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Christophe Mallet,1 Jules Desmeules,2 Rassa Pegahi,3 Alain Eschalier1 1Université Clermont Auvergne, INSERM, NEURO-DOL Basics & Clinical Pharmacology of Pain, Clermont-Ferrand, France; 2Faculty of Medicine and The School of Pharmaceutical Sciences, Faculty of Sciences, Geneva University, Geneva, Switzerland; 3Medical Affairs Department, UPSA, Paris, FranceCorrespondence: Alain Eschalier, Faculté de Médecine, UMR Neuro-Dol, 49 Bd François Mitterrand, Clermont-Ferrand, 63000, France, Email alain.eschalier@uca.frAbstract: Paracetamol remains the recommended first-line option for mild-to-moderate acute pain in general population and particularly in vulnerable populations. Despite its wide use, debate exists regarding the analgesic mechanism of action (MoA) of paracetamol. A growing body of evidence challenged the notion that paracetamol exerts its analgesic effect through cyclooxygenase (COX)-dependent inhibitory effect. It is now more evident that paracetamol analgesia has multiple pathways and is mediated by the formation of the bioactive AM404 metabolite in the central nervous system (CNS). AM404 is a potent activator of TRPV1, a major contributor to neuronal response to pain in the brain and dorsal horn. In the periaqueductal grey, the bioactive metabolite AM404 activated the TRPV1 channel‐mGlu5 receptor‐PLC‐DAGL‐CB1 receptor signaling cascade. The present article provides a comprehensive literature review of the centrally located, COX-independent, analgesic MoA of paracetamol and relates how the current experimental evidence can be translated into clinical practice. The evidence discussed in this review established paracetamol as a central, COX-independent, antinociceptive medication that has a distinct MoA from non-steroidal anti-inflammatory drugs (NSAIDs) and a more tolerable safety profile. With the establishment of the central MoA of paracetamol, we believe that paracetamol remains the preferred first-line option for mild-to-moderate acute pain

BACKGROUND Fat layers in obese patients can impair R-wave detection and diagnostic performance of a subcutaneous insertable cardiac monitor (ICM). We compared safety and ICM sensing quality between obese patients [body mass index (BMI) ≥ 30 kg/m$^{2}$] and normal-weight controls (BMI <30 kg/m$^{2}$) in terms of R-wave amplitude and time in noise mode (noise burden) detected by a long-sensing-vector ICM. MATERIALS AND METHODS Patients from two multicentre, non-randomized clinical registries are included in the present analysis on January 31, 2022 (data freeze), if the follow-up period was at least 90 days after ICM insertion, including daily remote monitoring. The R-wave amplitudes and daily noise burden averaged intraindividually for days 61-90 and days 1-90, respectively, were compared between obese patients (n = 104) and unmatched (n = 268) and a nearest-neighbour propensity score (PS) matched (n = 69) normal-weight controls. RESULTS The average R-wave amplitude was significantly lower in obese (median 0.46 mV) than in normal-weight unmatched (0.70 mV, P < 0.0001) or PS-matched (0.60 mV, P = 0.003) patients. The median noise burden was 1.0% in obese patients, which was not significantly higher than in unmatched (0.7%; P = 0.056) or PS-matched (0.8%; P = 0.133) controls. The rate of adverse device effects during the first 90 days did not differ significantly between groups. CONCLUSION Although increased BMI was associated with reduced signal amplitude, also in obese patients the median R-wave amplitude was >0.3 mV, a value which is generally accepted as the minimum level for adequate R-wave detection. The noise burden and adverse event rates did not differ significantly between obese and normal-weight patients.Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04075084 and NCT04198220.

Background: Although the presence of a thrombus contraindicates left atrial appendage closure procedure (LAAC), a previous study reported the feasibility of the thrombus trapping procedure (TTP) technique to overcome this limitation. Aims: This study aimed to analyse the short-term outcomes in a series of patients who underwent LAAC using the TTP (TTP-LAAC). Methods: This retrospective series included patients who underwent TTP-LAAC between January 2018 and May 2020 in 13 European centres. Device choice, pre-interventional work-up and post-discharge antithrombotic therapy regimens were left to the discretion of the operators. The primary endpoint was the 30-day occurrence of stroke, systemic embolism or cardiovascular death. Results: During the study period, a total of 1,918 patients underwent LAAC. A thrombus was identified in 71 cases but completely disappeared in 24 patients before procedure. TTP-LAAC was finally performed in 53 cases (3%). Thrombi were identified ahead of the actual day of implantation in 47 patients (87%) and were mostly limited in size (50 cases with extension <50% of the LAA surface). The Amplatzer Amulet and WATCHMAN FLX occluders were implanted in 44 and 9 patients, respectively. A single deployment approach was applied in 70% and a cerebral embolic protection system was used in 9% of the patients. The overall success rate was 100%. Small pericardial effusion without tamponade was observed in 6% of the cases. Patients were discharged with 72% under antiplatelet therapy and 10% under short-term oral anticoagulation. The primary endpoint occurred in one patient. Conclusions: TTP-LAAC might be used in a minority of LAAC procedures but appears to be feasible and safe in the short-term, in select cases.

Paracetamol, one of the most widely used pain-relieving drugs, is deacetylated to 4-aminophenol (4-AP) that undergoes fatty acid amide hydrolase (FAAH)-dependent biotransformation into N-arachidonoylphenolamine (AM404), which mediates TRPV1-dependent antinociception in the brain of rodents. However, paracetamol is also converted to the liver-toxic metabolite N-acetyl-p-benzoquinone imine already at therapeutic doses, urging for safer paracetamol analogues. Primary amine analogues with chemical structures similar to paracetamol were evaluated for their propensity to undergo FAAH-dependent N-arachidonoyl conjugation into TRPV1 activators both in vitro and in vivo in rodents. The antinociceptive and antipyretic activity of paracetamol and primary amine analogues was examined with regard to FAAH and TRPV1 as well as if these analogues produced acute liver toxicity. 5-Amino-2-methoxyphenol (2) and 5-aminoindazole (3) displayed efficient target protein interactions with a dose-dependent antinociceptive effect in the mice formalin test, which in the second phase was dependent on FAAH and TRPV1. No hepatotoxicity of the FAAH substrates transformed into TRPV1 activators was observed. While paracetamol attenuates pyrexia via inhibition of brain cyclooxygenase, its antinociceptive FAAH substrate 4-AP was not antipyretic, suggesting separate mechanisms for the antipyretic and antinociceptive effect of paracetamol. Furthermore, compound 3 reduced fever without a brain cyclooxygenase inhibitory action. The data support our view that analgesics and antipyretics without liver toxicity can be derived from paracetamol. Thus, research into the molecular actions of paracetamol could pave the way for the discovery of analgesics and antipyretics with a better benefit-to-risk ratio. (C) 2020 The Author(s). Published by Elsevier Masson SAS., Funding Agencies|Medical Faculty of Lund University [ALFSKANE-450751]; AFA Forsakring [140376]; Hjarnfonden [FO2019-0316]; Stiftelsen Olle Engkvist ByggmastareSwedish Research Council [189-290]; Swedish Research CouncilSwedish Research CouncilEuropean Commission [07879]; Royal Physiographic Society, Lund Sweden; Clermont Auvergne University, INSERM; Agence Nationale de la Recherche of the French government through the program "Investissements dAvenir (I-Site CAP 20-25)French National Research Agency (ANR)

