Evidence for an opioid inhibitory effect on T cell proliferation

doi:10.1016/0165-5728(93)90266-2

Journal of Neuroimmunology

Volume 44, Issue 1, April 1993, Pages 43-48

https://doi.org/10.1016/0165-5728(93)90266-2 Get rights and content

Abstract

The proliferative response of human or rat T lymphocytes to phytohemagglutinin (PHA) or concanavalin A (ConA) was measured after acute (30 min) or chronic (8 days) treatment with the opiate receptor antagonists naloxone or naltrexone. Both in the rat and in the human, proliferation was significantly enhanced by acute treatment with the opiate receptor antagonists. In contrast, after chronic treatment proliferation always decreased. The sudden removal of an opioid inhibitory tone might be the basis for the increased proliferative responses observed after acute treatment. The decrease after chronic treatment could be ascribed to the amplification of the inhibitory effect of endogenous opioids due to the up-regulation of opiate receptors that follows chronic antagonist administration. Receptor binding studies of β-endorphin receptors on splenocytes of chronically naloxone treated rats confirmed this hypothesis: a higher number of β-endorphin receptors were expressed on splenocytes of naloxone-treated rats compared to controls (B_max = 9.8 × 10⁻¹² vs. 1.16 × 10⁻¹², respectively).

References (8)

L. Jia et al.
Regulation of β-endorphin receptor expression in mouse speen cells with Con A and rIL-2
Int. J. Immunopharmacol.
(1992)
P. Sacerdote et al.
Pharmacological modulation of neuropeptides in peripheral mononuclear cells
J. Neuroimmunol.
(1991)
Y. Shavit et al.
Opioid peptides mediate the suppressive effect of stress on natural killer cell cytotoxicity
Science
(1984)
J.E. Blalock
A molecular basis for bidirectional communication between the immune and endocrine system
Physiol. Rev
(1989)

There are more references available in the full text version of this article.

Cited by (84)

