Morphine-induced Neuroimmunomodulation in Murine Visceral Leishmaniasis: The Role(s) of Cytokines and Nitric Oxide

Abstract

Opioid modulation of host resistance to infectious diseases is well documented; however, not much is known during visceral leishmaniasis (VL). Low doses of morphine, administered subcutaneously in Leishmania donovani-infected BALB/c mice, on days 0 and +15, significantly (p < 0.05) suppressed (1 mg/kg/day) or even sterile-cleared (2 mg/kg/day) the infection; paradoxically, high doses (10 and 30 mg/kg/day) exacerbated the infection. In vitro, low concentration (1 x 10(-9) and 1 x 10(-11) M) morphine treatment of L. donovani-infected mouse peritoneal macrophages (PM), endowed them with significant (p < 0.05) leishmanicidal activity, whereas a high-concentration (1 x 10(-5) M) treatment augmented intramacrophage parasite growth. Naloxone pre-treatment of infected-mice (4 mg/kg x 2) and of infected-PM (1 x 10(-5) M), blocked only the morphine low dose/concentration-induced protective effect. The splenocytes from protected mice and morphine low concentration-treated infected-PM, elaborated significantly (p < 0.05) enhanced levels of interleukin-12, interferon-gamma, tumor necrosis factor-alpha, granulocyte-macrophage colony-stimulating factor and nitrite in the culture medium; a high dose/concentration suppressed their elaboration. Curiously, only morphine high dose/concentration-treated infected mice splenocytes and infected PM, produced significantly (p < 0.05) increased quantity of transforming growth factor-beta1. Aminoguanidine, significantly (p < 0.05) blocked the morphine low dose/concentration-induced protective effect, in vivo and in vitro. This first study demonstrates dose-dependent biphasic modulatory effects of morphine in L. donovani-infected mice and PM, in vitro, apparently via nitric oxide-dependent mechanisms. These results thus demonstrate the implications of opiate abuse on the efficacy assessment of antileishmanial drugs and vaccines, and on the reactivation of latent VL in areas where both drug abuse and VL are rampant.

Effect of morphine on Mycobacterium smegmatis infection in mice and macrophages

“…Opioids can modulate the in vivo course of parasitic and bacterial infections in a dose-dependent manner [8,9,11,15,20]. In the present study, we report, apparently M. smegmatis-infected mice were treated with indicated doses of morphine on day 0 and day +3 and sacrifi ced to determine bacterial load in lungs and spleen as described in Materials and methods.…”

“…Previous reports on immunomodulatory activity of morphine have demonstrated the protective effects of low doses of morphine in experimental models of malaria [11], leishmania [8,9] and TB [15]. However, relatively higher doses of morphine were found to be protective in M. smegmatis infection in vivo.…”

“…NOS activation is, in turn, under the control of cytokines like interferon-γ and tumor necrosis factor-α. Morphine can alter the generation of NO through modulation of NOS activity [3,8,26] or cytokine production by immune cells [8,10], leading to alteration in host susceptibility to infections. In the present study, the effect of dexamethasone (an immunosuppresant) and AG (NOS inhibitor; Fig.…”

“…Morphine can augment protective immune responses, both in vitro and in vivo, leading to suppression of infection [6][7][8]. The effects observed are dose-dependent and biphasic in nature [8][9][10][11].…”

“…Recently, we have reported the protective effects of morphine in M. tuberculosis infection in mice and macrophages [15]. The protective role of opioids may result from macrophage activation at lower concentrations leading to enhanced production of cytokines and nitric oxide (NO) [3,[8][9][10][11]15]. These molecules play a crucial role in intramacrophage and in vivo killing of mycobacteria as well [15][16][17][18].…”