The activation of μ‐opioid receptor potentiates LPS‐induced NF‐kB promoting an inflammatory phenotype in microglia

Abstract

Increased production of proinflammatory cytokines has a prominent role in tolerance to opioids. The objectives of this study were to examine whether μ‐opioid receptor affects proinflammatory signalling through the activation of NF‐kB in microglia. The novelty of the described research is that a low dose of morphine, exerting its effects via the μ‐opioid receptor, increases the DNA‐binding activity of NF‐kB via PKCε, while a high dose of morphine triggers a nonopiate receptor response mediated by TLR4 and, interestingly, PKCε signalling. The identification of morphine as a crucial upstream regulator of PKCε‐NF‐κB signalling in microglia argues for a central role of these pathways in neuroinflammation development and progression. Therefore, the morphine‐PKCε‐NF‐κB pathway may provide novel targets to induce neuroprotective mechanisms, thereby reducing tolerance to opioids.

Biphalin, a Dimeric Enkephalin, Alleviates LPS-Induced Activation in Rat Primary Microglial Cultures in Opioid Receptor-Dependent and Receptor-Independent Manners

“…Our results show that biphalin reduced pain-related behavior in a preclinical model of neuropathy in rats, and these analgesic effects seem to be very important from a clinical point of view, especially because preclinical studies have revealed that biphalin has 1000-fold greater analgesic potency than morphine and induces less side effects [17, 18]. Moreover, our results provide strong evidence that biphalin, in contrast to morphine [32, 40, 41], is able to beneficially modulate crucial members of both microglial intracellular signaling pathways and proinflammatory factors, which are known to play a key role in neuropathic pain development.…”

“…Our previous studies have shown that minocycline, an inhibitor of microglial activation [27, 30], strongly delayed the development of morphine tolerance [55, 56] and potentiated MOP, KOP, and NOP ligand analgesia [29, 30]. Several lines of evidence have revealed that morphine increases microglial reactivity [31, 57, 58] and promotes the proinflammatory phenotype of those cells [31, 32, 40]. Moreover, chronic morphine treatment leads to the development of hyperalgesia and allodynia [6–9].…”

“…Several studies demonstrated that proinflammatory actions of morphine are related with microglial MOP receptor [31, 32]. The other interesting theory suggests that morphine is engaged in the microglial TLR4 (Toll-like receptor 4) signaling, which also seems to be responsible for the proinflammatory properties of this drug [32, 33]. However, there is no data showing a role of biphalin on TLR4, as well as MOP, receptor pathway activity.…”

Imaging Biomarkers of the Neuroimmune System among Substance Use Disorders: A Systematic Review

“…First, opioids elicit an acute inflammatory response likely via TLR4s [77, 78] and/or MORs [224-226]. There is reliable preclinical [227-229] and non-human primate [223] evidence indicating acute opioid administration is proinflammatory in the periphery and brain.…”

“…For example, opioids exert neuroimmune effects via directly binding receptors on microglia, e.g. TLR4s [77, 78] and MORs [224-226]. Other substances, e.g.…”