The opioid antagonist naloxone inhibits Leishmania major infection in BALB/c mice
2012, Experimental Parasitology
Citation Excerpt :
The data obtained from experiments show that beta-endorphin (BE) inhibits the PHA-induced proliferative response of splenocytes (Panerai et al. 1995) and that the physiological increase of BE concentrations, e.g. after stress, induces immunosuppression (Sacerdote et al., 1994). Previously, it was shown that, in rat and human, naloxone increased T lymphocytes proliferation, increased NK cell activity, and worsened the development of inflammatory responses (Manfredi et al., 1993; Sacerdote et al., 1996). Here in our experiment, naloxone showed two different and opposite effects: exacerbation of reaction at a lower dose, which is consistent with its antagonistic effect, and inhibition of the reaction at a higher dose, which can not be explained by antagonistic properties of naloxone.
BALB/c mice are susceptible to develop non-healing, progressive infection with Leishmania major (L. major) due to the development of a non-protective Th2 response. Resistance to L. major infection is dependent to Th1 response. Treatment of mice with the opioid antagonist naloxone can promote the activation of Th1 responses. Here we study the effect of chronic administration of various doses of naloxone on susceptibility of BALB/c mice to L. major infection. Our results showed that naloxone has dose-dependent biphasic effect on L. major infection in BALB/c mice. While administration of 1 mg/kg × 2/day tends to exacerbate the local reaction to L. major infection, treatment with 10 mg/kg × 2/day of naloxone suppresses the local reaction and progress of infection. On the other hand treatment of mice with middle dose (5 mg/kg whether 1 or 2 times per day) does not have significant effect on the infection. This study demonstrates that administration of high dose of naloxone could improve protection against L. major infection in BALB/c mice, presumably by modulation in Th1/Th2 balance or by affecting macrophages through binding to Toll-like receptors.
Naloxone can improve the anti-tumor immunity by reducing the CD4+CD25+Foxp3+ regulatory T cells in BALB/c mice
2009, International Immunopharmacology
New strategies that stimulate cell-mediated immunity (CMI) against tumors and inhibit regulatory T cells are needed to improve the outcome of cancer immunotherapy. The aim of this study was to enhance the anti-tumor immunity of gp96 vaccine through naloxone administration. Therefore, we used BALB/c mouse model of fibrosarcoma tumor and analyzed the tumor size, splenocyte proliferation, spleen and tumor-infiltrated lymphocytes. Tumor and spleen CD4⁺CD25⁺Foxp3⁺ regulatory T lymphocytes, cytotoxic activity of the splenocytes, IFN-γ and IL-4 secretion were assessed to describe the anti-tumor immune response. Our findings showed that co-administration of gp96 and naloxone has resulted in a significant reduction in CD4⁺CD25⁺Foxp3⁺ regulatory T cells in the spleen. The results indicated that on days 27 and 32 the tumors in the gp96 + Nal group grew significantly slower. Moreover, co-administration of gp96 and naloxone significantly increased the intra-tumor CD8⁺ T cells and cytotoxic activity. In addition the results indicated a significant increase in the proliferation of splenocytes and IFN-γ production. Our results demonstrate that naloxone is an effective immunoadjuvant in cancer immunotherapy.
Long-term immune-endocrine effects of bereavement: Relationships with anxiety levels and mood
2003, Psychiatry Research
Psychological, endocrine and immune parameters were measured over a 6-month period in 14 healthy subjects who underwent an unpredictable acute emotional stress (e.g. sudden death of a loved one) compared with 14 controls who did not. Probands were profoundly stressed as assessed 10 days after bereavement by their scores on the Hamilton Rating Scales of Anxiety and Depression, adrenocorticotropin and cortisol plasma concentrations, and non-suppression in response to dexamethasone. Functional alterations of immune parameters, such as responsiveness of peripheral blood lymphocytes to mitogens, were found 40 days after bereavement. Despite a normal number of circulating lymphocyte subsets, the functional activity of natural killer (NK) cells was markedly reduced at day 40. Changes in the intracellular concentration of β-endorphin in peripheral blood mononuclear cells correlated with anxiety and depression scores. Controls showed no changes in psychometric, endocrine and immune measures during the 6-month study. Cluster analysis revealed two groups of bereaved subjects with different patterns of immune and endocrine changes: (1) Five subjects, characterized by harm-avoidant temperament and long-lasting dysphoric mood, showed reduced responsiveness of peripheral blood lymphocytes to mitogens, decreased NK cell activity and non-suppression in response to dexamethasone that persisted for 6 months. (2) Nine subjects showed significant changes only during the early phase after bereavement. Our data suggest that the immunological consequences of stress do not simply overlap with psychological and endocrine alterations, and are particularly severe and long-lasting in a subgroup of subjects, indicating the importance of individual variability in the capacity to cope with stress.
Individual housing induces altered immuno-endocrine responses to psychological stress in male mice
2003, Psychoneuroendocrinology
Social isolation and lack of social support have deleterious effects on health, thus being regarded as one of the most relevant causes of diseases in human and other mammalian species. However, only few are the studies aimed at evaluating the psychoneuroimmunological functions of individually housed subjects. The present study was designed to understand how the behavior and the physiology of male house mice might be affected by individual housing. We first analyzed whether individual housing of different duration (1–42 days) would result in immuno-endocrine dysfunction (experiment 1). Then we investigated whether housing conditions would affect the reaction to an acute mild psychological stress (experiments 2 and 3). There were three main findings: first, individually housing mice for increasing time periods did not induce any major immuno-endocrine effects compared to a stable sibling group housing. Therefore, prolonged isolation does not seem to dramatically impair mice immuno-endocrine functions. Second, when exposed to a mild acute stress, i.e. forced exposure to a novel environment, isolated mice showed higher basal corticosterone and lower type 1 (IL-2) and type 2 (IL-4) cytokines as well as splenocytes proliferation compared to group housed male mice. Finally, when faced with a free choice between a novel environment and their home cage, individually housed mice showed reduced neophobic responses resulting in increased exploration of the novel environment, thus suggesting a low anxiety profile. Altogether, our findings suggest that individual housing in itself does not change immunocompetence and corticosterone level, but does affect reactivity to a stressor. In fact, individually housed mice showed high behavioral arousal, as well as altered immuno-endocrine parameters, when challenged with mild psychological novelty-stress.
Increased splenocyte proliferative response and cytokine production in β-endorphin-deficient mice
2002, Journal of Neuroimmunology
We used β-endorphin-deficient mice as a novel approach to confirm the physiological role that opioid peptides play in the development or regulation of the immune system. We found that mice lacking β-endorphin possessed an enhanced immune response, measured in terms of splenocyte proliferation and interleukin (IL)-2 mRNA levels, in vitro production of the splenic macrophage inflammatory cytokines IL-6 and Tumor Necrosis Factor (TNF)-α and plasma IL-6 following lipopolysaccharide (LPS) administration. β-Endorphin-deficient mice had attenuated increases of plasma ACTH and corticosterone levels in response to LPS. These results are consistent with a postulated inhibitory role of endogenous β-endorphin on the immune system at multiple levels.
Human peripheral blood mononuclear cells express nociceptin/orphanin FQ, but not μ, δ, or κ opioid receptors
2007, Anesthesia and Analgesia
Expression of opioid receptors on peripheral blood mononuclear cells (PBMC) is controversial. These receptors are currently classified as classical (MOP/mu/μ, DOP/delta/δ and KOP/kappa/κ) and nonclassical NOP (nociceptin/orphanin FQ; N/OFQ).
In this volunteer study we probed for the expression of both classical and nonclassical opioid receptors using 1) radioligand binding, 2) specific antibody binding, and 3) polymerase chain reaction-based experimental paradigms.
Membranes prepared from PBMC from healthy volunteers did not bind either [³H]diprenorphine (a nonselective radioligand for classical opioid receptors) or [³H]N/OFQ. There was significant concentration-dependent binding of each radioligand to control tissues expressing recombinant MOP and NOP. In addition, using fluorescence-activated cell sorting paradigms, there was no binding of fluorescent naloxone or either of two MOP antibodies to whole PBMC, though fluorescent naloxone did bind to recombinant MOP (as a positive control). Using primers specific for classical and nonclassical opioid receptors, and RNA extracted from the PBMC of 10 healthy volunteers, we were also unable to detect MOP, DOP, and KOP transcripts. In contrast, NOP was detected in all samples.
Despite using several complementary experimental strategies, we failed to demonstrate protein for classical or nonclassical opioid receptors on PBMC from healthy volunteers. We detected NOP mRNA, suggesting low-density NOP expression on these immunocytes. It is possible that N/OFQ, produced by the PBMC itself, may be involved in the control of immune function.