Paracetamol, one of the most widely used pain-relieving drugs, is deacetylated to 4-aminophenol (4-AP) that undergoes fatty acid amide hydrolase (FAAH)-dependent biotransformation into N-arachidonoylphenolamine (AM404), which mediates TRPV1-dependent antinociception in the brain of rodents. However, paracetamol is also converted to the liver-toxic metabolite N-acetyl-p-benzoquinone imine already at therapeutic doses, urging for safer paracetamol analogues. Primary amine analogues with chemical structures similar to paracetamol were evaluated for their propensity to undergo FAAH-dependent N-arachidonoyl conjugation into TRPV1 activators both in vitro and in vivo in rodents. The antinociceptive and antipyretic activity of paracetamol and primary amine analogues was examined with regard to FAAH and TRPV1 as well as if these analogues produced acute liver toxicity. 5-Amino-2-methoxyphenol (2) and 5-aminoindazole (3) displayed efficient target protein interactions with a dose-dependent antinociceptive effect in the mice formalin test, which in the second phase was dependent on FAAH and TRPV1. No hepatotoxicity of the FAAH substrates transformed into TRPV1 activators was observed. While paracetamol attenuates pyrexia via inhibition of brain cyclooxygenase, its antinociceptive FAAH substrate 4-AP was not antipyretic, suggesting separate mechanisms for the antipyretic and antinociceptive effect of paracetamol. Furthermore, compound 3 reduced fever without a brain cyclooxygenase inhibitory action. The data support our view that analgesics and antipyretics without liver toxicity can be derived from paracetamol. Thus, research into the molecular actions of paracetamol could pave the way for the discovery of analgesics and antipyretics with a better benefit-to-risk ratio. (C) 2020 The Author(s). Published by Elsevier Masson SAS., Funding Agencies|Medical Faculty of Lund University [ALFSKANE-450751]; AFA Forsakring [140376]; Hjarnfonden [FO2019-0316]; Stiftelsen Olle Engkvist ByggmastareSwedish Research Council [189-290]; Swedish Research CouncilSwedish Research CouncilEuropean Commission [07879]; Royal Physiographic Society, Lund Sweden; Clermont Auvergne University, INSERM; Agence Nationale de la Recherche of the French government through the program "Investissements dAvenir (I-Site CAP 20-25)French National Research Agency (ANR)

Paracetamol, one of the most widely used pain-relieving drugs, is deacetylated to 4-aminophenol (4-AP) that undergoes fatty acid amide hydrolase (FAAH)-dependent biotransformation into N-arachidonoylphenolamine (AM404), which mediates TRPV1-dependent antinociception in the brain of rodents. However, paracetamol is also converted to the liver-toxic metabolite N-acetyl-p-benzoquinone imine already at therapeutic doses, urging for safer paracetamol analogues. Primary amine analogues with chemical structures similar to paracetamol were evaluated for their propensity to undergo FAAH-dependent N-arachidonoyl conjugation into TRPV1 activators both in vitro and in vivo in rodents. The antinociceptive and antipyretic activity of paracetamol and primary amine analogues was examined with regard to FAAH and TRPV1 as well as if these analogues produced acute liver toxicity. 5-Amino-2-methoxyphenol (2) and 5-aminoindazole (3) displayed efficient target protein interactions with a dose-dependent antinociceptive effect in the mice formalin test, which in the second phase was dependent on FAAH and TRPV1. No hepatotoxicity of the FAAH substrates transformed into TRPV1 activators was observed. While paracetamol attenuates pyrexia via inhibition of brain cyclooxygenase, its antinociceptive FAAH substrate 4-AP was not antipyretic, suggesting separate mechanisms for the antipyretic and antinociceptive effect of paracetamol. Furthermore, compound 3 reduced fever without a brain cyclooxygenase inhibitory action. The data support our view that analgesics and antipyretics without liver toxicity can be derived from paracetamol. Thus, research into the molecular actions of paracetamol could pave the way for the discovery of analgesics and antipyretics with a better benefit-to-risk ratio. (C) 2020 The Author(s). Published by Elsevier Masson SAS., Funding Agencies|Medical Faculty of Lund University [ALFSKANE-450751]; AFA Forsakring [140376]; Hjarnfonden [FO2019-0316]; Stiftelsen Olle Engkvist ByggmastareSwedish Research Council [189-290]; Swedish Research CouncilSwedish Research CouncilEuropean Commission [07879]; Royal Physiographic Society, Lund Sweden; Clermont Auvergne University, INSERM; Agence Nationale de la Recherche of the French government through the program "Investissements dAvenir (I-Site CAP 20-25)French National Research Agency (ANR)

Paracetamol, one of the most widely used pain-relieving drugs, is deacetylated to 4-aminophenol (4-AP) that undergoes fatty acid amide hydrolase (FAAH)-dependent biotransformation into N-arachidonoylphenolamine (AM404), which mediates TRPV1-dependent antinociception in the brain of rodents. However, paracetamol is also converted to the liver-toxic metabolite N-acetyl-p-benzoquinone imine already at therapeutic doses, urging for safer paracetamol analogues. Primary amine analogues with chemical structures similar to paracetamol were evaluated for their propensity to undergo FAAH-dependent N-arachidonoyl conjugation into TRPV1 activators both in vitro and in vivo in rodents. The antinociceptive and antipyretic activity of paracetamol and primary amine analogues was examined with regard to FAAH and TRPV1 as well as if these analogues produced acute liver toxicity. 5-Amino-2-methoxyphenol (2) and 5-aminoindazole (3) displayed efficient target protein interactions with a dose-dependent antinociceptive effect in the mice formalin test, which in the second phase was dependent on FAAH and TRPV1. No hepatotoxicity of the FAAH substrates transformed into TRPV1 activators was observed. While paracetamol attenuates pyrexia via inhibition of brain cyclooxygenase, its antinociceptive FAAH substrate 4-AP was not antipyretic, suggesting separate mechanisms for the antipyretic and antinociceptive effect of paracetamol. Furthermore, compound 3 reduced fever without a brain cyclooxygenase inhibitory action. The data support our view that analgesics and antipyretics without liver toxicity can be derived from paracetamol. Thus, research into the molecular actions of paracetamol could pave the way for the discovery of analgesics and antipyretics with a better benefit-to-risk ratio. (C) 2020 The Author(s). Published by Elsevier Masson SAS., Funding Agencies|Medical Faculty of Lund University [ALFSKANE-450751]; AFA Forsakring [140376]; Hjarnfonden [FO2019-0316]; Stiftelsen Olle Engkvist ByggmastareSwedish Research Council [189-290]; Swedish Research CouncilSwedish Research CouncilEuropean Commission [07879]; Royal Physiographic Society, Lund Sweden; Clermont Auvergne University, INSERM; Agence Nationale de la Recherche of the French government through the program "Investissements dAvenir (I-Site CAP 20-25)French National Research Agency (ANR)

