Psilocybin as a novel treatment for chronic pain.

Psychedelic drugs are under active consideration for clinical use and have generated significant interest for their potential as anti-nociceptive treatments for chronic pain, and for addressing conditions like depression, frequently co-morbid with pain. This review primarily explores the utility of preclinical animal models in investigating the potential of psilocybin as an anti-nociceptive agent. Initial studies involving psilocybin in animal models of neuropathic and inflammatory pain are summarised, alongside areas where further research is needed.

From Llama to Nanobody: A Streamlined Workflow for the Generation of Functionalised VHHs.

Nanobodies are recombinant antigen-specific single domain antibodies (VHHs) derived from the heavy chain-only subset of camelid immunoglobulins. Their small molecular size, facile expression, high affinity, and stability have combined to make them unique targeting reagents with numerous applications in the biomedical sciences. From our work in producing nanobodies to over sixty different proteins, we present a standardised workflow for nanobody discovery from llama immunisation, library building, panning, and small-scale expression for prioritisation of binding clones.

Novel drugs approved by the EMA, the FDA, and the MHRA in 2023: A year in review.

In 2023, seventy novel drugs received market authorization for the first time in either Europe (by the EMA and the MHRA) or in the United States (by the FDA). Confirming a steady recent trend, more than half of these drugs target rare diseases or intractable forms of cancer. Thirty drugs are categorized as "first-in-class" (FIC), illustrating the quality of research and innovation that drives new chemical entity discovery and development.

Anti-AMPA Receptor Autoantibodies Reduce Excitatory Currents in Rat Hippocampal Neurons.

The GluR3 subunit of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) has been identified as a target for autoantibodies (Aabs) in autoimmune encephalopathy and other diseases. Recent studies have proposed mechanisms by which these Aabs act, but their exact role in neuronal excitability is yet to be established. Patient Aabs have been shown to bind to specific regions within the GluR3 subunit.

Protofibrillar Amyloid Beta Modulation of Recombinant hCaV2.2 (N-Type) Voltage-Gated Channels.

Cav2.2 channels are key regulators of presynaptic Ca influx and their dysfunction and/or aberrant regulation has been implicated in many disease states; however, the nature of their involvement in Alzheimer's disease (AD) is less clear. In this short communication, we show that recombinant hCav2.

Mechanisms of COVID-19-induced cerebellitis.

The COVID-19 pandemic caused by SARS-CoV2 has raised several important health concerns, not least increased mortality and morbidity. SARS-CoV2 can infect the central nervous system hematogenous or transneuronal routes, acting through different receptors including ACE2, DPP4, and neuropilin 1 and cause several issues, including the focus here, cerebellitis. The cerebellum is an essential part of the CNS located adjacent to the brainstem with a complex micro and macroscopic structure.

αδ-4 and Cachd1 Proteins Are Regulators of Presynaptic Functions.

The αδ auxiliary subunits of voltage-gated calcium channels (VGCC) were traditionally regarded as modulators of biophysical channel properties. In recent years, channel-independent functions of these subunits, such as involvement in synapse formation, have been identified. In the central nervous system, αδ isoforms 1, 2, and 3 are strongly expressed, regulating glutamatergic synapse formation by a presynaptic mechanism.

Planning experiments: Updated guidance on experimental design and analysis and their reporting III.

Scientists who plan to publish in British Journal of Pharmacology (BJP) must read this article before undertaking a study. This editorial provides guidance for the design of experiments. We have published previously two guidance documents on experimental design and analysis (Curtis et al.

Ca2.2 (N-type) voltage-gated calcium channels are activated by SUMOylation pathways.

SUMOylation is an important post-translational modification process involving covalent attachment of SUMO (Small Ubiquitin-like MOdifier) protein to target proteins. Here, we investigated the potential for SUMO-1 protein to modulate the function of the Ca2.2 (N-type) voltage-gated calcium channel (VGCC), a protein vital for presynaptic neurotransmitter release.

An Introduction to Patch Clamp Recording.

Electrophysiology is an essential tool aiding the study of the functions and dysfunctions of electrically excitable cells and their networks. The patch clamp method is a refined electrophysiological technique that can directly measure the membrane potential and/or the amount of current passing across the cell membrane. The patch clamp technique is also incredibly versatile and can be used in a variety of different configurations to study a range of properties, from spontaneous cell firing activity in native tissue to the activation and/or deactivation kinetics of individual channels expressed in recombinant cell lines.

Development of cannabidiol as a treatment for severe childhood epilepsies.

In recent years, there has been a growing appreciation by regulatory authorities that cannabis-based medicines can play a useful role in disease therapy. Although often conflagrated by proponents of recreational use, the legislative rescheduling of cannabis-derived compounds, such as cannabidiol (CBD), has been associated with the steady increase in the pursuit of use of medicinal cannabis. One key driver in this interest has been the scientific demonstration of efficacy and safety of CBD in randomised, placebo-controlled clinical trials in children and young adults with difficult-to-treat epilepsies, which has encouraged increasing numbers of human trials of CBD for other indications and in other populations.

Conjugation of haloperidol to PEG allows peripheral localisation of haloperidol and eliminates CNS extrapyramidal effects.

