Abstract
BackgroundMorphine tolerance is a clinical challenge, and its pathogenesis is closely related to the neuroinflammation mediated by Toll-like receptor 4 (TLR4). In Chinese pain clinic, lidocaine is combined with morphine to treat chronic pain. We found that lidocaine sufficiently inhibited neuroinflammation induced by morphine and improved analgesic tolerance on the basis of non-affecting pain threshold.MethodsCD-1 mice were utilized for tail-flick test to evaluate morphine tolerance. The microglial cell line BV-2 was utilized to investigate the mechanism of lidocaine. Neuroinflammation-related cytokines were measured by western blotting and real-time PCR. The level of suppressor of cytokine signaling 3 (SOCS3) and adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK)-related signaling pathway was evaluated by western blotting, real-time PCR, enzyme-linked immunosorbent assay (ELISA), and immunofluorescence staining.ResultsLidocaine potentiated an anti-nociceptive effect of morphine and attenuated the chronic analgesic tolerance. Lidocaine suppressed morphine-induced activation of microglia and downregulated inflammatory cytokines, interleukin-1β (IL-1β), and tumor necrosis factor-alpha (TNF-α) via upregulating SOCS3 by activating AMPK. Lidocaine enhanced AMPK phosphorylation in a calcium-dependent protein kinase kinase β (CaMKKβ)-dependent manner. Furthermore, lidocaine decreased the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and inhibited the nuclear factor-κB (NF-κB) in accordance with the inhibitory effects to TLR4.ConclusionsLidocaine as a prevalent local anesthetic suppresses morphine tolerance efficiently. AMPK-dependent upregulation of SOCS3 by lidocaine plays a crucial role in the improvement of analgesic tolerance.
Highlights
Morphine tolerance is a clinical challenge, and its pathogenesis is closely related to the neuroinflammation mediated by Toll-like receptor 4 (TLR4)
In this study, we demonstrated that lidocaine markedly inhibited the development of chronic morphine tolerance and had a significant inhibitory effect on morphineinduced activation of microglia and consequent neuroinflammation; second, we illuminated that the improvement of morphine tolerance achieved by lidocaine was based on its upregulation of the level of suppressor of cytokine signaling 3 (SOCS3) via AMPKdependent signal pathway (Fig. 7)
Our study indicated that lidocaine decreased the level of Calcitonin gene-related peptide (CGRP), which was a peptide released by a primary afferent and was able to mediate the activation of N-methyl-D-aspartic acid (NMDA) receptors in neurons [52]
Summary
Morphine tolerance is a clinical challenge, and its pathogenesis is closely related to the neuroinflammation mediated by Toll-like receptor 4 (TLR4). Many studies have shown that neuroinflammation especially mediated by Toll-like receptor 4 (TLR4) is a very important reason for the development of tolerance [6,7,8]. In the central nervous system (CNS), microglia are important TLR4-expressing cells that mediate neuroinflammation. Chronic administration of morphine activates microglia and increases proinflammatory cytokines via TLR4/p38/NF-κB pathway [11, 12]. The proinflammatory cytokines, especially interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), further induce the activation of PKC in neurons, leading to central sensitization and weakened analgesic effect [13]. Inhibiting TLR4-mediated neuroinflammation would be an effective strategy for improving morphine tolerance [15]. Up till there is no available safe and efficient drug for suppressing TLR4, IL-1β, and TNF-α in clinical to alleviate tolerance
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