P. Sarret - Academia.edu (original) (raw)

Papers by P. Sarret

L. Dore-Savard, L. Tremblay, M. Archambault, J-F. Beaudoin, N. Beaudet, E. E. Turcotte, R. Lecomt... more L. Dore-Savard, L. Tremblay, M. Archambault, J-F. Beaudoin, N. Beaudet, E. E. Turcotte, R. Lecomte, P. Sarret, and M. Lepage Physiologie et biophysique, Universite de Sherbrooke, Sherbrooke, Quebec, Canada, Centre des Neurosciences de Sherbrooke, Sherbrooke, Quebec, Canada, Médecine nucléaire et radiobiologie, Universite de Sherbrooke, Sherbrooke, Quebec, Canada, Centre d'imagerie moléculaire de Sherbrooke, Sherbrooke, Quebec, Canada

Douleur et Analgésie

In the past few years, several biased ligands acting at the mu-opioid receptor were reported in t... more In the past few years, several biased ligands acting at the mu-opioid receptor were reported in the literature. These agonists are aimed at reducing pain while having fewer side effects than morphine, the gold standard of opioid analgesics. In this mini-review, we describe and discuss the recent advances in mu-biased ligands actually in preclinical and clinical development stages, including the latest U.S. Food and Drug Administration review of oliceridine, a biased mu-agonist for moderate to severe acute pain treatment developed by the company Trevena.

Journal of the Canadian Association of Gastroenterology

Background: Colorectal cancer (CRC) is the third most prevalent form of cancer worldwide and the ... more Background: Colorectal cancer (CRC) is the third most prevalent form of cancer worldwide and the second most diagnosed form of cancer in Canada. G proteincoupled receptors (GPCRs) are suspected to play a key role in CRC tumorigenesis. The tumorigenic process is divided into three steps: initiation, promotion and tumor progression. Formation of metastases is based on cell cancer capacity to migrate during early stages of tumorigenesis. Identification of new targets involved in CRC development is a major challenge to improve diagnostic and treatment of this form of cancer. Aims: Past research has identified the GPCR P2Y 6 as such innovative target. In fact, P2Y 6 activities were involved in different stages of colorectal tumorigenesis. We demonstrated that P2y 6-/mice significantly develop fewer tumors than control mice in a CRC mouse model. Other studies confirmed that P2Y 6 played a role in the epithelial to mesenchymal transition (EMT) and accelerated migration of breast cancer MDA-MB-468 cells. Surprisingly, there is sparse information about the potential influence of P2Y 6 action in cancer cell migration and on the mechanism involved in this process. That's why, in this study, we wanted to characterise P2Y 6 signalling in cell migration. Methods: We studied effects of this receptor on cell migration by using wound healing assays and we showed migrating structures by immunofluorescence assays and western blots. Results: In this work, we showed that P2Y 6 activation lead to cell migration using wound healing assays. This migratory stimulating effect was the result of the formation of filopodia and focal adhesions, known as migrating structures, and the cofilin phosphorylation. The formation of filopodia was associated to the P2Y 6 dependent modulation of CDC42 protein expression whereas cofilin phosphorylation was correlated to the Rho/ROCK pathway. Conclusions: These results are thus supporting the idea that the P2Y 6 receptor is involved in cell migration and it could be a target for the treatment of CRC.

Neuropharmacology

ABSTRACT Neuropeptides are often co‐expressed in neurons, and may therefore be working together t... more ABSTRACT Neuropeptides are often co‐expressed in neurons, and may therefore be working together to coordinate proper neural circuit function. However, neurophysiological effects of neuropeptides are commonly studied individually possibly underestimating their modulatory roles. Here, we triggered the release of endogenous neuropeptides in brain slices from male mice to better understand their modulation of central amygdala (CeA) inhibitory inputs onto oval (ov) BNST neurons. We found that locally‐released neurotensin (NT) and dynorphin (Dyn) antagonistically regulated CeA inhibitory inputs onto ovBNST neurons. NT and Dyn respectively increased and decreased CeA‐toovBNST inhibitory inputs through NT receptor 1 (NTR1) and kappa opioid receptor (KOR). Additionally, NT and Dyn mRNAs were highly co‐localized in ovBNST neurons suggesting that they may be released from the same cells. Together, we showed that NT and Dyn are key modulators of CeA inputs to ovBNST, paving the way to determine whether different conditions or states can alter the neuropeptidergic regulation of this particular brain circuit. HIGHLIGHTSEndogenous NT and Dyn bi‐directionally modulate CeA to ovBNST inhibitory transmission through NTR1 and KOR, respectively.NT and Dyn are co‐localized, co‐released, and co‐modulate transmission at inhibitory synapses in the ovBNST.NTR1 and NTR2 activation have opposing modulatory effects at ovBNST inhibitory synapses.First demonstration of a neuromodulatory role of NTR2 at GABA synapses.Study highlights importance of neuropeptidergic co‐modulation of synaptic transmission.

