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(Drug information on codeine), morphine(Drug information on morphine)), and synthetic opiates (eg, oxycodone(Drug information on 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.²

Antidepressant 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(Drug information on 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(Drug information on 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.¹¹