Paracetamol, one of the most widely used pain-relieving drugs, is deacetylated to 4-aminophenol (4-AP) that undergoes fatty acid amide hydrolase (FAAH)-dependent biotransformation into N-arachidonoylphenolamine (AM404), which mediates TRPV1-dependent antinociception in the brain of rodents. However, paracetamol is also converted to the liver-toxic metabolite N-acetyl-p-benzoquinone imine already at therapeutic doses, urging for safer paracetamol analogues. Primary amine analogues with chemical structures similar to paracetamol were evaluated for their propensity to undergo FAAH-dependent N-arachidonoyl conjugation into TRPV1 activators both in vitro and in vivo in rodents. The antinociceptive and antipyretic activity of paracetamol and primary amine analogues was examined with regard to FAAH and TRPV1 as well as if these analogues produced acute liver toxicity. 5-Amino-2-methoxyphenol (2) and 5-aminoindazole (3) displayed efficient target protein interactions with a dose-dependent antinociceptive effect in the mice formalin test, which in the second phase was dependent on FAAH and TRPV1. No hepatotoxicity of the FAAH substrates transformed into TRPV1 activators was observed. While paracetamol attenuates pyrexia via inhibition of brain cyclooxygenase, its antinociceptive FAAH substrate 4-AP was not antipyretic, suggesting separate mechanisms for the antipyretic and antinociceptive effect of paracetamol. Furthermore, compound 3 reduced fever without a brain cyclooxygenase inhibitory action. The data support our view that analgesics and antipyretics without liver toxicity can be derived from paracetamol. Thus, research into the molecular actions of paracetamol could pave the way for the discovery of analgesics and antipyretics with a better benefit-to-risk ratio. (C) 2020 The Author(s). Published by Elsevier Masson SAS., Funding Agencies|Medical Faculty of Lund University [ALFSKANE-450751]; AFA Forsakring [140376]; Hjarnfonden [FO2019-0316]; Stiftelsen Olle Engkvist ByggmastareSwedish Research Council [189-290]; Swedish Research CouncilSwedish Research CouncilEuropean Commission [07879]; Royal Physiographic Society, Lund Sweden; Clermont Auvergne University, INSERM; Agence Nationale de la Recherche of the French government through the program "Investissements dAvenir (I-Site CAP 20-25)French National Research Agency (ANR)

Contains fulltext : 220908.pdf (Publisher’s version ) (Closed access), BACKGROUND: Morphology algorithms are currently recommended as a standalone discriminator in single-chamber implantable cardioverter defibrillators (ICDs). However, these proprietary algorithms differ in both design and nominal programming. OBJECTIVE: To compare three different algorithms with nominal versus advanced programming in their ability to discriminate between ventricular (VT) and supraventricular tachycardia (SVT). METHODS: In nine European centers, VT and SVTs were collected from Abbott, Boston Scientific, and Medtronic dual- and triple-chamber ICDs via their respective remote monitoring portals. Percentage morphology matches were recorded for selected episodes which were classified as VT or SVT by means of atrioventricular comparison. The sensitivity and related specificity of each manufacturer discriminator was determined at various values of template match percentage from receiving operating characteristics (ROC) curve analysis. RESULTS: A total of 534 episodes were retained for the analysis. In ROC analyses, Abbott Far Field MD (area under the curve [AUC]: 0.91; P < .001) and Boston Scientific RhythmID (AUC: 0.95; P < .001) show higher AUC than Medtronic Wavelet (AUC: 0.81; P < .001) when tested for their ability to discriminate VT from SVT. At nominal % match threshold all devices provided high sensitivity in VT identification, (91%, 100%, and 90%, respectively, for Abbott, Boston Scientific, and Medtronic) but contrasted specificities in SVT discrimination (85%, 41%, and 62%, respectively). Abbott and Medtronic's nominal thresholds were similar to the optimal thresholds. Optimization of the % match threshold improved the Boston Scientific specificity to 79% without compromising the sensitivity. CONCLUSION: Proprietary morphology discriminators show important differences in their ability to discriminate SVT. How much this impact the overall discrimination process remains to be investigated.

Contains fulltext : 220908.pdf (Publisher’s version ) (Closed access), BACKGROUND: Morphology algorithms are currently recommended as a standalone discriminator in single-chamber implantable cardioverter defibrillators (ICDs). However, these proprietary algorithms differ in both design and nominal programming. OBJECTIVE: To compare three different algorithms with nominal versus advanced programming in their ability to discriminate between ventricular (VT) and supraventricular tachycardia (SVT). METHODS: In nine European centers, VT and SVTs were collected from Abbott, Boston Scientific, and Medtronic dual- and triple-chamber ICDs via their respective remote monitoring portals. Percentage morphology matches were recorded for selected episodes which were classified as VT or SVT by means of atrioventricular comparison. The sensitivity and related specificity of each manufacturer discriminator was determined at various values of template match percentage from receiving operating characteristics (ROC) curve analysis. RESULTS: A total of 534 episodes were retained for the analysis. In ROC analyses, Abbott Far Field MD (area under the curve [AUC]: 0.91; P < .001) and Boston Scientific RhythmID (AUC: 0.95; P < .001) show higher AUC than Medtronic Wavelet (AUC: 0.81; P < .001) when tested for their ability to discriminate VT from SVT. At nominal % match threshold all devices provided high sensitivity in VT identification, (91%, 100%, and 90%, respectively, for Abbott, Boston Scientific, and Medtronic) but contrasted specificities in SVT discrimination (85%, 41%, and 62%, respectively). Abbott and Medtronic's nominal thresholds were similar to the optimal thresholds. Optimization of the % match threshold improved the Boston Scientific specificity to 79% without compromising the sensitivity. CONCLUSION: Proprietary morphology discriminators show important differences in their ability to discriminate SVT. How much this impact the overall discrimination process remains to be investigated.

