Endogenous activators of the pain receptor TRPV1 From cell to man

N-acylethanolamines (NAEs) belong to a growing family of endogenous signalling molecules acting on a variety of receptors and ion channels. In 1992, it was reported that the N-acylethanolamine anandamide is present in the brain and activates the central cannabinoid (CB) receptor. Anandamide and other NAEs are considered to be generated on demand following receptor activation or cell stress. The tissue level of anandamide increases during ischemic tissue injury and inflammation. Hydrolytic cleavage of the amide bond by fatty acid amide hydrolase is responsible for the elimination of anandamide and other N-acylethanolamines. Studies on whole animals or isolated tissues have shown that anandamide induces a variety of effects in the cardiovascular system, including vasodilatation, bradycardia and hypotension. Macrophages and monocytes, endothelial cells and sensory nerves are possible cellular sources of anandamide in the vascular system. The mechanisms behind the cardiovascular effects of anandamide are not fully understood, but seem to depend on the bioassay and the mode of administration of anandamide. In isolated arterial segments, anandamide produces vasorelaxation via activation of transient receptor potential vanilloid 1 (TRPV1) on perivascular sensory nerves and the subsequent release of the potent vasodilator calcitonin gene-related peptide. TRPV1 is a nonselective cation channel, belonging to the transient receptor potential ion channel superfamily, and the receptor for the pungent ingredient in hot chilli peppers. In this work, we show that anandamide and its metabolically stable analogue methanandamide are able to cause vasodilatation in intact vascular beds by a similar TRPV1-dependent mechanism. The vasodilator response to methanandamide in rat isolated perfused mesenteric arterial bed is inhibited by the TRPV1 antagonist ruthenium red. More importantly, anandamide together with well known plant-derived or synthetic TRPV1 agonists are able to cause vasodilatation in vivo in human skin, an effect inhibited by the selective TRPV1 antagonist capsazepine. The endogenous C18 NAEs N-linolenoylethanolamine (18:3 NAE), N-linoleoylethanolamine (18:2 NAE), N-oleoylethanolamine (18:1 NAE) and N-stearoylethanolamine (18:0 NAE) are structurally related to anandamide, but these lipids are poor ligands at cannabinoid CB1 receptors. Here we show that these lipids are present in rat sensory ganglia and vascular tissue in levels that may substantially exceed those of anandamide. 18:3 NAE, 18:2 NAE and 18:1 NAE, but not 18:0 NAE and oleic acid, activate rat TRPV1 on perivascular sensory nerves and human TRPV1 expressed in eukaryotic cells. In conclusion, this study clearly show that, in the rat isolated mesenteric arterial bed, the vasodilator response to methanandamide is mediated predominantly via activation of TRPV1 on sensory nerves. We also demonstrate for the first time that anandamide has biological activity in man, causing vasodilatation in human skin microcirculation via activation of TRPV1. We also identify novel endogenous TRPV1 ligands, belonging to the C18 NAE family of lipids. These unsaturated C18 NAEs, which are poor ligands at the cannabinoid CB1 receptor, may act in concert with anandamide as endogenous TRPV1 modulators in conditions associated with activation of capsaicin-sensitive sensory nerves, including pain, inflammation, ischemia and bladder instability

Safety of and response to electroconvulsive therapy during pregnancy: Results from population‐based nationwide registries

Introduction: Psychiatric disorders are common during pregnancy, affectingup to 16% of pregnant women. Severe depression and anxiety have significantnegative effects on the health of both the mother and the developing fetus.Electroconvulsive therapy (ECT) is considered a treatment option for pregnantwomen with severe psychiatric disorders when other treatments have beenineffective or pose risks to the fetus. Knowledge of the safety and efficacy ofECT during pregnancy, however, remains limited. Methods: Data were obtained from nationwide registries of pregnant womenin Sweden who received ECT for a severe psychiatric disorder from January2008 to December 2021. ECT-related outcomes in pregnant women were com-pared by propensity score matching with a group of non-pregnant women whoalso received ECT. Pregnancy-related outcomes were compared with two addi-tional control groups: one consisting of the same group of women who did notreceive ECT during another pregnancy and the other composed of pregnantwomen admitted to inpatient psychiatric care but who did not receive ECT,matched based on propensity score. Results: Ninety-five pregnant women received ECT during the study period,accounting for 97 pregnancies. The response rate to ECT in pregnant women(n=54) was similar to the matched control group of non-pregnant women(74% vs. 65%; OR 1.61; 95% CI 0.79–3.27). Rates of adverse events related toECT were similar to those in the control group. There were no pre-term birthsor severe adverse outcomes related to the pregnancy, that were close in time toECT. Therefore, no adverse outcomes related to pregnancy and childbirthcould be directly attributed to ECT. The likelihood of premature birth and a5-min Apgar score <7 in the newborn were both significantly higher in theECT group, compared with the matched non-ECT group (OR 2.33, 95% CI1.15–4.73,p=0.008, and OR 3.68, 95% CI 1.58–8.55,p< 0.001, respectively).By contrast, no significant differences were observed when women in the pregnant ECT group were compared with the same group lacking ECT duringanother pregnancy. Conclusions: ECT was associated with a positive treatment response in preg-nant women with severe psychiatric disorders. The response rate to ECT wassimilar in pregnant and non-pregnant women. Nevertheless, the risks of pre-mature birth and of a slightly poorer condition in newborns were higher inwomen who did than did not receive ECT, emphasizing the need for increasedattention to severe psychiatric disorders during pregnancy

