Design, Synthesis, and Characterization of Proteolytically-Stable Opioid-Neurotensin Hybrid Peptidomimetics.

Linking an opioid to a nonopioid pharmacophore represents a promising approach for reducing opioid-induced side effects during pain management. Herein, we describe the optimization of the previously reported opioid-neurotensin hybrids (OPNT-hybrids), & , containing the μ-/δ-opioid agonist H-Dmt-d-Arg-Aba-β-Ala-NH and NT(8-13) analogs optimized for NTS2 affinity. In the present work, the constrained dipeptide Aba-β-Ala was modified to investigate the optimal linker length between the two pharmacophores, as well as the effect of expanding the aromatic moiety within constrained dipeptide analogs, via the inclusion of a naphthyl moiety.

Reliability and minimal detectable change of dynamic temporal summation and conditioned pain modulation using a single experimental paradigm.

Background: Quantitative sensory tests (QST) are frequently used to explore alterations in somatosensory systems. Static and dynamic QST like pain threshold and temporal summation (TS) and conditioned pain modulation (CPM) are commonly used to evaluate excitatory and inhibitory mechanisms involved in pain processing. The aim of the present study was to document the reliability and the minimal detectable change (MDC) of these dynamic QST measurements using a standardized experimental paradigm.

Radiation-Activated Cobalamin-Kinase Inhibitors for Treatment of Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most dismal diagnoses that a patient can receive. PDAC is extremely difficult to treat, as drug delivery is challenging in part due to the lack of vascularization, high stromal content, and high collagen content of these tumors. We have previously demonstrated that attaching drugs to the cobalamin scaffold provides selectivity for tumors over benign cells due to a high vitamin demand in these rapidly growing cells and an overexpression of transcobalamin receptors in a variety of cancer types.

Specific olfactory deficit patterns observed in seniors and associated with cognitive decline.

Olfactory dysfunction is a common symptom in neurodegenerative disorders and is regarded as a potential early predictor of impending cognitive decline. This study was undertaken in order to determine if olfactory dysfunction observed in the elderly is due to a general loss of smell or the inability to detect specific odours, and if misidentification of odours correlates with cognitive scores. Seniors for the Olfactory Response and Cognition in Aging (ORCA) sub-study were recruited from the Quebec Nutrition and Successful Aging (NuAge) cohort.

Spinal sensorimotor circuits play a prominent role in hindlimb locomotor recovery after staggered thoracic lateral hemisections but cannot restore posture and interlimb coordination during quadrupedal locomotion in adult cats.

Unlabelled: Spinal sensorimotor circuits interact with supraspinal and peripheral inputs to generate quadrupedal locomotion. Ascending and descending spinal pathways ensure coordination between the fore-and hindlimbs. Spinal cord injury disrupts these pathways.

Triple Thorpe-Ingold Effect in the Synthesis of 18-Membered C Symmetric Lactams Stacking as Endless Supramolecular Tubes.

Three C symmetric macrolactams were very efficiently cyclized from their linear precursors. Adequately located substituents are responsible for the enhancement of reactivity that is not observed in the unsubstituted parent. DFT calculations show that the properly folded cyclization precursor, the reactive conformer, is more populated than other conformers, leading to a decrease of free energy of activation.

Modulation of the gait pattern during split-belt locomotion after lateral spinal cord hemisection in adult cats.

Most previous studies investigated the recovery of locomotion in animals and people with incomplete spinal cord injury (SCI) during relatively simple tasks (e.g., walking in a straight line on a horizontal surface or a treadmill).

Development and Validation of a Predictive Model of Pain Modulation Profile to Guide Chronic Pain Treatment: A Study Protocol.

Quantitative sensory testing is frequently used in research to assess endogenous pain modulation mechanisms, such as Temporal Summation (TS) and Conditioned Pain Modulation (CPM), reflecting excitatory and inhibitory mechanisms, respectively. Numerous studies found that a dysregulation of these mechanisms is associated with chronic pain conditions. In turn, such a patient's "profile" (increased TS and/or weakened CPM) could be used to recommend different pharmacological treatments.

Comparison of Thermal and Electrical Modalities in the Assessment of Temporal Summation of Pain and Conditioned Pain Modulation.

Temporal summation of pain (TSP) and conditioned pain modulation (CPM) can be measured using a thermode and a cold pressor test (CPT). Unfortunately, these tools are complex, expensive, and are ill-suited for routine clinical assessments. Building on the results from an exploratory study that attempted to use transcutaneous electrical nerve stimulation (TENS) to measure CPM and TSP, the present study assesses whether a "new" TENS protocol can be used instead of the thermode and CPT to measure CPM and TSP.

Knock-In Mouse Models to Investigate the Functions of Opioid Receptors .

Due to their low expression levels, complex multi-pass transmembrane structure, and the current lack of highly specific antibodies, the assessment of endogenous G protein-coupled receptors (GPCRs) remains challenging. While most of the research regarding their functions was performed in heterologous systems overexpressing the receptor, recent advances in genetic engineering methods have allowed the generation of several unique mouse models. These animals proved to be useful to investigate numerous aspects underlying the physiological functions of GPCRs, including their endogenous expression, distribution, interactome, and trafficking processes.