Background: Loop diuretics are used for congestion relief, and dose adaptations are usually a consequence of the clinicians' clinical judgement about the congestive status of the patient. In EPHESUS (Eplerenone in Patients With Systolic Dysfunction After Myocardial Infarction), many patients required diuretics for congestion relief. We thus hypothesized that blinded allocation to eplerenone would lead clinicians to reduce loop diuretics, as a consequence of the improvement in patients' status. Methods: Cox and mixed-effects models were used over a median follow-up of 1.3 years in 6632 patients. Results: A total of 6632 patients were included; at baseline, 3352 (50.5%) did not have diuretics, 2195 (33.1%) had diuretic doses between 1 and 40 mg/day, and 1085 (16.4%) had diuretic doses >40 mg/day. Patients with higher furosemide equivalent doses had a worse clinical status. Both baseline and follow-up incremental loop diuretic doses were associated with worse prognosis. Eplerenone treatment was associated with lower prescribed loop diuretic doses throughout the follow-up; lower doses were observed at 90 days and decreased further at 180 days and beyond. Eplerenone treatment led to a mean furosemide equivalent dose reduction of -2.2 mg/day (-2.9 to -1.6) throughout the follow-up. Eplerenone was effective in reducing morbidity and mortality regardless of the baseline loop diuretic dose used: hazard ratio for the outcome of cardiovascular death or heart failure hospitalization was 0.83 ([95% CI, 0.75-0.92]; P for interaction, 0.54). Conclusions: Eplerenone treatment led to a loop diuretic dose reduction during follow-up without evidence of treatment effect modification by loop diuretics. These findings suggest that eplerenone reduces congestive signs and symptoms, which enables clinicians to reduce loop diuretic doses.

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BACKGROUND: The subcutaneous implantable cardioverter-defibrillator (S-ICD) remains a new technology requiring accurate assessment of the various aspects of its functioning. Isolated cases of delayed sensing of ventricular arrhythmia have been described. OBJECTIVE: The purpose of this multicenter study was to assess the quality of sensing during induced ventricular fibrillation (VF). METHODS: One hundred thirty-seven patients underwent induction of VF at the end of the S-ICD implantation. RESULTS: VF induction was successful in 133 patients (97%). Mean time to first therapy was 16.2 ± 3.1 seconds, with a substantial range from 12.5 to 27.0 seconds. Four different detection profiles were arbitrarily defined: (1) optimal detection (n = 39 [29%]); (2) undersensing with moderate prolongation of time to therapy (<18 seconds; n = 68 [51%]); (3) undersensing with significant prolongation of the time to therapy (>18 seconds; n = 19 [14%]); and (4) absence of therapy or prolonged time to therapy related to noise oversensing (n = 7 [6%]). In some of the patients in the last group, despite induction of VF the initial counter was never filled, the device did not charge the capacitors, and the shock was not delivered because of a sustained diagnosis of noise (n = 5). A manual shock by the device or an external shock had to be delivered to restore the sinus rhythm. CONCLUSION: Our study demonstrated a marked sensing delay leading to prolonged time to therapy in a large number of S-ICD patients. A few worrisome cases of noise oversensing inhibiting the therapies were detected. These results support the need for systematic intraoperative defibrillation testing.

Background: Electrocardiographic mapping (ECM) expresses electrical substrate through magnitude and direction of the activation delay vector (ADV). We investigated to what extent the response to cardiac resynchronization therapy (CRT) is determined by baseline ADV and by ADV modification through CRT and optimization of left ventricular (LV) pacing site. Methods: ECM was performed in 79 heart failure patients (4 RBBB, 12 QRS <120 ms, 23 non-specific conduction delay [NICD] and 40 left bundle branch block [LBBB]). 67 patients (QRS >= 120 ms) underwent CRT implantation and in 26 patients multiple LV pacing site optimization was performed. ADV was calculated from locations/depolarization times of 2000 virtual epicardial electrodes derived from ECM. Acute response was defined as >= 10% LVdP/dt(max) increase, chronic response by composite clinical score at 6 months. Results: During intrinsic conduction, ADV direction was similar in patients with QRS < 120 ms, NICD and LBBB, pointing towards the LV free wall, while ADV magnitude was larger in LBBB (117 +/- 25 ms) than in NICD (70 +/- 29 ms, P < 0.05) and QRS < 120 ms (52 +/- 14 ms, P < 0.05). Intrinsic ADV accurately predicted the acute (AUC = 0.93) and chronic (AUC = 0.90) response to CRT. ADV change by CRT only moderately predicted response (highest AUC = 0.76). LV pacing site optimization had limited effects: +3 +/- 4% LVdP/dt(max) when compared to conventional basolateral LV pacing. Conclusion: The baseline electrical substrate, adequately measured by ADV amplitude, strongly determines acute and chronic CRT response, while the extent of its modification by conventional CRT or by varying LV pacing sites has limited effects. (c) 2018 Elsevier B.V. All rights reserved.

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Background: Electrocardiographic mapping (ECM) expresses electrical substrate through magnitude and direction of the activation delay vector (ADV). We investigated to what extent the response to cardiac resynchronization therapy (CRT) is determined by baseline ADV and by ADV modification through CRT and optimization of left ventricular (LV) pacing site. Methods: ECM was performed in 79 heart failure patients (4 RBBB, 12 QRS <120 ms, 23 non-specific conduction delay [NICD] and 40 left bundle branch block [LBBB]). 67 patients (QRS >= 120 ms) underwent CRT implantation and in 26 patients multiple LV pacing site optimization was performed. ADV was calculated from locations/depolarization times of 2000 virtual epicardial electrodes derived from ECM. Acute response was defined as >= 10% LVdP/dt(max) increase, chronic response by composite clinical score at 6 months. Results: During intrinsic conduction, ADV direction was similar in patients with QRS < 120 ms, NICD and LBBB, pointing towards the LV free wall, while ADV magnitude was larger in LBBB (117 +/- 25 ms) than in NICD (70 +/- 29 ms, P < 0.05) and QRS < 120 ms (52 +/- 14 ms, P < 0.05). Intrinsic ADV accurately predicted the acute (AUC = 0.93) and chronic (AUC = 0.90) response to CRT. ADV change by CRT only moderately predicted response (highest AUC = 0.76). LV pacing site optimization had limited effects: +3 +/- 4% LVdP/dt(max) when compared to conventional basolateral LV pacing. Conclusion: The baseline electrical substrate, adequately measured by ADV amplitude, strongly determines acute and chronic CRT response, while the extent of its modification by conventional CRT or by varying LV pacing sites has limited effects. (c) 2018 Elsevier B.V. All rights reserved.