Pain Research and Management

The Quebec Pain Registry (QPR) is a large research database of patients suffering from various ch... more The Quebec Pain Registry (QPR) is a large research database of patients suffering from various chronic pain (CP) syndromes who were referred to one of five tertiary care centres in the province of Quebec (Canada). Patients were monitored using common demographics, identical clinical descriptors, and uniform validated outcomes. This paper describes the development, implementation, and research potential of the QPR. Between 2008 and 2013, 6902 patients were enrolled in the QPR, and data were collected prior to their first visit at the pain clinic and six months later. More than 90% of them (mean age ± SD: 52.76 ± 4.60, females: 59.1%) consented that their QPR data be used for research purposes. The results suggest that, compared to patients with serious chronic medical disorders, CP patients referred to tertiary care clinics are more severely impaired in multiple domains including emotional and physical functioning. The QPR is also a powerful and comprehensive tool for conducting rese...

Intensive care medicine experimental, 2016

Intensive Care Medicine Experimental, 2014

Encyclopedia of Neuroscience, 2009

Neurotensin (NT) is a neuropeptide predominantly expressed in the brain and the gut. The peptide ... more Neurotensin (NT) is a neuropeptide predominantly expressed in the brain and the gut. The peptide exerts its effects through two G-protein-coupled receptors, the NTS1 and NTS2, and through a single transmembrane domain protein, the NTS3 or sortilin, that belongs to a small family of sorting receptors. In the brain, NT and its receptors are distributed in a regionalized fashion, and the peptide modulates the activity of neuronal systems involved in behavioral responses such as locomotor activity, rewarding, drug seeking, eating, and pain sensation.

The Journal of neuroscience : the official journal of the Society for Neuroscience, 1999

The neuropeptide neurotensin (NT) elicits hypothermic and naloxone-insensitive analgesic response... more The neuropeptide neurotensin (NT) elicits hypothermic and naloxone-insensitive analgesic responses after brain injection. Recent pharmacological evidence obtained with NT agonists and antagonists suggests that these effects are mediated by a receptor distinct from the initially cloned high-affinity NT receptor (NTR1). The recent cloning of a second NT receptor (NTR2) prompted us to evaluate its role in NT-induced analgesia. Intracerebroventricular injections in mice of two different antisense oligodeoxynucleotides from the NTR2 markedly decreased NTR2 mRNA and protein and reduced NT-induced analgesia. This effect was specific, because NTR1 levels were unaffected, and sense or scramble oligodeoxynucleotides had no effect. Structure-activity studies revealed a close correlation between the analgesic potency of NT analogs and their affinity for the NTR2 and disclosed potent and selective agonists of this receptor. These data confirm that NTR1 is involved in the NT-elicited turning beha...

Methods in Molecular Biology, 2010

Pain is the new burden of the twenty-first century, raising enormous socio-economic costs to deve... more Pain is the new burden of the twenty-first century, raising enormous socio-economic costs to developed and underdeveloped countries. Chronic pain is a central nervous system (CNS) pathology, affecting a large proportion of the population. Morphine and its derivatives are still the golden clinical standards for treating pain although they induce severe side effects. To this day, we still have poor understanding of nociceptive pain and its underlying complex mechanisms; furthermore, novelty in clinical analgesics is lacking.RNA interference technologies are promising both for pain research and treatment. This genetic approach will likely provide new insights into pain mechanisms and eventually offer nonpharmacological therapeutic approaches. In vivo research is thus crucial to reach this goal. Preclinical studies on rodents are necessary to validate small interfering RNA (siRNA) candidates and to target precise physiological pain modulators. Aiming treatment at the CNS is delicate work, and here we will describe how to perform adequate pain research using siRNA, including siRNA preparation and injection, animal behavioral models, and CNS tissue collection.

