The μ-Opioid System and Antidepressant Response

This article discusses the role of µ-opioid receptors (MORs) in antidepressant treatment and major depressive disorder (MDD). Specifically, it focuses on how the endogenous opioid system affects response to pharmaceuticals. In this article, we discuss how phenotypic variation in antidepressant response is linked to interindividual differences in the µ-opioid receptor gene (OPRM1). The differences in OPRM1 also contribute to variable thresholds of tolerance to antidepressants, as well as a patient's ability to achieve remission from MDD. In addition, we review the current understanding of the OPRM1 system and its implications in antidepressant and placebo response. This will be followed by a description of the structure of the OPRM1 gene and an overview of the highly studied single nucleotide polymorphism (SNP) in OPRM1 and corresponding association studies. The novel data presented here are a result of a large SNP association study with phenotypes relating to antidepressant response; specifically, response, tolerance, and remission. The OPRM1 system The OPRM1 system is well studied in the areas of pain, analgesic response, and substance abuse; however, research in the area of the µ-opioid system and MDD or antidepressant response phenotypes is not well established. The opioid system is involved in pain response and the reward system in humans. It responds to endogenous opioid peptides such as enkephalins, endorphins, and endomorphins, which act as opioid neurotransmitters. There are 4 classes of opioid receptors (µ, d, s, and k), which have a similar structure but variable binding affinities and efficiencies for ligands; each yields differential physiological effects when activated. MORs are pre-synaptic G-coupled transmembrane receptors with an affinity for endogenous opioid peptides, exogenous natural opiates (eg, codeine, morphine), and synthetic opiates (eg, oxycodone, heroin). Among the endogenous opioid agonists,enkephalins and b-endorphins bind with the greatest efficiency to MORs; however, there are interindividual differences. Gender differences Significant gender differences exist in the involvement of the OPRM1 system in response to pain. When measured using positron emission tomography (PET), there tends to be an activation of the µ-opioid system in the thalamus, nucleus accumbens, and amygdala in men, whereas in women there is an overall deactivation of the µ-opioid system in the same brain regions.1 This suggests either that women have less involvement of the µ-opioid system in response to pain (eg, use other opioid receptors), or that women show less sensitivity for responding to pain using the µ-opioid system. The gender differences seen in the µ-opioid system may parallel the gender disparities seen in MDD, antidepressant response, and placebo response. Implication of MDD Specific DNA variation in the OPRM1 gene has yet to be associated with MDD; however, the availability of the MOR (ie, its binding potential) has been measured in 14 healthy women and 14 women with MDD. At baseline, the binding potential of the OPRM1 for the fully synthetic opioid carfentanil is significantly lower in women with MDD than in women who do not have MDD. Furthermore, women with MDD who do not respond to antidepressant treatment exhibited lower binding potential for the MOR than did women with MDD who responded to medication.2Antidepressant response The interaction of the µ-opioid system and antidepressant response is not well studied in humans; however, several animal studies have investigated the interaction of the µ-opioid system and depressive-like behaviors in rodents. Of particular interest are studies that demonstrated the involvement of the µ-opioid system in eliciting an antidepressant-like effect in mice.3 This study showed that administration of endomorphins, ligands for the MOR, to the brains of mice decreased the time spent immobile on the forced-swimming test and the tail-suspension test, both proxies for measures of antidepressant-like behavioral effects. Similar implications of the OPRM1 system and antidepressant response were made in a study of rats and their response to uncontrollable stress.4 Administration of the OPRM1 agonist, morphine, to rats exposed to foot shock had the same effect as that of tricyclic antidepressants in reducing the number of increased escape failures. Furthermore, the MOR antagonist, naloxone, increased the number of escape failures, supporting