Electroconvulsive therapy in children and adolescents : results from a population‑based study utilising the Swedish National Quality Register

Electroconvulsive therapy (ECT) is effective and safe for adults with severe depression, but less studied in adolescents. Here, we examined the indications, prevalence, practice, response and remission rates, and side effects in young people treated with ECT in Sweden. We also examined the usage of ECT in the transition to adult psychiatry. Using data from national patient registers and the Swedish National Quality Register for ECT (Q-ECT), we identified patients aged up to 19 years treated with ECT over a 5-year study period. Response and remission rates were analysed using the Clinical Global Impression (7-point scale)-Improvement (CGI-I) and Severity (CGI-S). A total of 118 individuals were identified, of which 105 were also enrolled in the Q-ECT. The most common indication for ECT was depression (68%; n = 80). Adolescents aged < 18 years were more severely ill before treatment than those aged 18 years (P < 0.01). Three of the hospitals in Sweden treated the majority of adolescents < 18 years old. The median number of sessions in each ECT series was seven. Unilateral placement of the electrodes was the most common (88%; n = 99). Fifty-seven percent (n = 54) of the patients responded (CGI-I, 1-2) to the treatment; remission (CGI-S, 1-2) was achieved by 32% (n = 30). Psychotic symptoms were associated with a higher response rate in patients with depression (P = 0.038). A deterioration of memory compared to pre-treatment was reported in six patients. ECT was associated with high response and remission rates in adolescents with severe psychiatric disorders after non-response to medication

Ketamine or ECT? What have we learned from the KetECT and ELEKT-D trials?

1. Two recent clinical trials, KetECT and ELEKT-D, compared the effectiveness of ketamine and electroconvulsive therapy (ECT) for major depressive disorder. Notably, these trials reported marked differences in ECT's clinical outcomes of, with remission rates of 63% for KetECT and a strikingly lower rate of 22% for ELEKT-D, while the remission rates for ketamine were 46% and 38%, respectively. Considering that the primary objective of both trials was to compare the standard treatment (ECT) with an experimental intervention (ketamine), it is crucial to highlight the pronounced disparities in ECT’s clinical outcomes. This article offers a comprehensive comparison of these trials while also exploring how patient characteristics, treatment protocols, and study designs may contribute to such pronounced outcome discrepancies. These differences highlight the heterogeneous nature of depression and underscore the need for personalized treatments. These studies also provide valuable insights into identifying the most suitable candidates for ketamine and ECT

Acute Mania and Catatonia in a Teenager Successfully Treated with Electroconvulsive Therapy and Diagnosed with Turner Syndrome and Bipolar Disorder

Background. Turner syndrome (TS) is an X-linked chromosomal abnormality with a global prevalence of 1/2000 live-born girls. The physiological symptoms of TS have been thoroughly characterized, but only a few studies have described associated psychiatric symptoms. We report a case of an adolescent girl who presented with acute mania with psychotic features and was successfully treated with electroconvulsive therapy (ECT). She was subsequently diagnosed with bipolar syndrome and TS. Case Presentation. A 17-year-old girl presented to us with manic symptoms, including disorganized speech, auditory hallucinations, and affect lability. Initially, she was treated with antipsychotics and benzodiazepines, whereby the positive affective symptoms declined. However, the psychotic symptoms progressed, and she developed a catatonic state. ECT was started 6 days after admission, with improvement after two treatments. When ECT was tapered after seven sessions, she relapsed, and the treatment was extended to twelve sessions, with successful outcome. Following discharge, she was diagnosed with TS with partial loss on one of the X-chromosomes (46X, del (X)(p21)), which might have contributed to the development of her sudden acute manic episode. Conclusions. This case demonstrates for the first time that ECT may be a safe and efficient treatment strategy for acute mania in adolescents with concomitant TS and that severely affected adolescents may require a prolonged series with gradual tapering of ECT. The present case also demonstrates a possible association between TS and bipolar syndrome and that the clinical presentation of a manic episode in a patient with this comorbidity could be more complex and the treatment response slower

Endogenous unsaturated C18 N-acylethanolamines are vanilloid receptor (TRPV1) agonists.

