2. Academic Validation
  3. Lidocaine alleviates morphine tolerance via AMPK-SOCS3-dependent neuroinflammation suppression in the spinal cord

Lidocaine alleviates morphine tolerance via AMPK-SOCS3-dependent neuroinflammation suppression in the spinal cord

  • J Neuroinflammation. 2017 Nov 2;14(1):211. doi: 10.1186/s12974-017-0983-6.
Yan Zhang 1 2,  Gao-Jian Tao 1 3,  Liang Hu 1,  Jie Qu 1,  Yuan Han 4,  Guangqin Zhang 2,  Yanning Qian 5,  Chun-Yi Jiang 6,  Wen-Tao Liu 7 8
Affiliations

Affiliations

  • 1 Neuroprotective Drug Discovery Key Laboratory of Nanjing Medical University, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, 211166, China.
  • 2 Research Division of Pharmacology, China Pharmaceutical University, Nanjing, Jiangsu, 211100, China.
  • 3 Department of Pain, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, 210008, China.
  • 4 Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China.
  • 5 Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, China.
  • 6 Neuroprotective Drug Discovery Key Laboratory of Nanjing Medical University, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, 211166, China. jcy@njmu.edu.cn.
  • 7 Neuroprotective Drug Discovery Key Laboratory of Nanjing Medical University, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, 211166, China. painresearch@njmu.edu.cn.
  • 8 Department of Pharmacy, Sir Run Run Shaw Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu, 210008, China. painresearch@njmu.edu.cn.
PMID: 29096659 DOI: 10.1186/s12974-017-0983-6
Abstract

Background: Morphine 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.

Methods: CD-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.

Results: Lidocaine 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.

Conclusions: Lidocaine 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.

Keywords

AMPK; Microglia; Morphine tolerance; Neuroinflammation; SOCS3.

Figures
Products