Phospholipase C-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate generates diacylglycerol, inositol 1,4,5-trisphosphate and protons, all of which can regulate TRPV1 activity via different mechanisms. Here we explored the possibility that the diacylglycerol metabolites 2-arachidonoylglycerol and 1-arachidonoylglycerol, and not metabolites of these monoacylglycerols, activate TRPV1 and contribute to this signaling cascade. 2-Arachidonoylglycerol and 1-arachidonoylglycerol activated native TRPV1 on vascular sensory nerve fibers and heterologously expressed TRPV1 in whole cells and inside-out membrane patches. The monoacylglycerol lipase inhibitors methylarachidonoyl-fluorophosphonate and JZL184 prevented the metabolism of deuterium-labeled 2-arachidonoylglycerol and deuterium-labeled 1-arachidonoylglycerol in arterial homogenates, and enhanced TRPV1-mediated vasodilator responses to both monoacylglycerols. In mesenteric arteries from TRPV1 knock-out mice, vasodilator responses to 2-arachidonoylglycerol were minor. Bradykinin and adenosine triphosphate, ligands of phospholipase C-coupled membrane receptors, increased the content of 2-arachidonoylglycerol in dorsal root ganglia. In HEK293 cells expressing the phospholipase C-coupled histamine H-1 receptor, exposure to histamine stimulated the formation of 2-AG, and this effect was augmented in the presence of JZL184. These effects were prevented by the diacylglycerol lipase inhibitor tetrahydrolipstatin. Histamine induced large whole cell currents in HEK293 cells co-expressing TRPV1 and the histamine H-1 receptor, and the TRPV1 antagonist capsazepine abolished these currents. JZL184 increased the histamine-induced currents and tetrahydrolipstatin prevented this effect. The calcineurin inhibitor ciclosporin and the endogenous "entourage'' compound palmitoylethanolamide potentiated the vasodilator response to 2-arachidonoylglycerol, disclosing TRPV1 activation of this monoacylglycerol at nanomolar concentration

Phospholipase C-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate generates diacylglycerol, inositol 1,4,5-trisphosphate and protons, all of which can regulate TRPV1 activity via different mechanisms. Here we explored the possibility that the diacylglycerol metabolites 2-arachidonoylglycerol and 1-arachidonoylglycerol, and not metabolites of these monoacylglycerols, activate TRPV1 and contribute to this signaling cascade. 2-Arachidonoylglycerol and 1-arachidonoylglycerol activated native TRPV1 on vascular sensory nerve fibers and heterologously expressed TRPV1 in whole cells and inside-out membrane patches. The monoacylglycerol lipase inhibitors methylarachidonoyl-fluorophosphonate and JZL184 prevented the metabolism of deuterium-labeled 2-arachidonoylglycerol and deuterium-labeled 1-arachidonoylglycerol in arterial homogenates, and enhanced TRPV1-mediated vasodilator responses to both monoacylglycerols. In mesenteric arteries from TRPV1 knock-out mice, vasodilator responses to 2-arachidonoylglycerol were minor. Bradykinin and adenosine triphosphate, ligands of phospholipase C-coupled membrane receptors, increased the content of 2-arachidonoylglycerol in dorsal root ganglia. In HEK293 cells expressing the phospholipase C-coupled histamine H-1 receptor, exposure to histamine stimulated the formation of 2-AG, and this effect was augmented in the presence of JZL184. These effects were prevented by the diacylglycerol lipase inhibitor tetrahydrolipstatin. Histamine induced large whole cell currents in HEK293 cells co-expressing TRPV1 and the histamine H-1 receptor, and the TRPV1 antagonist capsazepine abolished these currents. JZL184 increased the histamine-induced currents and tetrahydrolipstatin prevented this effect. The calcineurin inhibitor ciclosporin and the endogenous "entourage'' compound palmitoylethanolamide potentiated the vasodilator response to 2-arachidonoylglycerol, disclosing TRPV1 activation of this monoacylglycerol at nanomolar concentration

Phospholipase C-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate generates diacylglycerol, inositol 1,4,5-trisphosphate and protons, all of which can regulate TRPV1 activity via different mechanisms. Here we explored the possibility that the diacylglycerol metabolites 2-arachidonoylglycerol and 1-arachidonoylglycerol, and not metabolites of these monoacylglycerols, activate TRPV1 and contribute to this signaling cascade. 2-Arachidonoylglycerol and 1-arachidonoylglycerol activated native TRPV1 on vascular sensory nerve fibers and heterologously expressed TRPV1 in whole cells and inside-out membrane patches. The monoacylglycerol lipase inhibitors methylarachidonoyl-fluorophosphonate and JZL184 prevented the metabolism of deuterium-labeled 2-arachidonoylglycerol and deuterium-labeled 1-arachidonoylglycerol in arterial homogenates, and enhanced TRPV1-mediated vasodilator responses to both monoacylglycerols. In mesenteric arteries from TRPV1 knock-out mice, vasodilator responses to 2-arachidonoylglycerol were minor. Bradykinin and adenosine triphosphate, ligands of phospholipase C-coupled membrane receptors, increased the content of 2-arachidonoylglycerol in dorsal root ganglia. In HEK293 cells expressing the phospholipase C-coupled histamine H-1 receptor, exposure to histamine stimulated the formation of 2-AG, and this effect was augmented in the presence of JZL184. These effects were prevented by the diacylglycerol lipase inhibitor tetrahydrolipstatin. Histamine induced large whole cell currents in HEK293 cells co-expressing TRPV1 and the histamine H-1 receptor, and the TRPV1 antagonist capsazepine abolished these currents. JZL184 increased the histamine-induced currents and tetrahydrolipstatin prevented this effect. The calcineurin inhibitor ciclosporin and the endogenous "entourage'' compound palmitoylethanolamide potentiated the vasodilator response to 2-arachidonoylglycerol, disclosing TRPV1 activation of this monoacylglycerol at nanomolar concentration

Phospholipase C-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate generates diacylglycerol, inositol 1,4,5-trisphosphate and protons, all of which can regulate TRPV1 activity via different mechanisms. Here we explored the possibility that the diacylglycerol metabolites 2-arachidonoylglycerol and 1-arachidonoylglycerol, and not metabolites of these monoacylglycerols, activate TRPV1 and contribute to this signaling cascade. 2-Arachidonoylglycerol and 1-arachidonoylglycerol activated native TRPV1 on vascular sensory nerve fibers and heterologously expressed TRPV1 in whole cells and inside-out membrane patches. The monoacylglycerol lipase inhibitors methylarachidonoyl-fluorophosphonate and JZL184 prevented the metabolism of deuterium-labeled 2-arachidonoylglycerol and deuterium-labeled 1-arachidonoylglycerol in arterial homogenates, and enhanced TRPV1-mediated vasodilator responses to both monoacylglycerols. In mesenteric arteries from TRPV1 knock-out mice, vasodilator responses to 2-arachidonoylglycerol were minor. Bradykinin and adenosine triphosphate, ligands of phospholipase C-coupled membrane receptors, increased the content of 2-arachidonoylglycerol in dorsal root ganglia. In HEK293 cells expressing the phospholipase C-coupled histamine H-1 receptor, exposure to histamine stimulated the formation of 2-AG, and this effect was augmented in the presence of JZL184. These effects were prevented by the diacylglycerol lipase inhibitor tetrahydrolipstatin. Histamine induced large whole cell currents in HEK293 cells co-expressing TRPV1 and the histamine H-1 receptor, and the TRPV1 antagonist capsazepine abolished these currents. JZL184 increased the histamine-induced currents and tetrahydrolipstatin prevented this effect. The calcineurin inhibitor ciclosporin and the endogenous "entourage'' compound palmitoylethanolamide potentiated the vasodilator response to 2-arachidonoylglycerol, disclosing TRPV1 activation of this monoacylglycerol at nanomolar concentration

