痛情绪相关神经递质及神经环路研究进展＊

痛情绪是指因疼痛引发的情绪和情感体验，是疾病过程中最常见的一种情绪。痛情绪相关神经机制非常复杂，但主要与单胺类神经递质、神经肽和某些神经环路有关，笔者将结合目前研究现状分别从以上两方面展开，就痛情绪相关单胺类神经递质和神经肽在受体分类、脑区通路、共疾病以及各神经递质之间的联系和痛情绪相关神经环路中各个蛋白的作用机制等方面进行探讨。     

Risk of acute pancreatitis with incretin-based therapy: a systematic review and updated meta-analysis of cardiovascular outcomes trials

ABSTRACT

Background

The link of acute pancreatitis (AP) with Incretin based therapies (IBTs) in type 2 diabetes has existed since United States Food and Drug Administration alert in 2010. This issue still remains unresolved due to conflicting results among studies.     

Mechanical stimulation of cervical vertebrae modulates the discharge activity of ventral tegmental area neurons and dopamine release in the nucleus accumbens

BackgroundGrowing evidence suggests that mechanical stimulation modulates substrates in the supraspinal central nervous system (CNS) outside the canonical somatosensory circuits.Objective/Methods: We evaluate mechanical stimulation applied to the cervical spine at the C7-T1 level (termed “MStim”) on neurons and neurotransmitter release in the mesolimbic dopamine (DA) system, an area implicated in reward and motivation, utilizing electrophysiological, pharmacological, neurochemical and immunohistochemical techniques in Wistar rats.ResultsLow frequency (45–80 Hz), but not higher frequency (115 Hz), MStim inhibited the firing rate of ventral tegmental area (VTA) GABA neurons (52.8% baseline; 450 s) while increasing the firing rate of VTA DA neurons (248% baseline; 500 s). Inactivation of the nucleus accumbens (NAc), or systemic or in situ antagonism of delta opioid receptors (DORs), blocked MStim inhibition of VTA GABA neuron firing rate. MStim enhanced both basal (178.4% peak increase at 60 min) and evoked DA release in NAc (135.0% peak increase at 40 min), which was blocked by antagonism of DORs or acetylcholine release in the NAc. MStim enhanced c-FOS expression in the NAc, but inhibited total expression in the VTA, and induced translocation of DORs to neuronal membranes in the NAc.ConclusionThese findings demonstrate that MStim modulates neuron firing and DA release in the mesolimbic DA system through endogenous opioids and acetylcholine in the NAc. These findings demonstrate the need to explore more broadly the extra-somatosensory effects of peripheral mechanoreceptor activation and the specific role for mechanoreceptor-based therapies in the treatment of substance abuse.     

Recombinant M2e outer membrane vesicle vaccines protect against lethal influenza A challenge in BALB/c mice

Currently approved influenza vaccines predominantly protect through antibodies directed against the highly variable glycoprotein hemagglutinin (HA), necessitating annual redesign and formulation based on epidemiological prediction of predominant circulating strains. More conserved influenza protein sequences, such as the ectodomain of the influenza M2 protein, or M2e, show promise as a component of a universal influenza A vaccine, but require a Th1-biased immune response for activity. Recently, recombinant, bacterially derived outer membrane vesicles (OMVs) demonstrated potential as a platform to promote a Th1-biased immune response to subunit antigens. Here, we engineer three M2e-OMV vaccines and show that all elicit strong IgG titers, with high IgG2a:IgG1 ratios, in BALB/c mice. Additionally, the administration of one M2e-OMV construct containing tandem heterologous M2e peptides (M2e4xHet-OMV) resulted in 100% survival against lethal doses of the mouse-adapted H1N1 influenza strain PR8. Passive transfer of antibodies from M2e4xHet-OMV vaccinated mice to unvaccinated mice also resulted in 100% survival to challenge, indicating that protection is driven largely via antibody-mediated immunity. The potential mechanism through which M2e-OMVs initiated the immune response was explored and it was found that the constructs triggered TLR1/2, TLR4, and TLR5. Our data indicate that OMVs have potential as a platform for influenza A vaccine development due to their unique adjuvant profile and intrinsic pathogen-mimetic nature.     

