Effects of a single administration of morphine or footshock stress on natural killer cell cytotoxicity

doi:10.1016/0889-1591(87)90034-1

Brain, Behavior, and Immunity

Volume 1, Issue 4, December 1987, Pages 318-328

https://doi.org/10.1016/0889-1591(87)90034-1 Get rights and content

Abstract

We previously reported that daily exposure for 4 days to an inescapable form of footshock stress, known to cause opioid-mediated analgesia, suppressed the cytotoxic activity of splenic natural killer (NK) cells in rats. Similarly, daily injection of high doses of morphine (⩾30 mg/kg) for 4 days also suppressed splenic NK cell activity. We now report that a single exposure to the opioid form of footshock stress or a single high dose of morphine induces suppression of splenic NK cell cytotoxicity. This effect is evident 3 h after treatment, returning to normal by 24 h. Morphine-induced NK suppression is evident in both male and female rats, is blocked by the opiate antagonist naltrexone, and develops tolerance. Morphine-induced NK suppression is seen in cells derived simultaneously from the spleen, bone marrow, and peripheral blood, suggesting that this suppression does not result from a selective egress of NK cells from the spleen.

References (32)

C.E. Cherubin et al.
Systemic infection in heroin addicts
Lancet
(1968)
W.K.K. Ho et al.
The effect of morphine addiction on concanavalin A-mediated blastogenesis
Pharmacol. Res. Commun
(1979)
J.W. Lewis et al.
Stress and morphine affect survival of rats challenged with a mammary ascites tumor (MAT 13762B)
Nat. Immun. Cell Growth Regul
(1983)
J.W. Lewis et al.
Apparent involvement of opioid peptides in stress-induced enhancement of tumor growth
Peptides
(1983)
N.P. Plotnikoff et al.
Enkephalins as immunomodulators
Int. J. Immunopharmac
(1983)
C.W. Reynolds et al.
Natural killer activity in the rat. IV. Distribution of large granular lymphocytes (LGL) following intravenous and intraperitoneal transfer
Cell. Immunol
(1984)
Y. Shavit et al.
Effects of footshock stress and morphine on natural killer lymphocytes in rats: Studies of tolerance and cross-tolerance
Brain Res
(1986)
R.H. Simon et al.
Morphine increases metastatic tumor growth
Brain Res. Bull
(1986)
I.S. Zagon et al.
Heroin prolongs survival time and retards tumor growth in mice with neuroblastoma
Brain Res. Bull
(1981)
I.S. Zagon et al.
Naloxone prolongs the survival time of mice treated with neuroblastoma
Life Sci
(1981)

C.F. Aylsworth et al.

Opiate antagonists can inhibit mammary tumor growth in rats

S.M. Brown et al.

Immunologic dysfunction in heroin addicts

Arch. Intern. Med

(1974)

C.E. Cherubin et al.

Serologic investigations in narcotic addicts. I

Ann. Intern. Med

(1968)

B. Crary et al.

Epinephrine-induced changes in the distribution of lymphocyte subsets in peripheral blood of humans

J. Immunol

(1983)

C. De Carolis et al.

Evidence for an inhibitory role of β-endorphin and other opioids on human total T rosette formation

Experientia

(1984)

R.B. Herberman et al.

Natural killer cells: Their role in defenses against disease

Science

(1981)

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Surgical treatment of cancer is usually necessary but it can paradoxically aggravate the patient outcome by increasing the risk of recurrence. Many perioperative factors have been shown to contribute to the dissemination of the tumor: surgery itself, stress, inflammation, pain, anaesthetic drugs, blood transfusion, etc. The type of anaesthesia chosen in the cancer patient could then be crucial and influence the evolution of the disease. Experimental, preclinical and retrospective studies have suggested that a regional anesthesia associated or not with a general anesthesia for carcinologic surgery might reduce the risk of cancer recurrence. This text reviews the factors promoting the recurrence of tumors after carcinologic surgery and the potential possibilities of protection associated with the type of anaesthesia chosen.
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¹: Present address: Department of Psychology, The Hebrew University of Jerusalem, Mount Scopus, Jerusalem 91905, Israel.

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Regular articleEffects of a single administration of morphine or footshock stress on natural killer cell cytotoxicity

Abstract

Lancet

Pharmacol. Res. Commun

Nat. Immun. Cell Growth Regul

Peptides

Int. J. Immunopharmac

Cell. Immunol

Brain Res

Brain Res. Bull