Phospholipase C-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate generates diacylglycerol, inositol 1,4,5-trisphosphate and protons, all of which can regulate TRPV1 activity via different mechanisms. Here we explored the possibility that the diacylglycerol metabolites 2-arachidonoylglycerol and 1-arachidonoylglycerol, and not metabolites of these monoacylglycerols, activate TRPV1 and contribute to this signaling cascade. 2-Arachidonoylglycerol and 1-arachidonoylglycerol activated native TRPV1 on vascular sensory nerve fibers and heterologously expressed TRPV1 in whole cells and inside-out membrane patches. The monoacylglycerol lipase inhibitors methylarachidonoyl-fluorophosphonate and JZL184 prevented the metabolism of deuterium-labeled 2-arachidonoylglycerol and deuterium-labeled 1-arachidonoylglycerol in arterial homogenates, and enhanced TRPV1-mediated vasodilator responses to both monoacylglycerols. In mesenteric arteries from TRPV1 knock-out mice, vasodilator responses to 2-arachidonoylglycerol were minor. Bradykinin and adenosine triphosphate, ligands of phospholipase C-coupled membrane receptors, increased the content of 2-arachidonoylglycerol in dorsal root ganglia. In HEK293 cells expressing the phospholipase C-coupled histamine H1 receptor, exposure to histamine stimulated the formation of 2-AG, and this effect was augmented in the presence of JZL184. These effects were prevented by the diacylglycerol lipase inhibitor tetrahydrolipstatin. Histamine induced large whole cell currents in HEK293 cells co-expressing TRPV1 and the histamine H1 receptor, and the TRPV1 antagonist capsazepine abolished these currents. JZL184 increased the histamine-induced currents and tetrahydrolipstatin prevented this effect. The calcineurin inhibitor ciclosporin and the endogenous “entourage” compound palmitoylethanolamide potentiated the vasodilator response to 2-arachidonoylglycerol, disclosing TRPV1 activation of this monoacylglycerol at nanomolar concentrations.

Phospholipase C-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate generates diacylglycerol, inositol 1,4,5-trisphosphate and protons, all of which can regulate TRPV1 activity via different mechanisms. Here we explored the possibility that the diacylglycerol metabolites 2-arachidonoylglycerol and 1-arachidonoylglycerol, and not metabolites of these monoacylglycerols, activate TRPV1 and contribute to this signaling cascade. 2-Arachidonoylglycerol and 1-arachidonoylglycerol activated native TRPV1 on vascular sensory nerve fibers and heterologously expressed TRPV1 in whole cells and inside-out membrane patches. The monoacylglycerol lipase inhibitors methylarachidonoyl-fluorophosphonate and JZL184 prevented the metabolism of deuterium-labeled 2-arachidonoylglycerol and deuterium-labeled 1-arachidonoylglycerol in arterial homogenates, and enhanced TRPV1-mediated vasodilator responses to both monoacylglycerols. In mesenteric arteries from TRPV1 knock-out mice, vasodilator responses to 2-arachidonoylglycerol were minor. Bradykinin and adenosine triphosphate, ligands of phospholipase C-coupled membrane receptors, increased the content of 2-arachidonoylglycerol in dorsal root ganglia. In HEK293 cells expressing the phospholipase C-coupled histamine H-1 receptor, exposure to histamine stimulated the formation of 2-AG, and this effect was augmented in the presence of JZL184. These effects were prevented by the diacylglycerol lipase inhibitor tetrahydrolipstatin. Histamine induced large whole cell currents in HEK293 cells co-expressing TRPV1 and the histamine H-1 receptor, and the TRPV1 antagonist capsazepine abolished these currents. JZL184 increased the histamine-induced currents and tetrahydrolipstatin prevented this effect. The calcineurin inhibitor ciclosporin and the endogenous "entourage'' compound palmitoylethanolamide potentiated the vasodilator response to 2-arachidonoylglycerol, disclosing TRPV1 activation of this monoacylglycerol at nanomolar concentration

Phospholipase C-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate generates diacylglycerol, inositol 1,4,5-trisphosphate and protons, all of which can regulate TRPV1 activity via different mechanisms. Here we explored the possibility that the diacylglycerol metabolites 2-arachidonoylglycerol and 1-arachidonoylglycerol, and not metabolites of these monoacylglycerols, activate TRPV1 and contribute to this signaling cascade. 2-Arachidonoylglycerol and 1-arachidonoylglycerol activated native TRPV1 on vascular sensory nerve fibers and heterologously expressed TRPV1 in whole cells and inside-out membrane patches. The monoacylglycerol lipase inhibitors methylarachidonoyl-fluorophosphonate and JZL184 prevented the metabolism of deuterium-labeled 2-arachidonoylglycerol and deuterium-labeled 1-arachidonoylglycerol in arterial homogenates, and enhanced TRPV1-mediated vasodilator responses to both monoacylglycerols. In mesenteric arteries from TRPV1 knock-out mice, vasodilator responses to 2-arachidonoylglycerol were minor. Bradykinin and adenosine triphosphate, ligands of phospholipase C-coupled membrane receptors, increased the content of 2-arachidonoylglycerol in dorsal root ganglia. In HEK293 cells expressing the phospholipase C-coupled histamine H1 receptor, exposure to histamine stimulated the formation of 2-AG, and this effect was augmented in the presence of JZL184. These effects were prevented by the diacylglycerol lipase inhibitor tetrahydrolipstatin. Histamine induced large whole cell currents in HEK293 cells co-expressing TRPV1 and the histamine H1 receptor, and the TRPV1 antagonist capsazepine abolished these currents. JZL184 increased the histamine-induced currents and tetrahydrolipstatin prevented this effect. The calcineurin inhibitor ciclosporin and the endogenous "entourage" compound palmitoylethanolamide potentiated the vasodilator response to 2-arachidonoylglycerol, disclosing TRPV1 activation of this monoacylglycerol at nanomolar concentrations.

