This variant, formerly titled RESPONSE TO MORPHINE-6-GLUCURONIDE and SUSCEPTIBILITY TO OPIOID DEPENDENCE (Lotsch et al., 2002 and Bart et al., 2004), has been reclassified based on the findings of Hollt (2002) and Arias et al. (2006).
The 118A-G SNP in the OPRM1 gene results in an asn40-to-asp (N40D) substitution in the-N terminal region of the protein, and is predicted to result in the loss of a putative N-glycosylation site (Bond et al., 1998).
The overall frequency of the 118G allele is about 10.5%, but varies significantly between different ethnic groups (African American, 0.016; Caucasian, 0.115; Hispanic, 0.142) (Bond et al., 1998). The 118G allele has a frequency varying from 0.078 to 0.341 in various populations (LaForge et al., 2000). It is present in 49 to 60% of those of Asian ancestry (Mague et al., 2009).
Bond et al. (1998) found that the asp40 variant receptor bound the endogenous agonist beta-endorphin (see POMC, 176830) 3 times more tightly than the wildtype receptor in Xenopus oocytes. No differences in binding affinity were observed for other opioid alkaloids or peptides. In contrast, Beyer et al. (2004) and Mague et al. (2009) found no differences in binding affinities between the 2 SNP alleles for several agonists, including morphine, beta-endorphin, naxolone, and morphine-6-glucuronide in human embryonic kidney 293 cells and mouse brain, respectively.
Zhang et al. (2005) observed that the OPRM1 118A mRNA allele was 1.5- to 2.5-fold more abundant than the 118G allele in heterozygous brain autopsy tissues. Transfection and inhibition studies showed that only 118G, and not substitutions at position 118 with A, T, or C, resulted in lower mRNA levels, in spite of equal stability. Moreover, 118G caused a 10-fold lower OPRM1 protein level as measured by Western blot and receptor binding analyses. Zhang et al. (2005) concluded that 118G is a functional variant that results in decreased levels of OPRM1 mRNA and protein. These results were confirmed by Mague et al. (2009) in mice.
STUDIES OF PHENOTYPIC ASSOCIATIONS
The 118A-G SNP in OPRM1 has been widely studied for its association in a variety of drug addiction and pain sensitivity phenotypes; however, the results are conflicting and the mechanisms underlying these potential associations remain elusive (Mague et al., 2009).
Although Bart et al. (2004) and Drakenberg et al. (2006) independently reported an association between the 118G allele and opioid dependence (610064), a metaanalysis of 22 published papers on the subject (Arias et al., 2006) concluded that the N40D SNP does not affect the risk for substance dependence. Hollt (2002) also noted that association studies do not provide clear evidence that the 118A-G polymorphism is involved in opioid or alcohol addiction.
In a study of 20 healthy individuals, comprising 10 118A/A homozygotes, Lotsch et al. (2002) presented evidence that the 118G allele is associated with decreased pupil constrictory effect of morphine-6-glucuronide, the major metabolite of morphine. However, in reviewing the findings of Lotsch et al. (2002), Hollt (2002) concluded that differences in potencies most probably reflected a much lower blood-brain barrier permeability of M6G compared to morphine, since the receptor affinities of the 2 drugs are comparable (Wu et al., 1997).
In a study of 20 healthy individuals, comprising 10 118A/A homozygotes, 6 118G/G homozygotes, and 4 118A/G heterozygotes, Oertel et al. (2006) found that carriers of the 118G allele showed decreased tolerance to pain stimuli and decreased respiratory depression after alfentanil administration compared to those without the 118G allele. When compared to noncarriers, homozygous carriers needed 2 to 4 times higher alfentanil concentrations to produce the same amount of analgesia, and 10 to 12 times higher concentrations to produce the same degree of respiratory depression. Oertel et al. (2006) concluded that while both homozygous and heterozygous carriers of the 118G allele may show decreased opioid-induced analgesia, only homozygous carriers of 118G show decreased opioid-induced respiratory depressive effects.
Mague et al. (2009) found that mice homozygous for the 118G allele failed to exhibit morphine-induced hyperactivity, as seen in wildtype mice. Homozygous G/G mice also showed a decrease in morphine-induced antinociception compared to wildtype mice. Although G/G males were similar to wildtype in preference to morphine-paired environments, G/G females did not show a preference to morphine-paired environments.
