Toll-Like Receptor 4 (TLR4)/Opioid Receptor Pathway Crosstalk and Impact on Opioid Analgesia, Immune Function, and Gastrointestinal Motility

Abstract

Toll-like receptor 4 (TLR4) recognizes exogenous pathogen-associated molecular patterns (PAMPs) and endogenous danger-associated molecular patterns (DAMPs) and initiates the innate immune response. Opioid receptors (μ, δ, and κ) activate inhibitory G-proteins and relieve pain. This review summarizes the following types of TLR4/opioid receptor pathway crosstalk: (a) Opioid receptor agonists non-stereoselectively activate the TLR4 signaling pathway in the central nervous system (CNS), in the absence of lipopolysaccharide (LPS). Opioids bind to TLR4, in a manner parallel to LPS, activating TLR4 signaling, which leads to nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) expression and the production of the pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6. (b) Opioid receptor agonists inhibit the LPS-induced TLR4 signaling pathway in peripheral immune cells. Opioids operate as pro-inflammatory cytokines, resulting in neuroinflammation in the CNS, but they mediate immunosuppressive effects in the peripheral immune system. It is apparent that TLR4/opioid receptor pathway crosstalk varies dependent on the cell type and activating stimulus. (c) Both the TLR4 and opioid receptor pathways activate the mitogen-activated protein kinase (MAPK) pathway. This crosstalk is located downstream of the TLR4 and opioid receptor signaling pathways. Furthermore, the classic opioid receptor can also produce pro-inflammatory effects in the CNS via MAPK signaling and induce neuroinflammation. (d) Opioid receptor agonists induce the production of high mobility group box 1 (HMGB1), an endogenous TLR4 agonist, supporting intercellular (neuron-to-glia or glia-to-neuron) interactions. This review also summarizes the potential effects of TLR4/opioid receptor pathway crosstalk on opioid analgesia, immune function, and gastrointestinal motility. Opioids non-stereoselectively activate the TLR4 pathway, and together with the subsequent release of pro-inflammatory cytokines such as IL-1 by glia, this TLR4 signaling initiates the central immune signaling response and modifies opioid pharmacodynamics. The DAMP HMGB1 is associated with the development of neuropathic pain. To explain morphine-induced persistent sensitization, a positive feedback loop has been proposed; this involves an initial morphine-induced amplified release of IL-1β and a subsequent exacerbated release of DAMPs, which increases the activation of TLR4 and the purinergic receptor P2X7R. Opioid receptor (μ, δ, and κ) agonists are involved in many aspects of immunosuppression. The intracellular TLR4/opioid receptor signaling pathway crosstalk induces the formation of the β-arrestin-2/TNF receptor-associated factor 6 (TRAF6) complex, which contributes to morphine-induced inhibition of LPS-induced TNF-α secretion in mast cells. A possible molecular mechanism is that the TLR4 pathway initially triggers the formation of the β-arrestin-2/TRAF6 complex, which is amplified by opioid receptor signaling, suggesting that β-arrestin-...

Butorphanol Promotes Macrophage Phenotypic Transition to Inhibit Inflammatory Lung Injury via κ Receptors

“…Potential interactions can occur between TLR4 and opioid receptors (μ, δ and κ). These interactions are involved in immune function, opioid analgesia, and intestinal motility ( 25 ). The TLR4 signaling pathway was directly activated by opioid receptor agonists in the CNS in the absence of LPS, indicating interactions within the cell membrane.…”

“…The mechanisms may include inhibiting inflammation and oxidative stress ( 24 ). Moreover, TLR4 and opioid receptor interactions occur in the central nervous system (CNS), and effects on peripheral immune cells have also been demonstrated ( 25 ). However, whether butorphanol can regulate macrophage polarization in sepsis-induced ALI is not clear.…”

Oxycodone Enhances the Effects of Metformin Therapy in Mices With Painful Diabetic Neuropathy Induced by Alloxan

“…µ opioid receptor activation attenuates the increase in in ammatory cytokines. δ opioid receptor (DOR) activation inhibits the production of NO and increases superoxide dismutase (SOD) and GSH-Px activity (Zhang, Yang et al 2020). Different internal and external reasons effects on qeering antioxidant enzyme in opioid consumptions such as dose, duration of treatment, drug interaction and de ciency of drug biotransformation in different disease (Hsiao, Chang et al 2009).…”

“…µ opioid receptor activation attenuates the increase in in ammatory cytokines. δ opioid receptor (DOR) activation inhibits the production of NO and increases superoxide dismutase (SOD) and GSH-Px activity (Zhang, Yang et al 2020).…”

Modeling SARS-CoV-2 infection in individuals with opioid use disorder with brain organoids

“…151,189,190 In addition, brain organoid studies have revealed imbalanced excitatory/inhibitory neurotransmission, 72,73,88,93 which could further elucidate how chronic opioid exposure increases glutamatergic signaling. 153,154 Furthermore, HDPs shared commonly upregulated genes with those who have PTSD, AD, PD, and HD, including those related Lin et al, 109 Pavoni et al, 110 Gonzalez et al, 111 Meyer et al, 112 Arber et al, 113 Ghatak et al, 114 Perez et al, 115 Yan et al, 116 Yoon et al, 137 Zhang et al, 138 Zhou et al, 139 Janssens et al, 140 Nowakowski et al, 141 Allodynia, hyperalgesia, NF-κB activation 180,[183][184][185][186][187] to oxidative phosphorylation and metabolic pathways (ATP5D, ATP5H, HSD17B10/NDUFB11, NDUFA8, NDUFB7). 151 Opioid exposure additionally caused dysregulated programmed cell death, synapse organization, cell morphogenesis, brain volume, and neuron differentiation, 152,169,191 similar to several of the above brain organoid studies.…”