Background: Long-term morphine use is associated with serious side effects, such as morphine-induced hyperalgesia and analgesic tolerance. Previous investigations have documented the association between dopamine (DA) neurons in the ventral tegmental area (VTA) and pain. However, whether VTA DA neurons are implicated in morphine-induced hyperalgesia and analgesic tolerance remains elusive. Methods: Initially, we observed behavioural effects of lidocaine administration into VTA or ablation of VTA DA neurons on morphine-induced hyperalgesia and anti-nociceptive tolerance. Subsequently, c-Fos expression in nucleus accumbens (NAc) shell-projecting and medial prefrontal cortex (mPFC)-projecting VTA DA neurons after chronic morphine treatment was respectively investigated. Afterwards, the effects of chemogenetic manipulation of NAc shell-projecting or mPFC-projecting DA neurons on morphine-induced hyperalgesia and anti-nociceptive tolerance were observed. Additionally, effects of chemogenetic manipulation of VTA GABA neurons on c-Fos expression in VTA DA neurons were investigated. Results: Lidocaine injection into VTA relieved established hyperalgesia and anti-nociceptive tolerance whereas ablation of VTA DA neurons prevented the development of morphine-induced hyperalgesia and anti-nociceptive tolerance. Chronic morphine treatment increased c-Fos expression in NAc shell-projecting DA neurons, rather than in mPFC-projecting DA neurons. Chemogenetic manipulation of NAc shell-projecting DA neurons had influence on morphine-induced hyperalgesia and tolerance. However, chemogenetic manipulation of mPFC-projecting DA neurons had no significant effects on morphine-induced hyperalgesia and anti-nociceptive tolerance. Chemogenetic manipulation of VTA GABA neurons affected the c-Fos expression in VTA DA neurons. Conclusions: These findings revealed the involvement of NAc shell-projecting VTA DA neurons in morphine-induced hyperalgesia and anti-nociceptive tolerance, and may shed new light on the clinical management of morphine-induced hyperalgesia and analgesic tolerance. Perspective: This study demonstrated that NAc shell-projecting DA neurons rather than mPFC-projecting DA neurons in the VTA were implicated in morphine-induced hyperalgesia and anti-nociceptive tolerance. Our findings may pave the way for the discovery of novel therapies for morphine-induced hyperalgesia and analgesic tolerance.
IntroductionTechniques using local anaesthetics provide high-quality analgesia, while the anti-inflammatory properties of these drugs may represent an additional advantage. Perioperative intravenous lidocaine has shown positive effects not only on postoperative pain but also on bowel function and duration of hospital stay, due to its analgesic, anti-inflammatory and opioid-sparing effects. However, these potential benefits are not well established in patients undergoing resection with colorectal cancer. This research aims to determine the effect of perioperative intravenous lidocaine on postoperative outcomes in patients undergoing resection of colorectal cancer.Methods and analysisPubMed, Embase, Web of Science, CNKI, SinoMed and WanFang Data databases were electronically retrieved to include the randomised controlled trials comparing perioperative intravenous lidocaine with placebo infusion in patients undergoing resection of colorectal cancer before August 2021. Registers of clinical trials, potential grey literature and abstracts from conferences will also be searched. Two reviewers will screen literature, extract data and assess risk of bias of studies included independently. The primary outcome variable will be long-term survival outcome, tumour recurrence and metastasis rate, and restoration of intestinal function. The secondary outcome variables will consist of the severity of postoperative pain at 4, 12, 24 and 48 hours after surgery, the incidence of postoperative nausea and vomiting, and the length of hospital stay. A meta-analysis will be performed using RevMan V.5.4 software provided by the Cochrane Collaboration and Stata V.12.0. subgroup and sensitivity analyses will be conducted.Ethics and disseminationBecause the data used for this systematic review will be exclusively extracted from published studies, ethical approval and informed consent of patients will not be required. The systematic review will be published in a peer-reviewed journal, presented at conferences and shared on social media platforms.PROSPERO registration numberCRD42020216232.
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