the involvement of the µ-opioid system in depression-like symptoms and antidepressant response. Placebo response The placebo response may contribute to a substantial proportion of the observed response to a wide variety of pharmaceutical treatments.5 This is particularly true in response to antidepressants. It is plausible that the expectancy of symptomatic relief induces the endogenous opioid system, which, in turn, induces an elevation in mood, thereby decreasing symptoms of depression. Such an effect has been reported in a study of 14 healthy right-handed men aged 20 to 30 years.6 The brains of these men were analyzed 3 times using PET: at baseline, with a sustained pain challenge, and in a pain challenge with placebo. Zubieta and colleagues6 showed that there was an expectation of pain relief from the placebo among the men and that there were clear placebo responses. For the placebo condition, the endogenous opioid system exhibited increased activation of specific brain regions over the sustained pain condition. The placebo effect may be mediated by the endogenous opioid system. This would suggest that just the thought of getting something that will relieve pain may be enough to stimulate endogenous opioid peptides to bind to their receptor and inhibit the release of g-aminobutyric acid. This results in excessive amounts of dopamine being released, which is pleasurable (ie, mood-elevating) to many individuals. Alterations in the regulation of the endogenous opioid system may result in the inability to completely activate the system. Individuals with a properly functioning µ-opioid system may have the capacity to respond to antidepressant medication, resulting in complete remission of depressive symptoms. It is plausible that individuals who are unresponsive to antidepressant medication may have dysregulation of the µ-opioid system and, as a result, may not be able to benefit from the efficient activation of this system. Gene structure The µ-opioid receptor is encoded by its gene, the OPRM1 gene, which is located on chromosome 6q24-q25 in humans. The OPRM1 gene exhibits substantial alternative splicing that has been documented in mice, rats, and humans, and new isoforms are still being reported.7-10 Alternative splicing of the OPRM1 gene results in receptors with different structures and corresponding altered physiological function. For example, receptor-binding differences in affinity and selectivity exist between the splice variants and various pharmacological agents. Furthermore, the efficacy of the receptor signaling depends on the isoform expressed.11A variant in the OPRM1 gene Significant DNA sequence variation in humans also exists in the OPRM1 gene, and the frequencies of the variations differ between populations.12 A number of groups have investigated a particularly common DNA variant in the OPRM1 gene that is a functional exonic variation in the extracellular region of the protein. The variant is an alanine (A) to guanine (G) nucleotide substitution at position 118 from the start of translation, resulting in a change in the amino acid sequence at that site of an asparagine to an aspartic acid (N40D), which alters the chemical properties of the peptide. This SNP is commonly known by its database identification number- rs1799971. The asparagine variant of the protein leads to a 3-fold increase in β-endorphin binding to the receptor.13 In vitro studies suggest that the aspartic acid variant results in the production of 1.5 to 2.5 times less transcription of the gene's messenger RNA, as well as a 10-fold decrease in protein levels.14 Clinical studies of the SNP reveals a number of interesting associations with dysfunctions in the hypothalamic-pituitary-adrenal (HPA) axis. In a study of 39 healthy men, baseline levels of cortisol were not affected by the rs1799971 DNA variant; however, cortisol response to blockade of the opioid receptor with naloxone was dependent on the genotype at the A118G position. Higher serum cortisol concentrations, and faster cortisol responses, were detected in individuals with the G (aspartic acid) allele,which suggests that there is a connection between the G allele and altered HPA axis responsivity.15 Similar studies have replicated this finding and some found that participants with at least 1 copy of the G allele also exhibited higher cortisol levels at baseline, further suggesting a genetic marker for disorders of HPA axis dysfunction.16-18 Proopiomelanocortin is a peptide