Plos One
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Morphine and structurally related derivatives are highly effective analgesics, and the mainstay in the medical management of moderate to severe pain. Pharmacological actions of opioid analgesics are primarily mediated through agonism at the µ opioid peptide (MOP) receptor, a G protein-coupled receptor. Position 17 in morphine has been one of the most manipulated sites on the scaffold and intensive research has focused on replacements of the 17-methyl group with other substituents. ⋯ In vivo, they were highly effective against acute thermal nociception in mice with marked increased antinociceptive potency compared to the lead molecules. It was also demonstrated that a carbonyl group at position 6 is preferable to a hydroxyl function in these N-phenethyl derivatives, enhancing MOP receptor affinity and agonist potency in vitro and in vivo. These results expand the understanding of the impact of different moieties at the morphinan nitrogen on ligand-receptor interaction, molecular mode of action and signaling, and may be instrumental to the development of new opioid therapeutics.
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The endocannabinoid anandamide (AEA) is an antinociceptive lipid that is inactivated through cellular uptake and subsequent catabolism by fatty acid amide hydrolase (FAAH). Fatty acid binding proteins (FABPs) are intracellular carriers that deliver AEA and related N-acylethanolamines (NAEs) to FAAH for hydrolysis. The mammalian brain expresses three FABP subtypes: FABP3, FABP5, and FABP7. ⋯ The antinociceptive effects of FABP inhibitors mirrored their affinities for FABP5, while binding to FABP3 and FABP7 was not a predictor of in vivo efficacy. The antinociceptive effects of FABP inhibitors were mediated by cannabinoid receptor 1 (CB1) and peroxisome proliferator-activated receptor alpha (PPARα) and FABP inhibition elevated brain levels of AEA, providing the first direct evidence that FABPs regulate brain endocannabinoid tone. These results highlight FABPs as novel targets for the development of analgesic and anti-inflammatory therapeutics.
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When faced with sensory stimuli, an organism may be required to detect very small differences in a physical parameter (discrimination), while in other situations it may have to generalize over many possible values of the same physical parameter. This decision may be based both on learned information and on sensory aspects of perception. In the present study we describe frequency processing in the behaving mouse using both discrimination and generalization as two key aspects of behaviour. ⋯ In contrast, pre-exposure frequencies that were half an octave or less below the conditioned tone elicited latent inhibition, showing a generalization bandwidth of at least half an octave. Thus, in the same apparatus and using the same general memory paradigm, mice showed generalization gradients that were considerably wider than their discrimination threshold, indicating that environmental requirements and previous experience can determine whether the same two frequencies will be considered same or different. Remarkably, generalization gradients paralleled the typical bandwidths established in the auditory periphery and midbrain, suggesting that frequencies may be considered similar when falling within the same critical band.
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Review Meta Analysis Comparative Study
Minimally invasive midvastus versus standard parapatellar approach in total knee arthroplasty: a meta-analysis of randomized controlled trials.
Minimally invasive midvastus approach (mini-midvastus) has been widely used in total knee arthroplasty (TKA). However, the clinical effects still remains controversial. This meta-analysis was based on randomized controlled trials (RCTs) aiming to quantitatively analyze the clinical efficacy of mini-midvastus versus standard parapatellar approach in TKA. ⋯ Therapeutic study Level I.
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Review Meta Analysis Comparative Study
A systematic review and meta-analysis of unilateral versus bilateral pedicle screw fixation in transforaminal lumbar interbody fusion.
Transforaminal lumbar interbody fusion (TLIF) has become one of the most widely used procedures for lumbar spinal disorders. However, it is still unclear whether TLIF with unilateral pedicle screw (PS) fixation is as effective as that with bilateral PS fixation. We performed a meta-analysis of the literatures and aimed to gain a better understanding of whether TLIF with unilateral PS fixation was safe and effective for lumbar diseases. ⋯ Our meta-analysis suggested TLIF with unilateral PS fixation was as safe and effective as that with bilateral PS fixation for lumbar diseases in selected patients. Despite these findings, our meta-analysis was based on studies with small sample size and different study characteristics that might lead to the inconsistent results such as various functional outcomes among the included studies. Therefore, high-quality randomized controlled trials with larger sample size are also needed to further clarify these issues and to provide the long-term outcomes.