the 118G allele seems protective against chronic pain and may alter the response to opioid analgesics in chronic pain patients)
Lötsch et al^Citation71	CCP and CNCP	F, Mo, O, Me and othersa	Transdermal, oral, iv, sc	352	Caucasian		The daily control of pain (on a 11-point NRS) was worse in carriers of the 118G allele than 118AA patients	Patients were evaluated for nausea/vomiting, constipation, tiredness and fatigue: no association
Kolesnikov et al^Citation78	AP due to prostatectomy or hysterectomy	Mo	(PCA)	102	Caucasian		• The 1l8A>G SNP was not associated with Mo consumption in the first postoperative 48-hrs. The 118A>G SNP was not associated with the average post-operative pain score • The combination of OPRM1 118A>G and COMT G I947A SNPs was associated with significant variability in drug consumption in the first postoperative 48 hrs	• Patients were evaluated for nausea, sedation (Edmonton Symptom Assessment Scale), vomiting (number of events reported), respiratory depression and level of consciousness: the 118G allele was “protective” against morphine-induced nausea and sedation in the first postoperative 24 hrs • The combination of OPRM1 118A>G and COMT G1947A SNPs was associated with significant variability in scores for nausea and vomiting in the first post-operative 24 hrs

Note:

a Buprenorphine, dihydrocodeine, hydromorphone, piritramid, tilidine, tramadol.

Abbreviations: SNP, single nucleotide polymorphism; EP, experimental pain; AP, acute pain; CCP, chronic cancer pain; CNCP, chronic noncancer pain; F, fentanyl; Mo, morphine; O, oxycodone; Me, methadone; iv, intravenous; PCA, patient controlled analgesia; sc, subcutaneous; VAS, visual analogue scale; NRS, numerical rating scale; BPI, brief pain inventory; M6G, morphine-6-glucuronide; M3G, morphine-3-glucuronide; CNS, central nervous system.

Table 4 Concluding summary

• The 118A>G single nucleotide polymorphism (SNP) in OPRM1 results in amino acidic substitution at position 40 from asparagine to aspartic acid (N40D) that probably causes the loss of a N-glycosylation site in the extracellular region of the receptor. The 118G allele has a frequency of 27%–48% in Asians, of 11%–17% among Caucasians, of 2.2% in African-Americans and of 0.8% in Sub-Saharan Africans.

• In vitro experiments show that the variant receptors are associated to higher binding affinity and potency of the endogenous ligand β-endorphin, but, conversely, to lower potency of exogenous opioid ligands (i.e. morphine). The variant receptor was also less expressed than the wild-type.

• In vivo studies confirmed the higher binding affinity of the variant receptor for endogenous ligands and a lower potency of exogenous opioids observed in vitro. Transgenic mice carrying the variant allele show a lower analgesic effect of morphine compared to the wildtype.

• Studies on humans show that the effect of 118A>G SNP on interindividual sensitivity to pain and analgesic response to opioid is slight and not always confirmed. Despite patients carrying the 118G allele may require higher opioid doses to get the analgesic response of the drug compared to carriers of the 118 A allele they are not more at risk of opioid-related side effects. To date the analysis of 118A>G SNP alone seems to have a poor clinical (predictive) utility.

• Description of 118G-related phenotypes during clinical studies reveals that the 118A>G SNP has not the same influence on all opioid effects. The characteristics of variant μ-opioid receptors controlling gastrointestinal, respiratory and other opioid-related effects should be explored in future preclinical studies.

• Pain is a complex experience: the interaction of multiple genes, each with a small individual effect, in addition to emotional and environmental factors may influence opioid efficacy in clinical settings. Evaluation of the combined effects of OPRM1 118A>G and SNPs in other pain-related genes, as well as studies of 118A>G containing haplotypes emerge as intriguing tools in pharmacogenetics of opioids.

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