Differential barcoding of opioid receptors trafficking.

Over the past several years, studies have highlighted the δ-opioid receptor (DOPr) as a promising therapeutic target for chronic pain management. While exhibiting milder undesired effects than most currently prescribed opioids, its specific agonists elicit effective analgesic responses in numerous animal models of chronic pain, including inflammatory, neuropathic, diabetic, and cancer-related pain. However, as compared with the extensively studied μ-opioid receptor, the molecular mechanisms governing its trafficking remain elusive.

Identification of the interactome of the DP1 receptor for Prostaglandin D: Regulation of DP1 receptor signaling and trafficking by IQGAP1.

Background: Mechanisms governing localization, trafficking and signaling of G protein-coupled receptors (GPCRs) are critical in cell function. Protein-protein interactions are determinant in these processes. However, there are very little interacting proteins known to date for the DP1 receptor for prostaglandin D.

Transcutaneous electrical nerve stimulation (TENS): towards the development of a clinic-friendly method for the evaluation of excitatory and inhibitory pain mechanisms.

: Temporal summation and conditioned pain modulation (CPM) can be measured using a thermode and cold pressor test (CPTest). Unfortunately, these complex and expensive tools are ill-suited for routine clinical assessments. : We aimed to compare the temporal summation and CPM obtained with the thermode + CPTest paradigm to those obtained with a novel paradigm using transcutaneous electrical nerve stimulation (TENS).

The PAR2 inhibitor I-287 selectively targets Gα and Gα signaling and has anti-inflammatory effects.

Protease-activated receptor-2 (PAR2) is involved in inflammatory responses and pain, therefore representing a promising therapeutic target for the treatment of immune-mediated inflammatory diseases. However, as for other GPCRs, PAR2 can activate multiple signaling pathways and those involved in inflammatory responses remain poorly defined. Here, we describe a new selective and potent PAR2 inhibitor (I-287) that shows functional selectivity by acting as a negative allosteric regulator on Gα and Gα activity and their downstream effectors, while having no effect on G signaling and βarrestin2 engagement.

Altered rRNA processing disrupts nuclear RNA homeostasis via competition for the poly(A)-binding protein Nab2.

RNA-binding proteins (RBPs) are key mediators of RNA metabolism. Whereas some RBPs exhibit narrow transcript specificity, others function broadly across both coding and non-coding RNAs. Here, in Saccharomyces cerevisiae, we demonstrate that changes in RBP availability caused by disruptions to distinct cellular processes promote a common global breakdown in RNA metabolism and nuclear RNA homeostasis.

Optimized Opioid-Neurotensin Multitarget Peptides: From Design to Structure-Activity Relationship Studies.

Fusion of nonopioid pharmacophores, such as neurotensin, with opioid ligands represents an attractive approach for pain treatment. Herein, the μ-/δ-opioid agonist tetrapeptide H-Dmt-d-Arg-Aba-β-Ala-NH () was fused to analogues. Since the NTS1 receptor has been linked to adverse effects, selective MOR-NTS2 ligands are preferred.

In vivo mapping of a GPCR interactome using knockin mice.

With over 30% of current medications targeting this family of proteins, G-protein-coupled receptors (GPCRs) remain invaluable therapeutic targets. However, due to their unique physicochemical properties, their low abundance, and the lack of highly specific antibodies, GPCRs are still challenging to study in vivo. To overcome these limitations, we combined here transgenic mouse models and proteomic analyses in order to resolve the interactome of the δ-opioid receptor (DOPr) in its native in vivo environment.

The Delta-Opioid Receptor; a Target for the Treatment of Pain.

Nowadays, pain represents one of the most important societal burdens. Current treatments are, however, too often ineffective and/or accompanied by debilitating unwanted effects for patients dealing with chronic pain. Indeed, the prototypical opioid morphine, as many other strong analgesics, shows harmful unwanted effects including respiratory depression and constipation, and also produces tolerance, physical dependence, and addiction.

Use of a Noninvasive Brain-Penetrating Peptide-Drug Conjugate Strategy to Improve the Delivery of Opioid Pain Relief Medications to the Brain.

The analgesic potency of morphine-6-glucuronide (M6G) has been shown to be 50-fold higher than morphine after intracerebral injection. However, the brain penetration of M6G is significantly lower than morphine, thus limiting its usefulness in pain management. Here, we created new entities by the conjugation of the angiopep-2 peptide (An2) that crosses the blood-brain barrier (BBB) by low-density lipoprotein receptor-related protein 1 receptor-mediated transcytosis with either morphine or M6G.

Alleviating pain with delta opioid receptor agonists: evidence from experimental models.

The use of opioids for the relief of pain and headache disorders has been studied for years. Nowadays, particularly because of its ability to produce analgesia in various pain models, delta opioid receptor (DOPr) emerges as a promising target for the development of new pain therapies. Indeed, their potential to avoid the unwanted effects commonly observed with clinically used opioids acting at the mu opioid receptor (MOPr) suggests that DOPr agonists could be a therapeutic option.