Acute Morphine Administration Reduces White Blood Cells’ Capability to Induce Innate Resistance against HSV-1 Infection in BALB/c Mice

Abstract

Objective: It has been reported that acute morphine administration modulates innate immune response to herpes simplex virus 1 (HSV-1) infection. In this study, the effect of acute morphine on innate resistance and its probable mechanisms in increasing the mortality rate during HSV-1 infection were investigated. Methods: Mice were infected with HSV-1 24 h prior to different doses of morphine or saline administration and the mortality rate was recorded. Spleen cells were obtained from morphine- or saline-treated mice, then natural killer (NK) cell activity and interferon-γ (IFN-γ) production were evaluated. The effect of morphine on white blood cells’ capacity to induce protection against HSV-1 infection was evaluated by adoptive transfer of spleen cells to cyclophosphamide-treated mice that were previously infected with HSV-1. Furthermore, in a separate experiment, a different group of mice received corticosterone 24 h after HSV-1 infection. Results: Mortality rate in high-dose acute morphine-treated mice increased significantly compared to saline-treated mice (p = 0.035). NK cell cytotoxicity and IFN-γ mRNA levels also showed a significant reduction compared to those of control groups (p < 0.001 and p = 0.014, respectively). Corticosterone administration reduces innate resistance against HSV-1 infection compared to saline-treated mice (p = 0.044). Furthermore, adoptive transfer of normal but not morphine-treated spleen cells induces resistance against HSV infection in cyclophosphamide-injected mice (p = 0.009). Conclusions: The current study shows that acute morphine administration reduces white blood cells’ capability to induce protection against HSV-1 infection via suppression of IFN-γ production and NK cells activity. This may be due to the increase in corticosteroids. Further studies are needed to test the effect of acute morphine on other immune cells.

Opioids and Viral Infections: A Double-Edged Sword

“…Opioids administration is known to affect the course of HSV infection because of their immunosuppressive function. For example, morphine, a broadly studied and widely used opioid, is known to alter HSV infection, immune response, as well as latency (Jamali et al, 2007a , 2012 ; Mojadadi et al, 2009 ; Bauchat, 2010 ).…”

“…It has been clearly demonstrated that morphine alters innate immune responses, which affect the ability of an infected host to mount a specific immune response and clear HSV-1 (Sheridan and Moynihan, 2005 ). Acute morphine administration diminishes the ability of white blood cells to induce a protective innate immune defense against HSV-1 infection through inhibition of IFN-γ production and NK cell activity (Jamali et al, 2007a ). Mojadadi et al found that acute morphine administration significantly reduced cytolytic T lymphocyte response, lymphocyte proliferation, and IFN-γ production, which consequently reactivated HSV-1 latency in BALB/c mice (Mojadadi et al, 2009 ).…”

Current Research on Opioid Receptor Function

“…In general, opioids mediate immunosuppression although their actions are complicated, often indirect and not well understood. Nonetheless, acute and chronic opioid administration is known to have inhibitory effects on humoral and cellular immune responses including antibody production, natural killer cell activity, cytokine expression, and phagocytic activity [235, 236, 238–240]. In vivo and in vitro studies indicated that opioid receptor stimulation exerts suppression of multiple components of the immune defense response including natural killer (NK) cell activity [241], neutrophil complement and immunoglobulin receptor expression [242], chemokine-induced chemotaxis [243] and phagocytosis [244].…”

“…Treatment of normal human astrocytes with morphine leads to significant down-regulation of gene expression for β-chemokines, MCP-1, and MIP-1β, while reciprocal up-regulation of the expression of their specific receptors, CCR2b, CCR3, and CCR5, respectively, and reversed by naloxone [247]. In addition, acute administration of morphine significantly decreased NK cell cytotoxicity and interferon-gamma mRNA levels, and increased the mortality rate of mice infected with herpes simplex virus 1 [240]. DOR agonist, DPDPE, triggers monocyte adhesion [248].…”

Acute Morphine Administration Reduces Cell-Mediated Immunity and Induces Reactivation of Latent Herpes Simplex Virus Type 1 in BALB/c Mice

“…Our previous work has shown that acute morphine administration increases mortality during HSV-1 infection in BALB/c mice (7). In humans, morphine administration induces reactivation of latent herpes simplex labialis (8).…”