Annals New York Academy of Sciences pp 113 – 119

A Possible Opioid Receptor Dysfunction in Some Depressive Disorders

Irl Extein

1. L. C. Pottash and Mark S. Gold

Opioid receptors were discovered and characterized in the mammalian brain in the past decade, leading to the identification of endogenous opioid peptides (endorphins) in the brain.¹ The discovery of endorphins, which are thought to function as neuromodulators in the human brain, sparked interest in the possible role of endorphins in depressive illness.² The high concentration of opioid receptors and endorphins in limbic and hypothalamic regions, and their interaction with noradrenergic and dopaminergic systems, suggest involvement of endorphin systems in depression, as also suggested by certain clinical observations. These include anecdotal reports from the prepsychotropic era of the efficacy of opiates in depression, reports of the appearance—in some detoxified opiate addicts—of depression responsive to opiates and antidepressants,³ and reports of improvement in some depressed patients following b -endorphin.⁴ These observations, as well as the euphoric, analgesic, and calming effect of opiates, suggest that decreased functional activity in endorphin systems may be involved in the pathophysiology of depression. Because of technical difficulties in measuring endorphins, as well as the obvious difficulties in directly measuring opioid receptors in human brain, the possibility of alterations in endorphin systems in depressed patients has been difficult to investigate directly.

We have utilized two neuroendocrine challenge paradigms to investigate indirectly hypothesized decreased brain endorphin activities and/or decreased opioid receptor sensitivities in depressed patients. In the first study, we administered the opioid agonist morphine to depressed patients and controls and measured the prolactin response. Because the increased prolactin secretion in response to morphine is mediated through opiate receptor stimulation,^{5, 6} it may indirectly reflect changes in opioid receptors in depression. In the second study, we administered the opioid antagonist naloxone to depressed patients and controls and measured the cortisol response. Adrenocorticotropic hormone (ACTH) and b -endorphin both derive from the same peptide precursor, pro-opiocortin.¹ Cortisol is secreted in response to ACTH. Thus, cortisol secretion following naloxone⁷ probably parallels endorphin secretion in response to a blockade of endorphin receptors, and may indirectly reflect changes in endorphin systems in depression.

METHODS

This study was an open investigation in 10 patients with major depressive disorder as classified by the Research Diagnostic Criteria (RDC)⁸ (9unipolar, 1 bipolar;5 male, 5 female; mean age = 44 ± 5). The control group was comprised of two normal volunteers and four inpatients with personality disorders (2 male, 4 female; mean age = 33 ± 8). All subjects gave written informed consent to participate. Patients with recent neuroleptic use were excluded, and patients received no medication except flurazepam for at least 1 week prior to the study. After an overnight fast, subjects were at bedrest for placement of an indwelling venous catheter through which 5 mg morphine were infused at 9:00 a.m. Samples of blood were obtained via the catheter before, and 30, 60, 90, 120, and 180 min after, morphine infusion for assay of serum prolactin (PRL) in duplicate by radio immunoassay. We calculated the maximum prolactin response (D prolactin) for each patient by subtracting the baseline prolactin level from the maximum prolactin level after morphine infusion.

Each subject filled out an adjective checklist self-rating scale before the infusion and at the time of each blood drawing. Drug abusers were excluded.

Subjects in this study consisted of 9 normal volunteer controls (9 male, 0 female; mean age = 27 ± 2) and 19 depressed inpatients (10 male, 9 female, mean age 32 ± 4). Of the depressed patients, 14 met RDC for major depression (13 unipolar, 1 bipolar.) Three had minor depression by RDC, and 2 schizo-affective disorder, depressed type by RDC. All subjects gave written informed consent to participate in this study. Patients with endocrine disease or substance abuse were excluded. All were free of all medications except flurazepam and acetaminophen for at least one week prior to testing. Subjects were at bedrest after an overnight fast for placement of an indwelling venous catheter through which 20 mg of naloxone (Endo Labs) was infused. Blood samples were taken –15, 0, 15, 30, 45, 60, 75, and 105 minutes after naloxone infusion for assay of cortisol in duplicate by radioimmunoassay. The maximum cortisol response (D cortisol) for each patient was calculated by subtracting the baseline cortisol level from the maximum cortisol level after naloxone infusion. Statistical comparisons in both studies 1 and 2 was performed by the 2-tailed t-test, and data is presented as mean ± standard error (SE)>

RESULTS

Morphine infusion produced only small, nonsignificant antidepressant and antianxiety effects in both the depressed and control groups, but produced marked, significant increases (p<0.05) in serum prolactin levels 30, 60, 90, 120, and 180 minutes after infusion in the control subjects. There was no significant difference in the increase in prolactin levels in the patients with personality disorders compared with the normal volunteers. In the patients with major depressive disorder, morphine infusion produced only small, nonsignificant increases in serum prolactin (Figure 1). Mean baseline prolactin level of 9.0 ± 1.4 ng/ml in the control group did not differ from that of 10.5 ± 1.9 ng/ml in the depressed group. Mean prolactin levels in the depressed group were significantly lower than those in the control group at 60 (p<0.01), 90 (p<0.02), 120 (p<0.02), and 180 (p<0.05) minutes (Figure 1) The mean maximal prolactin response of 7.2 ± 2.7 ng/ml in the depressed group was significantly lower than that of 31.9 ± 9.5 ng/ml in the control group (p<0.01). . There was no significant correlation between maximal prolactin responses and baseline prolactin levels. The control subjects and the depressed patients did not differ significantly in age or sex distribution.