prehormone, which is cleaved to form adrenocorticotropic hormone, and β-endorphin, which has a high affinity for µ-opioid receptors. This affinity is variable, depending on the sequence variation present in the OPRM1 gene.13 No association was detected for the rs1799971 SNP and symptoms of anxiety and depression in a cross section of 867 community-living adults, a longitudinal study of 660 children, or 30 healthy subjects.17,19Variations in antidepressant response, tolerance, and remission We have examined the association of genetic variability in the OPRM1 gene and response, remission, and tolerance to the antidepressant citalopram, using a subset of participants from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. This is the largest study to date that analyzes markers across the entirety of the OPRM1 gene, and the first study investigating OPRM1 association with antidepressant treatment response, remission, and tolerance. It includes analysis of white Hispanics, whites, and non-Hispanic blacks separately, and controls for alcohol and drug dependence. We proposed that individuals without the capacity to respond to citalopram may have a defect in the endogenous opioid system, preventing full alleviation of symptoms in response to antidepressant medication. We focused on 53 genetic variants in the OPRM1 gene for this investigation. The preliminary data revealed 8 SNPs to be associated with antidepressant response (Table). Association was defined as a P value from an additive model of less than .05, and an odds ratio with 95% confidence intervals that did not exceed 1. Response was defined as having a 50% reduction in the Quick Inventory of Depressive Symptomatology (QIDS) score from baseline on the last visit.20 Of the 8 SNPs, 5 were found in the white Hispanic sample and 3 were in the white sample. No findings for the non-Hispanic black sample were detected for the response phenotype; however, 1 SNP was associated with the remission phenotype in the non-Hispanic black sample. This SNP, and 6 detected in the white Hispanic sample, compose the SNPs seen in the remission phenotype. Remission was defined as having a QIDS score of 5 during follow-up. No SNPs in the white sample were associated with the remission phenotype. Four SNPs were found in both the remission and response phenotypes for the white Hispanic sample. Only 2 SNPs were found to be associated with the tolerance phenotype in the white sample, when tolerance was defined based on study exit data of the STAR*D trial. If participants continued their treatment with citalopram, they were considered tolerant; however, if at the end of the study they discontinued citalopram or left the study because of adverse effects, they were considered intolerant. The most significantly associated SNP detected was correlated with the response phenotype in whites (rs540825). This SNP is located in an alternatively spliced exon of the OPRM1 gene and is found only in the MOR1X isoform. Preliminary data suggest that when expressed in cultured cells, this isoform differs significantly from the typical MOR1 isoform in its regulation by membrane trafficking (M. Tanowitz, M. von Zastrow, personal oral communication, 2008). The existence of this isoform is not well studied in humans, but we found it to be expressed in the human brain. Further signaling and trafficking experiments along with fine-mapping around the area of the associated SNP will aid in determining the role of this SNP in antidepressant response. It is possible that the interaction of the MORs and antidepressant response is a result of the activation of downstream signaling of the µ-opioid system. An alternative isoform of the MOR may be expressed at lower levels than the typical MOR1 isoform. Thus, if an alternative isoform of the MOR is the pre-dominant receptor expressed in the brain and results in degradation rather than recycling of the receptor, the downstream signaling will be negatively affected, potentially influencing a behavioral response. Furthermore, it is plausible that the associated SNP in the alternative exon may decrease the amount of MOR available, perhaps leading to an attenuation of the downstream signaling response that then adversely affects antidepressant responsiveness. Summary Substantial evidence in rodents exists to support the role of the µ-opioid system in antidepressant response and the pathophysiology of depressive-like symptoms. In humans, the placebo effect is clearly mediated by the µ-opioid