The endogenous C18 N-acylethanolamines (NAEs) N-linolenoylethanolamine (18:3 NAE), N-linoleoylethanolamine (18:2 NAE), N-oleoylethanolamine (18:1 NAE), and N-stearoylethanolamine (18:0 NAE) are structurally related to the endocannabinoid anandamide (20:4 NAE), but these lipids are poor ligands at cannabinoid CB1 receptors. Anandamide is also an activator of the transient receptor potential (TRP) vanilloid 1 (TRPV1) on primary sensory neurons. Here we show that C18 NAEs are present in rat sensory ganglia and vascular tissue. With the exception of 18:3 NAE in rat sensory ganglia, the levels of C18 NAEs are equal to or substantially exceed those of anandamide. At submicromolar concentrations, 18:3 NAE, 18:2 NAE, and 18:1 NAE, but not 18:0 NAE and oleic acid, activate native rTRPV1 on perivascular sensory nerves. 18:1 NAE does not activate these nerves in TRPV1 gene knock-out mice. Only the unsaturated C18 NAEs elicit whole cell currents and fluorometric calcium responses in HEK293 cells expressing hTRPV1. Molecular modeling revealed a low energy cluster of U-shaped unsaturated NAE conformers, sharing several pharmacophoric elements with capsaicin. Furthermore, one of the two major low energy conformational families of anandamide also overlaps with the cannabinoid CB1 receptor ligand HU210, which is in line with anandamide being a dual activator of TRPV1 and the cannabinoid CB1 receptor. This study shows that several endogenous non-cannabinoid NAEs, many of which are more abundant than anandamide in rat tissues, activate TRPV1 and thus may play a role as endogenous TRPV1 modulators

Pungent products from garlic activate the sensory ion channel TRPA1

Garlic belongs to the Allium family of plants that produce organosulfur compounds, such as allicin and diallyl disulfide (DADS), which account for their pungency and spicy aroma. Many health benefits have been ascribed to Allium extracts, including hypotensive and vasorelaxant activities. However, the molecular mechanisms underlying these effects remain unknown. Intriguingly, allicin and DADS share structural similarities with allyl isothiocyanate, the pungent ingredient in wasabi and other mustard plants that induces pain and inflammation by activating TRPA1, an excitatory ion channel on primary sensory neurons of the pain pathway. Here we show that allicin and DADS excite an allyl isothiocyanate-sensitive subpopulation of sensory neurons and induce vasodilation by activating capsaicin-sensitive perivascular sensory nerve endings. Moreover, allicin and DADS activate the cloned TRPA1 channel when expressed in heterologous systems. These and other results suggest that garlic excites sensory neurons primarily through activation of TRPA1. Thus different plant genera, including Allium and Brassica, have developed evolutionary convergent strategies that target TRPA1 channels on sensory nerve endings to achieve chemical deterrence

Racemic Ketamine as an Alternative to Electroconvulsive Therapy for Unipolar Depression : A Randomized, Open-Label, Non-Inferiority Trial (KetECT)

Background Ketamine has emerged as a fast-acting and powerful antidepressant, but no head to head trial has been performed, Here, ketamine is compared with electroconvulsive therapy (ECT), the most effective therapy for depression. Methods Hospitalized patients with unipolar depression were randomized (1:1) to thrice-weekly racemic ketamine (0.5 mg/kg) infusions or ECT in a parallel, open-label, non-inferiority study. The primary outcome was remission (Montgomery angstrom sberg Depression Rating Scale score &amp;lt;= 10). Secondary outcomes included adverse events (AEs), time to remission, and relapse. Treatment sessions (maximum of 12) were administered until remission or maximal effect was achieved. Remitters were followed for 12 months after the final treatment session. Results In total 186 inpatients were included and received treatment. Among patients receiving ECT, 63% remitted compared with 46% receiving ketamine infusions (P = .026; difference 95% CI 2%, 30%). Both ketamine and ECT required a median of 6 treatment sessions to induce remission. Distinct AEs were associated with each treatment. Serious and long-lasting AEs, including cases of persisting amnesia, were more common with ECT, while treatment-emergent AEs led to more dropouts in the ketamine group. Among remitters, 70% and 63%, with 57 and 61 median days in remission, relapsed within 12 months in the ketamine and ECT groups, respectively (P = .52). Conclusion Remission and cumulative symptom reduction following multiple racemic ketamine infusions in severely ill patients (age 18-85 years) in an authentic clinical setting suggest that ketamine, despite being inferior to ECT, can be a safe and valuable tool in treating unipolar depression.Funding Agencies|Swedish Research Council [2015-00799]; Crafoord Foundation; Skane Regional Council; Konigska Foundation; Lions forsknings foundation Skane; OM Perssons donation foundation</p