Cortisol concentrates in serum following naloxone infusion are presented in Figure 2. Mean baseline cortisol levels of 15.8 ± 1.7m g% in controls and 12.6 ± 1.1 in depressed patients did not differ significantly. Mean D cortisol of 5.0 ± 1.5 m g% in the controls did not differ significantly from that of 6.7 ± 1.6 in the depressed patients. The mean D cortisol in the unipolar patients also did not differ from that of controls.

DISCUSSION

The results of Study 1 show a blunted prolactin response to morphine in major depression, suggestive of alterations in endorphin systems or opioid receptors in this disorder. The results of Study 2 show no changes in cortisol response to naloxone in depression, and provide no evidende for possible changes in endorphin systems in depression.

With regard to the blunted prolactin response to morphine, both exogenous opioids and endogenous opioid peptides are potent stimulators of secretion of the pituitary hormone prolactin in animals^9-11 and man.^{4-6, 12, 13} Morphine in the dosage range we used has been reported to produce large and reliable increases in serum prolactin in normal subjects.⁵ Prolactin secretion is controlled in part by the dopaminergic tuberoinfundibular tract, which exerts an inhibitory effect over the secretion of prolactin.⁶ Serotonergic neurons have a stimulatory effect on prolactin secretion, and other neurotransmitters and neuromodulators, including norepinephrine and epinephrine, have been reported to modulate prolactin secretion as well.⁶ Researchers have located opioid receptors on dopaminergic neurons.¹ When these opioid receptors are activated, they inhibit the dopaminergic tonic inhibition of prolactin secretion. Such opioid receptor activation would therefore allow increased secretion of prolactin after administration of opioids¹¹ (Figure 3).

Thus the absent or blunted increase in serum prolactin occurring after morphine infusion in our patients with major depressive disorder may reflect abnormalities in central endorphin, dopamine, serotonin, or other neuroregulatory systems. Possible abnormalities in endorphin systems that could account for a blunted prolactin response to morphine in major depression include an opioid receptor deficit, an excess of endogenous opioid antagonist, or elevated endorphin levels with compensatory down-regulation of opioid receptors. Although there was no significant difference in baseline prolactin levels between the control subjects and the patients wit major depressive disorder, subtle changes in baseline prolactin secretion or diurnality might partially explain the blunted prolactin response to morphine exhibited by the patients with major depressive disorder. Halbreich and associates reported increased secretion of prolactin in depressed patients during the afternoon and evening.¹¹ An increased prolactin secretion at some time of the day in the patients with major depressive disorder could conceivably have decreased the sensitivity of the prolactin system to stimulation. Possibly the use of psychotropic medication by some of the depressed patients in the 6 weeks before the study may have influenced their prolactin response to morphine. If this were the case, however, one would probably expect a significant difference between mean baseline prolactin levels of patients with major depressive disorder and those of control subjects, or correlation between maximal prolactin responses and baseline prolactin levels. We observed neither of these. Researchers should explore other factors that might influence prolactin response to morphine in depression, such as corticosteroid or thyroid axis abnormalities or pharmacokinetic changes.

While we observed significant miosis, we noted only a small, nonsignificant subjective antidepressant effect in the depressed patients. This lack of antidepressant response to morphine parallels the lack of neuroendocrine response in depressed patients. Perhaps higher doses of morphine or other opioids are needed to stimulate prolactin secretion in depressed patients than in control subjects. Preliminary work shows elevation of serum prolactin in depressed patients after infusion of 5 mg methadone, which is about twice as potent as morphine.¹⁵

Despite the lack of change in cortisol response to naloxone (Figure 4) in depression in Study 2, further exploration of the involvement of endorphins in depression, and in changes in the hypothalamic-pituitary-adrenal (HPA) axis in depression, seems of interest. The decrease in plasma cortisol following opiates and methadone,¹⁵ as well as the increase in cortisol following naloxone,⁷ are interesting in view of the known hypersecretion of cortisol and the failure of suppression of cortisol on the dexamethasone suppression test in patients with major depression.¹⁶ Since ACTH and b -endorphin have a common precursor,¹ the relationship between these two in depression needs to be explored. The strategy used here in Study 2 measured brain endorphin systems function indirectly. This strategy has been demonstrated to be sensitive to the presumed endorphin deficit in detoxified methadone addicts.¹⁷ However, other, more direct measures may be sensitive to endorphin dysfunction in depression and the involvement of endorphins in HPA dysfunction in depression.

In conclusion, the neuroendocrine strategies reported here provide some indirect support for opioid receptor dysfunction in major depression.^{1-4, 18, 19} Other neuroendocrine strategies, as well as more direct methods for evaluating endorphin systems in depressed patients need to be pursued.

REFERENCES