The discovery that paracetamol is metabolized to the potent TRPV1 activator N-(4-hydroxyphenyl)-5Z, 8Z, 11Z, 14Z-eicosatetraenamide (AM404) and that this metabolite contributes to paracetamol's antinociceptive effect in rodents via activation of TRPV1 in the central nervous system (CNS) has provided a potential strategy for developing novel analgesics. Here we validated this strategy by examining the metabolism and antinociceptive activity of the de-acetylated paracetamol metabolite 4-aminophenol and 4-hydroxy-3-methoxybenzylamine (HMBA), both of which may undergo a fatty acid amide hydrolase (FAAH)-dependent biotransformation to potent TRPV1 activators in the brain. Systemic administration of 4-aminophenol and HMBA led to a dose-dependent formation of AM404 plus N-(4-hydroxyphenyl)-9Z-octadecenamide (HPODA) and arvanil plus olvanil in the mouse brain, respectively. The order of potency of these lipid metabolites as TRPV1 activators was arvanil = olvanil >> AM404. HPODA. Both 4-aminophenol and HMBA displayed antinociceptive activity in various rodent pain tests. The formation of AM404, arvanil and olvanil, but not HPODA, and the antinociceptive effects of 4-aminophenol and HMBA were substantially reduced or disappeared in FAAH null mice. The activity of 4-aminophenol in the mouse formalin, von Frey and tail immersion tests was also lost in TRPV1 null mice. Intracerebroventricular injection of the TRPV1 blocker capsazepine eliminated the antinociceptive effects of 4-aminophenol and HMBA in the mouse formalin test. In the rat, pharmacological inhibition of FAAH, TRPV1, cannabinoid CB1 receptors and spinal 5-HT3 or 5-HT1A receptors, and chemical deletion of bulbospinal serotonergic pathways prevented the antinociceptive action of 4-aminophenol. Thus, the pharmacological profile of 4-aminophenol was identical to that previously reported for paracetamol, supporting our suggestion that this drug metabolite contributes to paracetamol's analgesic activity via activation of

The transient receptor potential channel melastatin member 8 (TRPM8) is expressed in sensory neurons, where it constitutes the main receptor of environmental innocuous cold (10-25 degrees C). Among several types of G protein-coupled receptors expressed in sensory neurons, G(i)-coupled alpha 2A-adrenoreceptor (alpha 2A-AR), is known to be involved in thermoregulation; however, the underlying molecular mechanisms remain poorly understood. Here we demonstrated that stimulation of alpha 2A-AR inhibited TRPM8 in sensory neurons from rat dorsal root ganglia (DRG). In addition, using specific pharmacological and molecular tools combined with patch-clamp current recordings, we found that in heterologously expressed HEK-293 (human embryonic kidney) cells, TRPM8 channel is inhibited by the G(i) protein/adenylate cyclase (AC)/cAMP/protein kinase A (PKA) signaling cascade. We further identified the TRPM8 S9 and T17 as two key PKA phosphorylation sites regulating TRPM8 channel activity. We therefore propose that inhibition of TRPM8 through the alpha 2A-AR signaling cascade could constitute a new mechanism of modulation of thermosensation in both physiological and pathological conditions., Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

The transient receptor potential channel melastatin member 8 (TRPM8) is expressed in sensory neurons, where it constitutes the main receptor of environmental innocuous cold (10-25 degrees C). Among several types of G protein-coupled receptors expressed in sensory neurons, G(i)-coupled alpha 2A-adrenoreceptor (alpha 2A-AR), is known to be involved in thermoregulation; however, the underlying molecular mechanisms remain poorly understood. Here we demonstrated that stimulation of alpha 2A-AR inhibited TRPM8 in sensory neurons from rat dorsal root ganglia (DRG). In addition, using specific pharmacological and molecular tools combined with patch-clamp current recordings, we found that in heterologously expressed HEK-293 (human embryonic kidney) cells, TRPM8 channel is inhibited by the G(i) protein/adenylate cyclase (AC)/cAMP/protein kinase A (PKA) signaling cascade. We further identified the TRPM8 S9 and T17 as two key PKA phosphorylation sites regulating TRPM8 channel activity. We therefore propose that inhibition of TRPM8 through the alpha 2A-AR signaling cascade could constitute a new mechanism of modulation of thermosensation in both physiological and pathological conditions., Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

Acetaminophen is the most used analgesic/antipyretic drug. Its unclear mechanism of action could rely on cyclooxygenase inhibition, NO synthesis blockade or reinforcement of the serotonergic system. Here we show that in thermal, mechanical and chemical pain tests, AM-251, a specific CB(1) receptor antagonist, abolished the analgesic action of acetaminophen, which was also lost in CB(1) receptor knockout mice. Moreover, acetaminophen was shown unable to bind to CB(1) receptors demonstrating an indirect involvement of these receptors in the analgesic effect of this compound. Accordingly with these results, we also demonstrated that the inhibition of FAAH, an enzyme involved in the cerebral metabolism of acetaminophen into AM404, known to reinforce the activity of the endocannabinoid system, suppressed the antinociceptive effect of acetaminophen. In addition, similarly to the interaction of acetaminophen with bulbospinal serotonergic pathways and spinal serotonin receptors, we observed that the antinociceptive activity of ACEA, a CB(1) receptor agonist, was inhibited by lesion of bulbospinal serotonergic pathways and antagonists of spinal 5-HT receptors. We therefore propose that acetaminophen-induced analgesia could involve the following sequence: (1) FAAH-dependent metabolism of acetaminophen into AM404; (2) indirect involvement of CB(1) receptors by this metabolite; (3) endocannabinoid-dependent reinforcement of the serotonergic bulbospinal pathways, and (4) involvement of spinal pain-suppressing serotonergic receptors., Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

Acetaminophen is the most used analgesic/antipyretic drug. Its unclear mechanism of action could rely on cyclooxygenase inhibition, NO synthesis blockade or reinforcement of the serotonergic system. Here we show that in thermal, mechanical and chemical pain tests, AM-251, a specific CB(1) receptor antagonist, abolished the analgesic action of acetaminophen, which was also lost in CB(1) receptor knockout mice. Moreover, acetaminophen was shown unable to bind to CB(1) receptors demonstrating an indirect involvement of these receptors in the analgesic effect of this compound. Accordingly with these results, we also demonstrated that the inhibition of FAAH, an enzyme involved in the cerebral metabolism of acetaminophen into AM404, known to reinforce the activity of the endocannabinoid system, suppressed the antinociceptive effect of acetaminophen. In addition, similarly to the interaction of acetaminophen with bulbospinal serotonergic pathways and spinal serotonin receptors, we observed that the antinociceptive activity of ACEA, a CB(1) receptor agonist, was inhibited by lesion of bulbospinal serotonergic pathways and antagonists of spinal 5-HT receptors. We therefore propose that acetaminophen-induced analgesia could involve the following sequence: (1) FAAH-dependent metabolism of acetaminophen into AM404; (2) indirect involvement of CB(1) receptors by this metabolite; (3) endocannabinoid-dependent reinforcement of the serotonergic bulbospinal pathways, and (4) involvement of spinal pain-suppressing serotonergic receptors., Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

