Opioids and the immune system - friend or foe

Abstract

Systemically administered opioids are among the most powerful analgesics for treating severe pain. Several negative side effects (respiratory depression, addiction, nausea and confusion) and the risk of opioid-induced hyperalgesia accompany opioid administration. One other side effect is the potential of opioids to suppress the immune response and thereby to increase the vulnerability to infections. The link between opioids and immunosuppression has been investigated both in vitro and in vivo as well as in patients. However, the results are inconsistent: Exogenous opioids such as morphine and fentanyl have been found to impair the function of macrophages, natural killer cells and T-cells and to weaken the gut barrier in vitro and in animal studies. In epidemiological studies, high doses and the initiation of opioid therapy for non-malignant pain have been correlated with a higher risk of infectious diseases such as pneumonia. However clear randomized controlled studies are missing. Furthermore, immune cells including neutrophils, macrophages and T-cells have been shown to secrete endogenous opioid peptides, which then bind to peripheral opioid receptors to relieve inflammatory and neuropathic pain. In addition to cytokines, hormones and bacterial products, the release of opioid peptides is stimulated by the application of exogenous opioids. In summary, there is a reciprocal interaction between the immune system and endogenous as well as exogenous opioids. Further to the existing epidemiological studies, controlled clinical studies are needed in the future to elucidate the role of the opioid-immune system interaction in patients and to determine its clinical relevance.

Linked articles: This article is part of a themed section on Emerging Areas of Opioid Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.14/issuetoc.

© 2017 The British Pharmacological Society.

Figures

Figure 1

Overview of the immunosuppressive effects of morphine. Morphine impairs the innate and adaptive immune systems and opens the gut barrier (modified from that of Roy et al.,2011).

Figure 2

Schematic depiction of endogenous opioid peptide release from immune cells of the innate and adaptive immune system. Neutrophils, monocytes/macrophages and T‐cells migrate into inflamed tissue in response to chemokines. Release of opioid peptides (green circles) is triggered by cytokines, chemokines and bacterial products. Opioid peptides bind to opioid receptors (green) expressed in peripheral sensory neurons (yellow) (Mambretti et al.,2016). This cascade causes peripheral antinociception. Inset: The presence and reactivity of peripheral μ receptors was shown via double immunostaining. DsRed mcherry immunolabelling of μ receptors in sciatic fibre bundles; green, sensory fibre marker CGRP.

Figure 3

The connection between exogenous and endogenous opioids. Immune cells (blue) within the blood vessels (red) release endogenous opioids when exogenous opioids (not shown) are present. Stimulation of μ receptors (orange) induces activation of PLC. This triggers the formation of diacylglycerol (DAG), which activates PKC and results in the formation of inositol‐3 phosphate (IP3). The binding of IP3 to its receptor releases Ca2+ from its intracellular stores in the endoplasmatic reticulum (ER) promoting the release of opioid peptides (purple star). Opioid peptides bind to opioid receptors on nociceptors (green) inhibiting the neuropathic pain evoked by chronic constriction injury (CCI) (modified version of those presented by Rittner et al.,2006 and Celik et al.,2016). DRG, dorsal root ganglion.