Journal of Medicinal Chemistry, 2015

Apelin is the endogenous ligand of the APJ receptor, a member of the G protein-coupled receptor f... more Apelin is the endogenous ligand of the APJ receptor, a member of the G protein-coupled receptor family. This system plays an important role in the regulation of blood pressure and cardiovascular functions. To better understand the role of its C-terminal Phe 13 residue on ligand binding, receptor signaling and hypotension, we report a series of modified analogs in which Phe 13 was substituted by unnatural amino acids. These modifications delivered new compounds exhibiting higher affinity and potency to inhibit cAMP accumulation compared to apelin-13. In particular, analogs Bpa 13 or (α-Me)Phe 13 were 30-fold more potent to inhibit cAMP accumulation than apelin-13. Tyr(OBn) 13 substitution led to a 60-fold improvement in binding affinity and induced stronger and more sustained drop in blood pressure compared to apelin-13. Our study identified new potent analogs of apelin-13, which represent valuable probes to better understand its structure-function relationship.

Journal of Neuroscience, 2005

Intrathecal administration of the neuropeptide neurotensin (NT) was shown previously to exert ant... more Intrathecal administration of the neuropeptide neurotensin (NT) was shown previously to exert antinociceptive effects in a variety of acute spinal pain paradigms including hotplate, tail-flick, and writhing tests. In the present study, we sought to determine whether some of these antinociceptive effects might be elicited via stimulation of low-affinity NTS2 receptors. We first established, using immunoblotting and immunohistochemical techniques, that NTS2 receptors were extensively associated with putative spinal nociceptive pathways, both at the level of the dorsal root ganglia and of the superficial layers of the dorsal horn of the spinal cord. We then examined the effects of intrathecal administration of NT or selective NTS2 agonists on acute thermal pain. Both NT and NTS2 agonists, levocabastine and Boc-Arg-Arg-Pro-Tyr⌿(CH 2 NH)Ile-Leu-OH (JMV-431), induced dose-dependent antinociceptive responses in the tail-flick test. The effects of levocabastine and of JMV-431 were unaffected by coadministration of the NTS1-specific antagonist 2-[(1-(7-chloro-4quinolinyl)-5-(2,6-dimethoxy-phenyl)pyrazol-3-yl)carboxylamino]tricyclo)3.3.1.1. 3.7)-decan-2-carboxylic acid (SR48692), confirming that they were NTS2 mediated. In contrast, the antinociceptive effects of NT were partly abolished by coadministration of SR48692, indicating that NTS1 and NTS2 receptors were both involved. These results suggest that NTS2 receptors play a role in the regulation of spinal nociceptive inputs and that selective NTS2 agonists may offer new avenues for the treatment of acute pain.

Journal of Neuroscience, 2010

High levels of reactive oxygen species (ROS) are associated with deficits in learning and memory ... more High levels of reactive oxygen species (ROS) are associated with deficits in learning and memory with age as well as in Alzheimer's disease. Using DNA microarray, we demonstrated the overexpression of quinone reductase 2 (QR2) in the hippocampus in two models of learning deficits, namely the aged memory impaired rats and the scopolamine-induced amnesia model. QR2 is a cytosolic flavoprotein that catalyzes the reduction of its substrate and enhances the production of damaging activated quinone and ROS. QR2-like immunostaining is enriched in cerebral structures associated with learning behaviors, such as the hippocampal formation and the temporofrontal cortex of rat, mouse, and human brains. In cultured rat embryonic hippocampal neurons, selective inhibitors of QR2, namely S26695 and S29434, protected against menadione-induced cell death by reversing its proapoptotic action. S26695 (8 mg/kg) also significantly inhibited scopolamine-induced amnesia. Interestingly, adult QR2 knockout mice demonstrated enhanced learning abilities in various tasks, including Morris water maze, object recognition, and rotarod performance test. Other behaviors related to anxiety (elevated plus maze), depression (forced swim), and schizophrenia (prepulse inhibition) were not affected in QR2-deficient mice. Together, these data suggest a role for QR2 in cognitive behaviors with QR2 inhibitors possibly representing a novel therapeutic strategy toward the treatment of learning deficits especially observed in the aged brain.