Projection-specific dopamine neurons in the ventral tegmental area participated in morphine-induced hyperalgesia and anti-nociceptive tolerance in male mice.

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.

Predisposition of Neonatal Maternal Separation to Visceral Hypersensitivity via Downregulation of Small-Conductance Calcium-Activated Potassium Channel Subtype 2 (SK2) in Mice.

Background: Visceral hypersensitivity is a common occurrence of gastrointestinal diseases such as irritable bowel syndrome (IBS), wherein early-life stress (ELS) may have a high predisposition to the development of visceral hypersensitivity in adulthood, with the specific underlying mechanism still elusive. Herein, we assessed the potential effect of small-conductance calcium-activated potassium channel subtype 2 (SK2) in the spinal dorsal horn (DH) on the pathogenesis of visceral hypersensitivity induced by maternal separation (MS) in mice. Methods: Neonatal mice were subjected to the MS paradigm, an established ELS model. In adulthood, the visceral pain threshold and the abdominal withdrawal reflex (AWR) were measured with an inflatable balloon. The elevated plus maze, open field test, sucrose preference test, and forced swim test were employed to evaluate the anxiety- and depression-like behaviors. The expression levels of SK2 in the spinal DH were determined by immunofluorescence and western blotting. The mRNA of SK2 and membrane palmitoylated protein 2 (MPP2) were determined by quantitative real-time polymerase chain reaction (qRT-PCR). Electrophysiology was applied to evaluate the neuronal firing rates and SK2 channel-mediated afterhyperpolarization current (I AHP). The interaction between MPP2 and SK2 was validated by coimmunoprecipitation. Results: In contrast to the naïve mice, ethological findings in MS mice revealed lowered visceral pain threshold, more evident anxiety- and depression-like behaviors, and downregulated expression of membrane SK2 protein and MPP2 protein. Moreover, electrophysiological results indicated increased neuronal firing rates and decreased I AHP in the spinal DH neurons. Nonetheless, intrathecal injection of the SK2 channel activator 1-ethyl-2-benzimidazolinone (1-EBIO) in MS mice could reverse the electrophysiological alterations and elevate the visceral pain threshold. In the naïve mice, administration of the SK2 channel blocker apamin abated I AHP and elevated spontaneous neuronal firing rates in the spinal DH neurons, reducing the visceral pain threshold. Finally, disruption of the MPP2 expression by small interfering RNA (siRNA) could amplify visceral hypersensitivity in naïve mice. Conclusions: ELS-induced visceral pain and visceral hypersensitivity are associated with the underfunction of SK2 channels in the spinal DH.

Relationship between disease progression of primary gastric cancer and preoperative neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio / 中国现代普通外科进展

Objective:To investigate The relationship between the disease progression of primary gastric cancer and preoperative neutrophil-to-lymphocyte ratio、platelet-to-lymphocyte ratio.Methods:A retrospective analysis of the clinical data of 188 cases treated in our hospital from April 2015 to February 2015 with primary gastric cancer.according to the peripheral venous blood NLR、PLR,analyze the relationship of NLR、PLR with different tumor infiltration depth、lymph node staging and TNM staging with statistical methods.Results:There is statistically significance of NLR、PLR between different groups (P＜0.01);tumor infiltration depth,lymph node staging and TNM stage of high NLR、PLR group in patients with gastric cancer were higher than low NLR、PLR group,the difference is statistically significant (P＜0.01);NLR is significantly positive correlated to PLR (r=0.379,P＜0.001);Multiple linear regression analysis shows the above factors had significant effects on preoperative NLR,PLR (P＜0.05).Conclusions:Preoperative peripheral blood NLR and PLR levels may be value in predicting the progression of gastric cancer,High preoperative NLR indicates later disease progression and worse prognosis.

Relationship between disease progression of primary gastric cancer and preoperative neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio / 中国现代普通外科进展

Objective:To investigate The relationship between the disease progression of primary gastric cancer and preoperative neutrophil-to-lymphocyte ratio、platelet-to-lymphocyte ratio.Methods:A retrospective analysis of the clinical data of 188 cases treated in our hospital from April 2015 to February 2015 with primary gastric cancer.according to the peripheral venous blood NLR、PLR,analyze the relationship of NLR、PLR with different tumor infiltration depth、lymph node staging and TNM staging with statistical methods.Results:There is statistically significance of NLR、PLR between different groups (P＜0.01);tumor infiltration depth,lymph node staging and TNM stage of high NLR、PLR group in patients with gastric cancer were higher than low NLR、PLR group,the difference is statistically significant (P＜0.01);NLR is significantly positive correlated to PLR (r=0.379,P＜0.001);Multiple linear regression analysis shows the above factors had significant effects on preoperative NLR,PLR (P＜0.05).Conclusions:Preoperative peripheral blood NLR and PLR levels may be value in predicting the progression of gastric cancer,High preoperative NLR indicates later disease progression and worse prognosis.