We have previously reported the synthesis of a poly(ethylene glycol)-haloperidol (PEG-haloperidol) conjugate that retained affinity for its target D receptor and was stable in simulated physiological conditions. We hypothesised that this polymer-drug conjugate would localise haloperidol's activity either centrally or peripherally, dependent on the location of administration, due to the polymer preventing penetration through the blood-brain barrier (BBB). Herein, we validate this hypothesis using in vitro and in vivo studies.

The Cannabinoid-Like Compound, VSN16R, Acts on Large Conductance, Ca-Activated K Channels to Modulate Hippocampal CA1 Pyramidal Neuron Firing.

Large conductance, Ca-activated K (BK) channels are widely expressed in the central nervous system, where they regulate action potential duration, firing frequency and consequential neurotransmitter release. Moreover, drug action on, mutations to, or changes in expression levels of BK can modulate neuronal hyperexcitability. Amongst other potential mechanisms of action, cannabinoid compounds have recently been reported to activate BK channels.

CACHD1 is an α2δ-Like Protein That Modulates Ca3 Voltage-Gated Calcium Channel Activity.

The putative cache (Ca channel and chemotaxis receptor) domain containing 1 (CACHD1) protein has predicted structural similarities to members of the α2δ voltage-gated Ca channel auxiliary subunit family. CACHD1 mRNA and protein were highly expressed in the male mammalian CNS, in particular in the thalamus, hippocampus, and cerebellum, with a broadly similar tissue distribution to Ca3 subunits, in particular Ca3.1.

Recent advances in targeting ion channels to treat chronic pain.

This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.

Species-specific susceptibility to cannabis-induced convulsions.

Background And Purpose: Numerous claims are made for cannabis' therapeutic utility upon human seizures, but concerns persist about risks. A potential confounder is the presence of both Δ -tetrahydrocannabinol (THC), variously reported to be pro- and anticonvulsant, and cannabidiol (CBD), widely confirmed as anticonvulsant. Therefore, we investigated effects of prolonged exposure to different THC/CBD cannabis extracts on seizure activity and associated measures of endocannabinoid (eCB) system signalling.

SUMOylation and calcium signalling: potential roles in the brain and beyond.

Small ubiquitin-like modifier (SUMO) conjugation (or SUMOylation) is a post-translational protein modification implicated in alterations to protein expression, localization and function. Despite a number of nuclear roles for SUMO being well characterized, this process has only started to be explored in relation to membrane proteins, such as ion channels. Calcium ion (Ca) signalling is crucial for the normal functioning of cells and is also involved in the pathophysiological mechanisms underlying relevant neurological and cardiovascular diseases.

A Brain on a Roller Coaster: Can the Dopamine Reward System Act as a Protagonist to Subdue the Ups and Downs of Bipolar Disorder?

One of the most interesting but tenebrous parts of the bipolar disorder (BD) story is the switch between (hypo)mania and depression, which can give bipolar patients a thrilling, but somewhat perilous, 'ride'. Numerous studies have pointed out that there are some recognizable differences (either state-dependent or state-independent) in several brain regions of people with BD, including components of the brain's reward system. Understanding the underpinning mechanisms of high and low mood statuses in BD has potential, not only for the development of highly specific and selective pharmaceutical agents, but also for better treatment approaches and psychological interventions to manage BD and, thus, give patients a safer ride.

Cannabinoids and Tremor Induced by Motor-related Disorders: Friend or Foe?

Tremor arises from an involuntary, rhythmic muscle contraction/relaxation cycle and is a common disabling symptom of many motor-related diseases such as Parkinson disease, multiple sclerosis, Huntington disease, and forms of ataxia. In the wake of anecdotal, largely uncontrolled, observations claiming the amelioration of some symptoms among cannabis smokers, and the high density of cannabinoid receptors in the areas responsible for motor function, including basal ganglia and cerebellum, many researchers have pursued the question of whether cannabinoid-based compounds could be used therapeutically to alleviate tremor associated with central nervous system diseases. In this review, we focus on possible effects of cannabinoid-based medicines, in particular on Parkinsonian and multiple sclerosis-related tremors and the common probable molecular mechanisms.

Synaptic vesicle glycoprotein 2A modulates vesicular release and calcium channel function at peripheral sympathetic synapses.

Synaptic vesicle glycoprotein (SV)2A is a transmembrane protein found in secretory vesicles and is critical for Ca(2+) -dependent exocytosis in central neurons, although its mechanism of action remains uncertain. Previous studies have proposed, variously, a role of SV2 in the maintenance and formation of the readily releasable pool (RRP) or in the regulation of Ca(2+) responsiveness of primed vesicles. Such previous studies have typically used genetic approaches to ablate SV2 levels; here, we used a strategy involving small interference RNA (siRNA) injection to knockdown solely presynaptic SV2A levels in rat superior cervical ganglion (SCG) neuron synapses.

Exogenous α-synuclein decreases raft partitioning of Cav2.2 channels inducing dopamine release.

α-Synuclein is thought to regulate neurotransmitter release through multiple interactions with presynaptic proteins, cytoskeletal elements, ion channels, and synaptic vesicles membrane. α-Synuclein is abundant in the presynaptic compartment, and its release from neurons and glia has been described as responsible for spreading of α-synuclein-derived pathology. α-Synuclein-dependent dysregulation of neurotransmitter release might occur via its action on surface-exposed calcium channels.