Mu-opioid receptor mediates chronic restraint stress-induced lymphocyte apoptosis.
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, mu-opioid receptor knockout (MORKO) mice were used to investigate whether the mu-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-gamma 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 mu-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.
Wang
Jinghua
J
Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA.
Charboneau
Richard
R
Barke
Roderick A
RA
Loh
Horace H
HH
Roy
Sabita
S
D000315:Adrenalectomy; D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D003345:Corticosterone / Q000097:blood; D005260:Female; D007030:Hypothalamo-Hypophyseal System / Q000276:immunology; D007165:Immunosuppression Therapy; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000235:genetics; D018655:Lymphocyte Count; D016131:Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010913:Pituitary-Adrenal System / Q000276:immunology; D011333:Pro-Opiomelanocortin / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D017465:Receptors, Opioid, delta / Q000502:physiology; D017473:Receptors, Opioid, kappa / Q000502:physiology; D017450:Receptors, Opioid, mu / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012149:Restraint, Physical; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013315:Stress, Psychological / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D019014:fas Receptor / Q000096:biosynthesis
D007376:Interleukin-2; D012333:RNA, Messenger; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D019014:fas Receptor; D011333:Pro-Opiomelanocortin; D007371:Interferon-gamma; D003345:Corticosterone