The mechanism of action of acetaminophen is currently widely discussed. Direct inhibition of cyclooxygenase isoforms remains the commonly advanced hypothesis. We combined behavioral studies with molecular techniques to investigate the mechanism of action of acetaminophen in a model of tonic pain in rats. We show that acetaminophen indirectly stimulates spinal 5-hydroxytryptamine (5-HT)1A receptors in the formalin test, thereby increasing transcript and protein levels of low-affinity neurotrophin receptor, insulin-like growth factor-1 (IGF-1) receptor alpha subunit, and growth hormone receptor and reducing the amount of somatostatin 3 receptor (sst3R) mRNA. Those cellular events seem to be important for the antinociceptive activity of acetaminophen. Indeed, down-regulation of sst3R mRNA depends on acetaminophen-elicited, 5-HT1A receptor-dependent increase in neuronal extracellular signal-regulated kinase 1/2 (ERK1/2) activities that mediate antinociception. In addition, spinal growth hormone (GH) and IGF-1 receptors would also be involved in the antinociceptive activity of the analgesic at different degrees. Our results show the involvement of specific 5-HT1A receptor-dependent cellular events in acetaminophen-produced antinociception and consequently indicate that inhibition of cyclooxygenase activities is not the exclusive mechanism involved. Furthermore, we propose that the mechanisms of 5-HT1A receptor-elicited antinociception and the role of the spinal ERK1/2 pathway in nociception are more intricate than suspected so far and that the GH/IGF-1 axis is an interesting new player in the regulation of spinal nociception., info:eu-repo/semantics/published

The regulation of nociceptive processing by 5-HT at the spinal level is intricate since the neurotransmitter has been implicated in both pro and antinociception. The aim of our study was to investigate, according to the nature of the noxious stimulus, how the blockade of spinal 5-HT(1A) receptors could influence the antinociceptive actions of exogenous 5-HT as well as two analgesics involving endogenous 5-HT, paracetamol and venlafaxine. Rats were submitted either to the formalin test (tonic pain) or the paw pressure test (acute pain). WAY-100635 (40 microg/rat, i.t.), a selective 5-HT(1A) receptor antagonist, had no intrinsic action in either test. However, in the formalin test, it blocked the antinociceptive action of 5-HT (50 microg/rat, i.t.) and paracetamol (300 mg/kg, i.v.) in both phases of biting/licking behaviour and that of venlafaxine (2.5 mg/kg, s.c.) in the late phase only. In the paw pressure test, the combination of sub-effective doses of 5-HT (0.01 microg/rat, i.t.), paracetamol (50 mg/kg, i.v.) or venlafaxine (20 mg/kg, s.c.) with WAY-100635 led to a significant antinociceptive effect, which seems to depend on the reinforcement of the activity of inhibitory GABAergic interneurones. In conclusion, both direct stimulation of the spinal 5-HT(1A) receptors by 5-HT, and indirect stimulation using paracetamol or venlafaxine can differently influence pain transmission. We propose that the nature of the applied nociceptive stimulus would be responsible for the dual effect of the 5-HT(1A) receptors rather than the hyperalgesic state or the supraspinal integration of the pain message., info:eu-repo/semantics/published

The reversal of the antinociceptive effect of systemically administered acetaminophen (paracetamol) by intrathecal administration of the potent 5-HT(3) receptor antagonist tropisetron has been reported in rats subjected to the paw pressure test, suggesting that acetaminophen action is mediated through spinal 5-HT(3) receptors. However, more recent data, showing differences between the pharmacological profiles of various 5-HT(3) receptor antagonists, led us to reconsider the involvement of spinal 5-HT(3) receptors. To address this question, two different approaches were used: 1) electrophysiological recordings to assess whether acetaminophen directly modulates 5-HT(3) receptor activity and 2) pharmacological investigations with various 5-HT(3) receptor antagonists and spinal 5-HT(3) receptors antisense oligodeoxynucleotides (AODNs) to determine how those treatments might affect the antinociceptive action of acetaminophen. Electrophysiological studies demonstrated that acetaminophen had no direct agonist or antagonist effects on 5-HT(3A) receptors. Unlike tropisetron, other 5-HT(3) receptor antagonists, such as ondansetron and granisetron, injected intrathecally were unable to reverse the antinociceptive effect of acetaminophen. Moreover, pretreatment with AODNs did not reverse the acetaminophen-induced antinociceptive effect, although it suppressed the antinociceptive effect of m-chlorophenylbiguanide, a specific agonist of 5-HT(3) receptors, and significantly reduced (30%) the expression of these receptors in the dorsal horn of the spinal cord. These results suggest that acetaminophen-induced antinociceptive action involves a spinal tropisetron-sensitive receptor that is not the 5-HT(3) receptor and that remains to be identified., info:eu-repo/semantics/published

The mechanism of action of paracetamol (acetaminophen) remains elusive because it is still under discussion as to whether it acts locally and/or centrally. The primary aim of this study was to clarify its site(s) of action (central and/or local) using the rat formalin test., info:eu-repo/semantics/published

The mechanism of action of paracetamol (acetaminophen) is still not clearly understood. Unlike morphine, for example, paracetamol has no known endogenous high-affinity binding sites. In addition, paracetamol does not appear to share with nonsteroidal anti-inflammatory drugs (NSAIDs) the capacity to inhibit peripheral cyclo-oxygenase (COX) activity. There is currently considerable evidence to support the hypothesis of a central antinociceptive effect. Although various biochemical studies point to inhibition of central COX-2 activity, the existence of a COX activity that is selectively susceptible to paracetamol (COX-3?) is an alternative hypothesis. Modulation of the serotoninergic system has also been suggested on the basis of biochemical and behavioural studies supporting an indirect serotoninergic (5-HT) effect. Paracetamol may stimulate the activity of descending 5-HT pathways that inhibit nociceptive signal transmission in the spinal cord. Support for this possibility has come from evidence that spinally administered antagonists of several 5-HT receptor subtypes abolish the antinociceptive activity of paracetamol. These hypotheses have yet to be confirmed by further studies. Until then, the primary pharmacological mechanism underlying the analgesic effect of paracetamol has still to be clearly defined., info:eu-repo/semantics/published

Contient une table des matières, Avec mode texte

Contient une table des matières, Avec mode texte