A new splice of life for the μ-opioid receptor

Abstract

C o m m e n t a r y2 5 Opioids in the vanguardA more complete understanding of the neurobiological, molecular, and cellular systems involved in pain sensation and pain control continues to be a challenging, yet productive, proposition. Opioid drugs are unquestionably the most effective treatment available for moderate to severe pain and can provide additional benefits, such as relieving anxiety, reducing the physical or mental effects of trauma, and acting as a soporific and euphorigenic. Unfortunately, the clinical efficacy of these drugs is accompanied by a panoply of perturbing side effects that include respiratory depression, nausea, vomiting, constipation, and sedation, not to mention the development of tolerance and the potential for addiction. All of these effects can be explained at the neurobiological level by the distribution of μ-opioid receptor-expressing neurons. It is noteworthy that investigations of opioid pharmacology and neurobiology include many early, seminal observations in recombinant DNA technology, molecular pharmacology, and medicinal chemistry. Opioid receptors were first identified in the brain through evaluation of radioligand binding with a tritiated form of the opioid antagonist naloxone (1), which in turn led to isolation of enkephalin, one of the first neuropeptides identified (2). One of the first mRNAs to be cloned was a partial transcript coding for β-endorphin (3), which was isolated from rodent pituitary tumor cells. Subsequently, the full-length mRNAs coding for the precursor proteins of all three families of endogenous opioids proopiomelanocortin (POMC), preproenkephalin (PENK), and preprodynorphin (PDYN) (4-7) were also cloned. After a concerted research effort, the μ-, δ-, and κ-opioid receptors were cloned and sequenced (8-11). The advent of gene targeting and homologous recombination technologies resulted in the opioid receptors being knocked out one at a time and in combination (12, 13) to evaluate their function and ligands. The KO data clearly showed that morphine analgesia is due to expression of the μ-opioid receptor (14). More recently, the crystal structures of the three receptors have been determined (15-17), and through in vivo expression of receptor-fusion proteins, the circuits and cell types that contain these receptors are being defined (18). Many of these milestones were achieved via long-term research investments, such as the membrane protein structural biology initiative component of the NIH Roadmap for Medical Research that began in 2004 (19). This partial account serves to show how opioid research has frequently been in the vanguard of many research fields, and current opioid pharmacology investigations suggest that new steps are being formed. Medicinal chemistryWoven throughout these approximately 40 years has been an intensive and unrelenting search for new opioid analgesicsa search that dates back more than 100 years. Heroin was introduced as an improved opioid analog to avoid the side effects of morphine at the end of the 1800s (20). Heroin not wit...

Anatomical Analysis of Transient Potential Vanilloid Receptor 1 (Trpv1+) and Mu-Opioid Receptor (Oprm1+) Co-expression in Rat Dorsal Root Ganglion Neurons

“…While there are three canonical opioid receptors (μ, δ, and κ), and a fourth opioid-like paralog ( Oprl1 ), only μ-receptor agonists are used clinically at this time, although extensive medicinal chemical and preclinical development on the other receptors has occurred or is in progress (Calo et al, 2000 ; Floyd et al, 2009 ; Bardoni et al, 2014 ; Viscusi et al, 2021 ). Additionally, some controversy exists over detection of these receptors, as they are frequently expressed to a low degree and difficult to quantify accurately (Imlach and Christie, 2014 ; Iadarola et al, 2015 ; Sapio et al, 2016 ). In this regard, the present study fills a critical knowledge gap by delineating the co-expression matrix of these receptors in detail.…”

Abuse Liability, Anti-Nociceptive, and Discriminative Stimulus Properties of IBNtxA

“…26,97 While these results support the hypothesis that 6TM/E11 MOR splice variants have distinct receptor signaling properties and agonist binding capabilities, thus making them potential druggable targets, the prevalence of substantial 6TM/E11 expression in wild-type animals is of some dispute. For example, Xu et al 98 reported variable expression of 6TM/E11 MOR splice variants across brain regions and mouse strains using qPCR, but Iadarola et al 99 found little evidence of splice variants containing exon 11 in mouse dorsal root ganglion cells using RNA-Seq. Future studies using MOR exon 11 knockout mice 31 could more fully dissect the role of 6TM/E11 MOR splice variants in mediating the discriminative properties of IBNtxA and other opioid drugs.…”

“…Follow-up studies using genetically modified mice indicated that in vivo analgesia and behavioral responses induced by IBNtxA could be largely attributed to 6TM/E11 MOR splice variant signaling. , In MOR/KOR/DOR triple knockout animals, IBNtxA-mediated analgesia, but not morphine-mediated analgesia, could be rescued via intrathecal administration of lentivirus containing 6TM/E11 MOR splice variants. , While these results support the hypothesis that 6TM/E11 MOR splice variants have distinct receptor signaling properties and agonist binding capabilities, thus making them potential druggable targets, the prevalence of substantial 6TM/E11 expression in wild-type animals is of some dispute. For example, Xu et al reported variable expression of 6TM/E11 MOR splice variants across brain regions and mouse strains using qPCR, but Iadarola et al found little evidence of splice variants containing exon 11 in mouse dorsal root ganglion cells using RNA-Seq. Future studies using MOR exon 11 knockout mice could more fully dissect the role of 6TM/E11 MOR splice variants in mediating the discriminative properties of IBNtxA and other opioid drugs.…”

Abuse liability, antinociceptive, and discriminative stimulus properties of IBNtxA

“…While these results support the hypothesis that 6TM/E11 MOR splice variants have distinct receptor signaling properties and agonist binding capabilities-thus making them potential druggable targets-the prevalence of substantial 6TM/E11 expression in wild-type animals is of some dispute. For example, Xu et al (2014a) reported variable expression of 6TM/E11 splice variants across brain regions and mouse strains using qPCR, but Iadarola et al (2015) found little evidence of exon 11-containing splice variants in mouse dorsal root ganglion cells using RNA-Seq. Future studies using MOR exon 11 knockout mice ) could more fully dissect the role of 6TM/E11 MOR splice variants in mediating the discriminative properties of IBNtxA and other opioid drugs.…”