View all citing articles on Scopus

¹: Present address: Immunology Research Center, Belgrade, Yugoslavia.

View full text

Article preview

Journal of Neuroimmunology

Abstract

References (8)

Regulation of β-endorphin receptor expression in mouse speen cells with Con A and rIL-2

Int. J. Immunopharmacol.

Pharmacological modulation of neuropeptides in peripheral mononuclear cells

J. Neuroimmunol.

Opioid peptides mediate the suppressive effect of stress on natural killer cell cytotoxicity

Science

A molecular basis for bidirectional communication between the immune and endocrine system

Physiol. Rev

Cited by (84)

The opioid antagonist naloxone inhibits Leishmania major infection in BALB/c mice

Naloxone can improve the anti-tumor immunity by reducing the CD4<sup>+</sup>CD25<sup>+</sup>Foxp3<sup>+</sup> regulatory T cells in BALB/c mice

Long-term immune-endocrine effects of bereavement: Relationships with anxiety levels and mood

Individual housing induces altered immuno-endocrine responses to psychological stress in male mice

Increased splenocyte proliferative response and cytokine production in β-endorphin-deficient mice

Human peripheral blood mononuclear cells express nociceptin/orphanin FQ, but not μ, δ, or κ opioid receptors

Research paperEvidence for an opioid inhibitory effect on T cell proliferation

Abstract

Int. J. Immunopharmacol.

J. Neuroimmunol.

Science

A molecular basis for bidirectional communication between the immune and endocrine system

Physiol. Rev

Research paper
Evidence for an opioid inhibitory effect on T cell proliferation