Cardiovascular outcomes with SGLT-2 inhibitors and GLP-1 receptor agonist in Asians with type 2 diabetes: A systematic review and meta-analysis of cardiovascular outcome trials

Background and aimsBoth type 2 diabetes and cardiovascular (CV) disease develops at a younger age in Asians and often have a higher risk of mortality. Both sodium-glucose co-transport-2 inhibitors (SGLT-2Is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown a significant reduction in CV end-points in CV outcome trials (CVOTs). Whether similar CV benefit exists in Asians, is not yet clearly known.MethodsWe systematically searched relevant medical database up to January 31, 2020 and retrieved all the dedicated CVOTs conducted with SGLT-2Is and GLP-1RAs. Subsequently, we meta-analyzed the pooled data of hazard ratio (HR) of major adverse cardiac events (MACE) in Asians. We additionally analyzed the data of heart failure hospitalization (HHF) or CV-death with SGLT-2Is in Asians.ResultsThe meta-analysis of three CVOTs conducted with SGLT-2Is (N = 4987), did not find any significant reduction in MACE (HR, 0.88; 95% CI, 0.67 to 1.15; P = 0.35) and HHF or CV-death (HR, 0.86; 95% CI, 0.55 to 1.36; P = 0.53) in Asians, compared to the placebo. In contrast, the meta-analysis of seven CVOTs conducted with GLP-1RAs (N = 4298) demonstrated a significant reduction in MACE, compared to the placebo (HR, 0.71; 95% CI, 0.59 to 0.86; P < 0.0001).ConclusionsThis meta-analysis found a significant reduction in MACE with GLP-1RAs but not with SGLT-2Is in Asians. No significant reduction in HHF or CV-death demonstrated either with SGLT-2Is in Asians. Whether these results are related to an inadequate statistical power, or due to underrepresentation of Asians, or a true ethnic difference, remains to be established.     

Minimal parkinsonism in the elderly is associated with striatal dopamine loss and pontine structural damage

IntroductionTo investigate whether neurodegeneration underlying Parkinson's disease (PD) accounts for a substantial proportion of cases of minimal parkinsonism in the elderly.MethodsWe recruited 48 consecutive subjects with minimal parkinsonism who visited the clinic with cognitive complaints. All subjects did not show findings compatible with PD on ¹⁸F-FP-CIT PET scans, and had no evidence of other neurodegenerative disorders. Striatal dopamine transporter (DAT) availability was quantified, and mean diffusivity (MD) values in the pons were calculated to characterize structural damage using diffusion tensor imaging. Additionally, 35 patients with PD and 21 healthy controls were included as reference groups.ResultsIndividuals with minimal parkinsonism (mean age, 73.23 ± 7.03 years) exhibited mild decrease in DAT availability in the posterior putamen, which was at a level between that of healthy controls and patients with PD. DAT availability in the caudate and anterior putamen was also mildly decreased in the minimal parkinsonism group. Individuals with minimal parkinsonism also tended to have higher MD values in the pons compared to healthy controls.ConclusionsOur results suggest that a substantial proportion of minimal parkinsonism is associated with nigrostriatal dopamine depletion and pontine structural damage, which may be related to the disease process of prodromal PD.     

Parkinson's disease,visual hallucinations and apomorphine: A review of the available evidence

BackgroundVisual hallucinations (VH) occur in the clinical course of Parkinson's disease (PD) and are predictive for PD dementia. The genesis of VH is related to impaired bottom-up and/or top-down visual processing which can be linked to cholinergic dysfunction and mono-amine imbalance. The risk of developing VH with oral dopamine agonists seems to increase with advancing disease, while in contrast some clinical studies suggest that apomorphine does not worsen VH, or might even improve VH.MethodsThe aim of this study is to review the current evidence of apomorphine and its effects on VH in PD patients.ResultsApomorphine is well-tolerated in PD patients with VH, also in long-term follow-up studies. Apomorphine is also suggested to have the potential to alleviate VH. Some data suggest that the positive effect of apomorphine on VH is related to its piperidine moiety, part of many anti-psychotics. Irrespective this piperidine moiety, apomorphine has a high D₁–like receptor affinity, and acts as a serotonin 5-HT_2A receptor antagonist, which might explain the potential anti-hallucinogenic properties as well.ConclusionThe anecdotal evidence suggesting that apomorphine has a relatively low proclivity to induce VH in PD may be due to its capacity to reduce serotonergic activity in particular. Therefore apomorphine is still an option to consider in fluctuating PD patients with VH, if they are treated properly with respect to their cholinergic deficits and existing VH.