Pharmacology/Drug Development

Fluorescent probes have been used as effective methods for profiling proteins in biological system because of their high selectivity, sensitivity and temporal-spatial resolution. A specific fluorescent probe for understanding the function of the transient receptor potential ankyrin 1 (TRPA1) channel that is closely related with various diseases like persistent pain, respiratory and chronic itch syndromes, however, is still lacking. Here, we report a "turn-on" fluorescent probe (A1CA) for visualizing TRPA1 channels in the plasma membrane of live cells based on a photochromic ligand derived from 4-(phenylazo)benzenamine. Evaluating of the specificity and sensitivity of A1CA by electrophysiology and confocal imaging showed that A1CA probe displays higher affinity and selectivity to TRPA1 channel versus all other ion channels including TRPV1, TRPV3, Nav1.4, Nav1.5 and hERG. Based on the supporting evidence, A1CA has great potential as a molecular imaging probe for high-throughput screening of novel TRPA1 agonists.

The purpose of this article is to provide readers with a basis for understanding the emerging science of clinical trials and to provide a set of practical, evidence-based suggestions for designing and executing confirmatory clinical trials in a manner that minimizes measurement error. The most important step in creating a mindset of quality clinical research is to abandon the antiquated concept that clinical trials are a method for capturing data from clinical practice and shifting to a concept of the clinical trial as a measurement system, consisting of an interconnected set of processes, each of which must be in calibration for the trial to generate an accurate and reliable estimate of the efficacy (and safety) of a given treatment. The status quo of inaccurate, unreliable, and protracted clinical trials is unacceptable and unsustainable. This article gathers aspects of study design and conduct under a single broad umbrella of techniques available to improve the accuracy and reliability of confirmatory clinical trials across traditional domain boundaries.

Chronic pain is a significant unmet medical problem. Current research regarding sodium channel function in pathological pain is advancing with the hope that it will enable the development of isoform-specific sodium channel blockers, a promising treatment for chronic pain. Before advancements in the pharmacological field, an elucidation of the roles of Nav1.7 and Nav1.8 in the pathophysiology of pain states is required. Thus, the aim of this report is to present what is currently known about the contributions of these sodium channel subtypes in the pathophysiology of neuropathic and inflammatory pain. The electrophysiological properties and localisation of sodium channel isoforms is discussed. Research concerning the genetic links of Nav1.7 and Nav1.8 in acquired neuropathic and inflammatory pain states from the scientific literature in this field is reported. The role of Nav1.7 and Nav1.8 in the generation and maintenance of abnormal neuronal electrogenesis and hyperexcitability highlights the importance of these channels in the development of pathological pain. However, further research in this area is required to fully elucidate the roles of Nav1.7 and Nav1.8 in the pathophysiology of pain for the development of subtype-specific sodium channel blockers.

Opioids are frequently overprescribed after surgery. The 2018 American Urological Association position statement on opioid use suggests using the lowest dose and potency to achieve pain control, but a lack of procedure-specific prescribing guidelines contributes to wide variation in prescribing patterns. To address this gap, this study aims to develop opioid prescribing recommendations through an expert panel consensus.

This article reviews the role of analgesic drugs with a particular emphasis on opioids. Opioids are the oldest and most potent drugs for the treatment of severe pain, but they are burdened by detrimental side effects such as respiratory depression, addiction, sedation, nausea, and constipation. Their clinical application is undisputed in acute (e.g., perioperative) and cancer pain, but their long-term use in chronic pain has met increasing scrutiny and has contributed to the current opioid crisis. We discuss epidemiological data, pharmacological principles, clinical applications, and research strategies aiming at novel opioids with reduced side effects.

Acid-sensing ion channels (ASICs) are voltage-independent cation channels that detect decreases in extracellular pH. Dysregulation of ASICs underpins a number of pathologies. Of particular interest is ASIC3, which is recognised as a key sensor of acid-induced pain and is important in the establishment of pain arising from inflammatory conditions, such as rheumatoid arthritis. Thus, the identification of new ASIC3 modulators and the mechanistic understanding of how these compounds modulate ASIC3 could be important for the development of new strategies to counteract the detrimental effects of dysregulated ASIC3 activity in inflammation. Here, we report the identification of novel ASIC3 modulators based on the ASIC3 agonist, 2-guanidine-4-methylquinazoline (GMQ). Through a GMQ-guided in silico screening of Food and Drug administration (FDA)-approved drugs, 5 compounds were selected and tested for their modulation of rat ASIC3 (rASIC3) using whole-cell patch-clamp electrophysiology. Of the chosen drugs, guanabenz (GBZ), an α-adrenoceptor agonist, produced similar effects to GMQ on rASIC3, activating the channel at physiological pH (pH 7.4) and potentiating its response to mild acidic (pH 7) stimuli. Sephin1, a GBZ derivative that lacks α-adrenoceptor activity, has been proposed to act as a selective inhibitor of a regulatory subunit of the stress-induced protein phosphatase 1 (PPP1R15A) with promising therapeutic potential for the treatment of multiple sclerosis. However, we found that like GBZ, sephin1 activates rASIC3 at pH 7.4 and potentiates its response to acidic stimulation (pH 7), i.e. sephin1 is a novel modulator of rASIC3. Furthermore, docking experiments showed that, like GMQ, GBZ and sephin1 likely interact with the nonproton ligand sensor domain of rASIC3. Overall, these data demonstrate the utility of computational analysis for identifying novel ASIC3 modulators, which can be validated with electrophysiological analysis and may lead to the development of better compounds for targeting ASIC3 in the treatment of inflammatory conditions.