system, which potentially explains a portion of the response seen with many pharmaceuticals. Furthermore, the present data also suggest a role in antidepressant response and tolerance, as well as remission from major depression in humans. The interindividual differences in variations in the OPRM1 gene, and the associations described above, have implications in personalized medicine. One could imagine selecting one antidepressant over another based on genotypic constitution, and predictability of response rate, tolerance to the particular medication. Together this body of literature points to a new direction for research into novel antidepressant treatments and the pathology of MDD. References: References 1. Zubieta JK, Smith YR, Bueller JA, et al. Mu-opioid receptor-mediated antinociceptive responses differ in men and women. J Neurosci. 2002;22:5100-5107. 2. Kennedy SE, Koeppe RA, Young EA, Zubieta JK. Dysregulation of endogenous opioid emotion regulation circuitry in major depression in women. Arch Gen Psychiatry. 2006;63:1199-1208. 3. Fichna J, Janecka A, Piestrzeniewicz M, et al. Antidepressant-like effect of endomorphin-1 and endomorphin-2 in mice. Neuropsychopharmacology. 2007;32:813-821. 4. Besson A, Privat AM, Eschalier A, Fialip J. Effects of morphine, naloxone and their interaction in the learned-helplessness paradigm in rats. Psychopharmacology (Berl). 1996;123:71-78. 5. Lichtigfeld FJ, Gillman MA. Possible role of the endogenous opioid system in the placebo response in depression. Int J Neuropsychopharmacol. 2002;5: 107-108. 6. Zubieta JK, Bueller JA, Jackson LR, et al. Placebo effects mediated by endogenous opioid activity on mu-opioid receptors. J Neurosci. 2005;25:7754-7762. 7. Pan YX, Xu J, Mahurter L, et al. Identification and characterization of two new human mu opioid receptor splice variants, hMOR-1O and hMOR-1X. Biochem Biophys Res Commun. 2003;301:1057-1061. 8. Pan YX, Xu J, Bolan E, et al. Identification and characterization of three new alternatively spliced mu-opioid receptor isoforms. Mol Pharmacol. 1999;56: 396-403. 9. Pan YX. Diversity and complexity of the mu opioid receptor gene: alternative pre-mRNA splicing and promoters. DNA Cell Biol. 2005;24:736-750. 10. Doyle GA, Rebecca Sheng X, Lin SS, et al. Identification of three mouse mu-opioid receptor (MOR) gene (Oprm1) splice variants containing a newly identified alternatively spliced exon. Gene. 2007;388:135-147. 11. Pan L, Xu J, Yu R, et al. Identification and characterization of six new alternatively spliced variants of the human mu opioid receptor gene, Oprm. Neuroscience. 2005;133:209-220. 12. Hoehe MR, Köpke K, Wendel B, et al. Sequence variability and candidate gene analysis in complex disease: association of mu opioid receptor gene variation with substance dependence. Hum Mol Genet. 2000;9:2895-2908. 13. Bond C, LaForge KS, Tian M, et al. Single-nucleotide polymorphism in the human mu opioid receptor gene alters beta-endorphin binding and activity: possible implications for opiate addiction. Proc Natl Acad Sci U S A. 1998;95:9608-9613. 14. Zhang Y, Wang D, Johnson AD, et al. Allelic expression imbalance of human mu opioid receptor (OPRM1) caused by variant A118G. J Biol Chem. 2005;280:32618-38624. 15. Wand GS, McCaul M, Yang X, et al. The mu-opioid receptor gene polymorphism (A118G) alters HPA axis activation induced by opioid receptor blockade. Neuropsychopharmacology. 2002;26:106-114. 16. Chong RY, Oswald L, Yang X, et al. The Micro-opioid receptor polymorphism A118G predicts cortisol responses to naloxone and stress. Neuropsychopharmacology. 2006;31:204-211. 17. Hernandez-Avila CA, Wand G, Luo X, et al. Association between the cortisol response to opioid blockade and the Asn40Asp polymorphism at the mu-opioid receptor locus (OPRM1). Am J Med Genet B Neuropsychiatr Genet. 2003;118:60-65. 18. Bart G, LaForge KS, Borg L, et al. Altered levels of basal cortisol in healthy subjects with a 118G allele in exon 1 of the Mu opioid receptor gene. Neuropsychopharmacology. 2006;31:2313-2317. 19. Jorm AF, Prior M, Sanson A, et al. Lack of association of a single-nucleotide polymorphism of the mu-opioid receptor gene with anxiety-related traits: results from a cross-sectional study of adults and a longitudinal study of children. Am J Med Genet. 2002; 114:659-664. 20. Rush AJ, Trivedi MH, Ibrahim HM, et al. The 16-Item Quick Inventory of Depressive Symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic major depression. Biol Psychiatry. 2003;54: 573-583.