Acute experimental changes in mood state regulate immune function in relation to central opioid neurotransmission: a model of human CNS-peripheral inflammatory interaction

Abstract

Although evidence shows depressed moods enhance risk for somatic diseases, molecular mechanisms underlying enhanced somatic susceptibility are ill-defined. Knowledge of these molecular mechanisms will inform development of treatment and prevention strategies across comorbid depressive and somatic illnesses. Existing evidence suggests that interleukin-18 (IL-18; an IL-1 family cytokine) is elevated in depression and implicated in pathophysiology underlying comorbid medical illnesses. We previously identified strong associations between baseline IL-18 and μ-opioid receptor availability in major depressive disorder (MDD) volunteers. Combined with the evidence in animal models, we hypothesized that experimental mood induction would change IL-18, the extent proportional to opioid neurotransmitter release. Using the Velten technique in a [(11)C]carfentanil positron emission tomography neuroimaging study, we examined the impact of experimentally induced mood (sad, neutral) on plasma IL-18 and relationships with concurrent changes in the central opioid neurotransmission in 28 volunteers (healthy, MDD). Results showed mood induction impacted IL-18 (F2,25=12.2, P<0.001), sadness increasing IL-18 (T27=2.6, P=0.01) and neutral mood reducing IL-18 (T27=-4.1, P<0.001). In depressed volunteers, changes in IL-18 were more pronounced (F2,25=3.6, P=0.03) and linearly proportional to sadness-induced μ-opioid activation (left ventral pallidum, bilateral anterior cingulate cortices, right hypothalamus and bilateral amygdala). These data demonstrate that dynamic changes of a pro-inflammatory IL-1 superfamily cytokine, IL-18, and its relationship to μ-opioid neurotransmission in response to experimentally induced sadness. Further testing is warranted to delineate the role of neuroimmune interactions involving IL-18 in enhancing susceptibility to medical illness (that is, diabetes, heart disease and persistent pain states) in depressed individuals.

Figure 1

(a) Illustrates volunteers' positive and negative affect schedule (PANAS) negative affect subscale scores at each of three time points (baseline, after neutral induction and after sadness induction) across all study subjects. (b) Illustrates the effect of diagnosis (healthy control vs major depressive disorder (MDD)) on mood-induced changes in PANAS negative affect subscale scores, healthy controls clustered on the left and MDD volunteers clustered on the right. Order of neutral and sustained sadness states were randomized and counterbalanced.

Figure 2

(a) Illustrates log₁₀-normalized interleukin-18 (IL-18) concentrations at each of three time points (baseline, after neutral induction, and after sadness induction) across all study subjects. (b) Illustrates the effect of diagnosis on mood-induced changes in IL-18 concentration. A significant interaction between diagnosis and mood induction was observed, the effect of mood induction on IL-18 being greater in MDD volunteers as compared to healthy control volunteers. (c) Illustrates the effect of mood induction on IL-18, adrenocorticotropic hormone (ACTH) and cortisol across all volunteers. In contrast to mood-induced changes in IL-18 (reducing with neutral mood induction, increasing with sad mood induction), both ACTH and cortisol continue to decline over the duration of the study, regardless of whether neutral or sad mood was induced.

Figure 3

Here, we present data depicting relationships between brain endogenous opioid functional measures and plasma IL-18 and the impact of mood induction on these relationships. Within the brain images in a and b, the colors (ranging from red to bright yellow/white) represent regional z-scores of statistical significance superimposed on a standardized brain image. Depicted next to the brain images is the z-scale, a color-coded representation of z-scores of statistical significance. On the scales depicted here, dark red represents z-score of 0 and bright yellow (or white) represents z-scores of 6 and 8 in a and b, respectively. For simplicity of presentation, we have chosen not to present statistical images from every region of significance. All regions are outlined in Table 1. The brain images presented in a illustrate correlations between μ-OR availability and reduction in IL-18 during neutral mood induction in MDDs. The greater the reduction in IL-18, the more substantial the μ-OR availability within the brain regions depicted and following neutral mood induction. In a we present findings within both the amygdala (given its stress and immune regulatory roles) and the ventral pallidum. The brain image presented in b illustrates covariance between sadness-induced endogenous opioid release (also referred to as μ-OR activation) and sadness-induced increase in IL-18 in MDDs. The greater the sadness-induced increase in IL-18, the more substantial the sadness-induced endogenous opioid release within the brain regions depicted (centered on the cross-hair in this image is the left amygdala). Also illustrated in b (in the inset of the figure) are potential biological mechanisms underlying the covariate relationships confirmed via statistical testing in SPM. Release of endogenous opioids can contribute to inflammasome activation and a cascade of events resulting in activation and cellular release of IL-18. (c) Illustrates the mediation model tested using the process function within SPSS (IBM, Chicago, IL, USA). IL-18, interleukin-18; MDD, major depressive disorder; μ-OR, μ-opioid receptor.