Figure 1.

Peripheral and central mechanisms of opioid-induced immune suppression. Opioids can have direct effects on immune cells which express appropriate receptors such as the mu opioid receptor (MOR) and Toll-like receptor-4 (TLR-4); although there are differences between opioids [6,21,23,24]. Opioids can also have centrally mediated immunosuppressive effects [26,27]. Immediate central effects of opioids include enhancement of periaqueductal gray (PAG) activity. This in turn causes activation of the sympathetic nervous system (SNS). By innervating lymphoid organs, activation of the SNS leads to the release of biological amines which decreases cytotoxicity of NK cells and splenic lymphocyte proliferation [26]. In rodent models, morphine has acute effects via D1 dopamine receptors in the nucleus accumbens shell, which leads to an increase in the release of neuropeptide Y (NPY), this then reduces splenic NK cell cytotoxicity [27]. Chronic opioid administration increases activity in the hypothalamic pituitary adrenal (HPA) axis leading to glucocorticoid production, decreasing cytotoxicity of NK cells [26]. Reproduced with permission by Boland, J.W. et al. Br. J. Cancer 2014, 111, 866–873. [22].