μ-Opioid Receptor Mediates Chronic Restraint Stress-Induced Lymphocyte Apoptosis

Abstract

Psychological stress is associated with immunosuppression in both humans and animals. Although it was well established that psychological stressors stimulate the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system, resulting in the release of various hormones and neurotransmitters, the mechanisms underlying these phenomena are poorly understood. In this study, μ-opioid receptor knockout (MORKO) mice were used to investigate whether the μ-opioid receptor mediates the immunosuppression induced by restraint stress. Our results showed that wild-type (WT) mice subjected to chronic 12-h daily restraint stress for 2 days exhibited a significant decrease in splenocyte number with a substantial increase in apoptosis and CD95 (Fas/APO-1) expression of splenocytes. The effects are essentially abolished in MORKO mice. Furthermore, inhibition of splenic lymphocyte proliferation, IL-2, and IFN-γ production induced by restraint stress in WT mice was also significantly abolished in MORKO mice. Interestingly, both stressed WT and MORKO mice showed a significant elevation in plasma corticosterone and pituitary proopiomelanocortin mRNA expression, although the increase was significantly lower in MORKO mice. Adrenalectomy did not reverse restraint stress-induced immunosuppression in WT mice. These data clearly established that the μ-opioid receptor is involved in restraint stress-induced immune alterations via a mechanism of apoptotic cell death, and that the effect is not mediated exclusively through the glucocorticoid pathway.

Adrenalectomy in mice does not prevent loss of intestinal lymphocytes after exercise

“…Mice given a 90-min session of treadmill exercise had a marked reduction 24 h later in the cellularity and phenotype distribution of T lymphocyte subpopulations resident in the gastrointestinal tract. That ADX failed to buffer the loss of lymphocytes (either total or by phenotype) 24-h postexercise stress agrees with findings of others that ADX does not affect 12-h restraint-stress-induced reduction of lymphocytes from other lymphoid tissues (49).…”

Lymphocyte reduction induced by hindlimb unloading: distinct mechanisms in the spleen and thymus

“…This finding was recently corroborated using µ-opioid receptor knockout mice [49]. To determine whether endogenous opioids play a similar role in the lymphocyte reduction seen in HU treatment, Balb/c mice were injected with naltrexone (10 mg/kg i.p.)…”

Immobilization Stress Inhibits Intimal Fibromuscular Proliferation in the Process of Arterial Remodeling in Rats

“…Mental stress stimulates the release of endogenous opioids and catecholamines, which activate nuclear factor-κB (NF-κB) of these cells, produce nitric oxide, free radicals, and proinflammatory cytokines, and upregulate both chemotaxic and phagocytotic functions (38)(39)(40)(41)(42). Also, in splenic lymphocytes, immobilization stress inhibits proliferation and induces apoptosis through a μ-opioid receptor-mediated mechanism (43). Therefore, we cannot completely exclude the possibility that the inhibition of SMC proliferation observed in our experiments in vivo was mediated by μ-opioid receptors on mononuclear cells (44).…”