Role of the mu-opioid receptor in opioid modulation of immune function

Abstract

Endogenous opioids are synthesized in vivo to modulate pain mechanisms and inflammatory pathways. Endogenous and exogenous opioids mediate analgesia in response to painful stimuli by binding to opioid receptors on neuronal cells. However, wide distribution of opioid receptors on tissues and organ systems outside the CNS, such as the cells of the immune system, indicate that opioids are capable of exerting additional effects in the periphery, such as immunomodulation. The increased prevalence of infections in opioid abuser-based epidemiological studies further highlights the immunosuppressive effects of opioids. In spite of their many debilitating side effects, prescription opioids remain a gold standard for treatment of chronic pain. Therefore, given the prevalence of opioid use and abuse, opioid-mediated immune suppression presents a serious concern in our society today. It is imperative to understand the mechanisms by which exogenous opioids modulate immune processes. In this review, we will discuss the role of opioid receptors and their ligands in mediating immune-suppressive functions. We will summarize recent studies on direct and indirect opioid modulation of the cells of the immune system, as well as the role of opioids in exacerbation of certain disease states.

Figures

Figure 1. Hyperalgesic and analgesic mechanisms in inflammation

In early inflammation, leukocytes, e.g., granulocytes (G) and monocytes (M), migrate into the inflamed tissue. Here, these leukocytes as well as resident cells release cytokines including TNF-α , interleukins (ILs), chemokines [CXC chemokine ligand 8 (CXCL8), CXCL1], NGF, and secondary mediators, such as sympathetic amines, leukotriene B4 (LTB4), and prostaglandins, culminating in hyperalgesia. TNF-α, IL-6, and IL-1 can also have direct hyperalgesic effects on nociceptors. During ongoining, late inflammation, lymphocytes (L) and monocytes/macrophages (M) start to produce anti-inflammatory cytokines, such as IL-4, IL-10 and IL-13. These cytokines inhibit the proinflammatory cytokines, such as TNF-α, IL-1, and IL-6, and block the cascade, resulting in analgesia.

Figure 2. Inflammation induced migration of opioid-producing leukocytes and opioid secretion

Resident macrophages of the inflammed tissue release chemokine gradient to recruit neutrophils form the blood stream. Chemokine secretion leads to upregulation of adhesion molecules (P-selectin, ICAM-1 etc.) on the capillary endothelium which facilitates neutrophil rolling, adhesion and extravasation. Once extravasated, leukocytes can be stimulated by releasing agents such as corticotropin-releasing factor (CRF), interleukin-1β (IL-1) and/or noradrenaline (NA). CRF, IL-1, and NA (derived from sympathetic neurons) elicit opioid release by activating their respective receptors on leukocytes. Opioids bind to peripheral opioid receptors (produced in dorsal root ganglia and transported to peripheral endings of sensory neurons) and produce analgesia by inhibiting the excitability of these neurons. Opioid agonists have easier access to neuronal opioid receptors during inflammation because inflammation disrupts the perineurium (normally a rather impermeable sheath encasing peripheral-nerve fibers). Arrow in the blood vessel and sensory neuron indicates the direction of the events.

Figure 3

Chemical structures of μ receptor agonists and antagonists

Figure 4. Pathways of opiate induced immune suppression

Morphine can modulate immune system via direct and indirect pathway. Indirectly morphine acts on CNS and the hypothalamic-pituitary-adrenal (HPA) axis which leads to release of corticosteroids, immunosuppressive hormones which lead to suppression of the immune system. Direct inhibitory pathway requires direct interaction of opioids on cells of the immune system.