Pharmacology/Drug Development

It is increasingly recognized that chronic opioid use leads to maladaptive changes in the composition and localization of gut bacteria. Recently, this "opioid-induced dysbiosis" (OID) has been linked to antinociceptive tolerance development in preclinical models and may therefore identify promising targets for new opioid-sparing strategies. Such developments are critical to curb dose escalations in the clinical setting and combat the ongoing opioid epidemic. In this article, we review the existing literature that pertains to OID, including the current evidence regarding its qualitative nature, influence on antinociceptive tolerance, and future prospects. Perspective: This article reviews the current literature on opioid-induced dysbiosis (OID) of gut bacteria, including its qualitative nature, influence on antinociceptive tolerance, and future prospects. This work may help identify targets for new opioid-sparing strategies.

Clinical outcome assessments (COAs) measure outcomes that are meaningful to patients in clinical trials and are critical for determining whether a treatment is effective. The objectives of this study are to (1) describe the different types of COAs and provide an overview of key considerations for evaluating COAs, (2) review COAs and other outcome measures for chronic pain treatments that are recommended by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) or other expert groups, and (3) review advances in understanding pain-related COAs that are relevant to clinical trials. The authors reviewed relevant articles, chapters, and guidance documents from the European Medicines Agency and U.S. Food and Drug Administration. Since the original core set of outcome measures were recommended by IMMPACT 14 years ago, several new advancements and publications relevant to the measurement or interpretation of COAs for chronic pain trials have emerged, presenting new research opportunities. Despite progress in the quality of measurement of several outcome domains for clinical trials of chronic pain, there remain some measurement challenges that require further methodological investigation.

Large amino acid transporter 1 (LAT1), also known as SLC7A5, is an essential amino acid transporter that forms a heterodimeric complex with the glycoprotein cell-surface antigen heavy chain (4F2hc (CD98, SLC3A2)). Within nociceptive pathways, LAT1 is expressed in the dorsal root ganglia and spinal cord. Although LAT1 expression is upregulated following spinal cord injury, little is known about LAT1 in neuropathic pain. To date, only circumstantial evidence supports LAT1/4F2hc's role in pain. Notably, LAT1's expression and regulation link it to key cell types and pathways implicated in pain. Transcriptional regulation of LAT1 expression occurs via the Wnt/frizzled/β-catenin signal transduction pathway, which has been shown to be involved in chronic pain. The LAT1/4F2hc complex may also be involved in pain pathways related to T- and B-cells. LAT1's expression induces activation of the mammalian target of rapamycin (mTOR) signaling axis, which is involved in inflammation and neuropathic pain. Similarly, hypoxia and cancer induce activation of hypoxia-inducible factor 2 alpha, promoting not only LAT1's expression but also mTORC1's activation. Perhaps the strongest evidence linking LAT1 to pain is its interactions with key voltage-gated ion channels connected to nociception, namely the voltage-gated potassium channels Kv1.1 and Kv1.2 and the voltage-gated sodium channel Nav1.7. Through functional regulation of these channels, LAT1 may play a role in governing the excitatory to inhibitory ratio which is altered in chronic neuropathic pain states. Remarkably, the most direct role for LAT1 in pain is to mediate the influx of gabapentin and pregabalin, two first-line neuropathic pain drugs, that indirectly inhibit high voltage-activated calcium channel auxiliary subunit α2δ-1. In this review, we discuss the expression, regulation, relevant signaling pathways, and protein interactions of LAT1 that may link it to the development and/or maintenance of pain. We hypothesize that LAT1 expressed in nociceptive pathways may be a viable new target in pain.

Imidazoline receptors historically referred to a family of nonadrenergic binding sites that recognize compounds with an imidazoline moiety, although this has proven to be an oversimplification. For example, none of the proposed endogenous ligands for imidazoline receptors contain an imidazoline moiety but they are diverse in their chemical structure. Three receptor subtypes (I, I, and I) have been proposed and the understanding of each has seen differing progress over the decades. I receptors partially mediate the central hypotensive effects of clonidine-like drugs. Moxonidine and rilmenidine have better therapeutic profiles (fewer side effects) than clonidine as antihypertensive drugs, thought to be due to their higher I/-adrenoceptor selectivity. Newer I receptor agonists such as LNP599 [3-chloro-2-methyl-phenyl)-(4-methyl-4,5-dihydro-3-pyrrol-2-yl)-amine hydrochloride] have little to no activity on -adrenoceptors and demonstrate promising therapeutic potential for hypertension and metabolic syndrome. I receptors associate with several distinct proteins, but the identities of these proteins remain elusive. I receptor agonists have demonstrated various centrally mediated effects including antinociception and neuroprotection. A new I receptor agonist, CR4056 [2-phenyl-6-(1-imidazol-1yl) quinazoline], demonstrated clear analgesic activity in a recently completed phase II clinical trial and holds great promise as a novel I receptor-based first-in-class nonopioid analgesic. The understanding of I receptors is relatively limited. Existing data suggest that I receptors may represent a binding site at the Kir6.2-subtype ATP-sensitive potassium channels in pancreatic -cells and may be involved in insulin secretion. Despite the elusive nature of their molecular identities, recent progress on drug discovery targeting imidazoline receptors (I and I) demonstrates the exciting potential of these compounds to elicit neuroprotection and to treat various disorders such as hypertension, metabolic syndrome, and chronic pain.