Regulation of δ Opioid Receptor-Mediated Signaling and Antinociception in Peripheral Sensory Neurons by Arachidonic Acid–Dependent 12/15-Lipoxygenase Metabolites

Sullivan, Laura C.; Chavera, Teresa A.; Gao, Xiaoli; Pando, Miryam M.; Berg, Kelly A.

doi:10.1124/jpet.117.241604

Cited by 9 publications

(23 citation statements)

References 30 publications

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“…Constitutive desensitization may also be operative for receptor systems in vivo. Mu and delta opioid receptors are expressed by peripheral pain-sensing neurons (nociceptors) in rats; however, application of opioid agonists to these neurons in vivo does not produce antinociception ( Rowan et al, 2009 ; Stein and Zollner, 2009 ; Berg et al, 2011 ; Sullivan et al, 2015b ; Sullivan et al, 2017 ). Similarly, mu and delta opioid receptor agonists do not inhibit adenylyl cyclase activity in these neurons in primary culture ( Patwardhan et al, 2005 ; Berg et al, 2007 ; Berg et al, 2011 , 2012 ; Sullivan et al, 2015b , 2017 ).…”

Section: Constitutive Activity and Inverse Agonismmentioning

confidence: 99%

“…Mu and delta opioid receptors are expressed by peripheral pain-sensing neurons (nociceptors) in rats; however, application of opioid agonists to these neurons in vivo does not produce antinociception ( Rowan et al, 2009 ; Stein and Zollner, 2009 ; Berg et al, 2011 ; Sullivan et al, 2015b ; Sullivan et al, 2017 ). Similarly, mu and delta opioid receptor agonists do not inhibit adenylyl cyclase activity in these neurons in primary culture ( Patwardhan et al, 2005 ; Berg et al, 2007 ; Berg et al, 2011 , 2012 ; Sullivan et al, 2015b , 2017 ). However, prolonged treatment (90 minutes) with the inverse agonist, naloxone ( Raehal et al, 2005b ; Wang et al, 2007 ; Connor and Traynor, 2010 ), in vivo promoted antinociceptive responses to opioid agonists and in culture promoted inhibition of adenylyl cyclase activity ( Sullivan et al, 2016 ).…”

Section: Constitutive Activity and Inverse Agonismmentioning

confidence: 99%

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Making Sense of Pharmacology: Inverse Agonism and Functional Selectivity

Berg¹,

Clarke²

2018

International Journal of Neuropsychopharmacology

125

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Constitutive receptor activity/inverse agonism and functional selectivity/biased agonism are 2 concepts in contemporary pharmacology that have major implications for the use of drugs in medicine and research as well as for the processes of new drug development. Traditional receptor theory postulated that receptors in a population are quiescent unless activated by a ligand. Within this framework ligands could act as agonists with various degrees of intrinsic efficacy, or as antagonists with zero intrinsic efficacy. We now know that receptors can be active without an activating ligand and thus display “constitutive” activity. As a result, a new class of ligand was discovered that can reduce the constitutive activity of a receptor. These ligands produce the opposite effect of an agonist and are called inverse agonists. The second topic discussed is functional selectivity, also commonly referred to as biased agonism. Traditional receptor theory also posited that intrinsic efficacy is a single drug property independent of the system in which the drug acts. However, we now know that a drug, acting at a single receptor subtype, can have multiple intrinsic efficacies that differ depending on which of the multiple responses coupled to a receptor is measured. Thus, a drug can be simultaneously an agonist, an antagonist, and an inverse agonist acting at the same receptor. This means that drugs have an additional level of selectivity (signaling selectivity or “functional selectivity”) beyond the traditional receptor selectivity. Both inverse agonism and functional selectivity need to be considered when drugs are used as medicines or as research tools.

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Section: Constitutive Activity and Inverse Agonismmentioning

confidence: 99%

Section: Constitutive Activity and Inverse Agonismmentioning

confidence: 99%

Making Sense of Pharmacology: Inverse Agonism and Functional Selectivity

Berg¹,

Clarke²

2018

International Journal of Neuropsychopharmacology

125

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“…Now, we apply our strategy to the Arachidonic Acid (AA) metabolic network. There have been some studies on drug combinations of AA metabolic network [23]. Inflammation is a type of nonspecific immune response to infection, irritation, or other injury.…”

Section: Applying the Strategy Of Screening Drug Target Combinations mentioning

confidence: 99%

Screening drug target combinations in disease-related molecular networks

2019

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Background For treating a complex disease such as cancer, some effective means are needed to control biological networks that underlies the disease. The one-target one-drug paradigm has been the dominating drug discovery approach in the past decades. Compared to single target-based drugs, combination drug targets may overcome many limitations of single drug target and achieve a more effective and safer control of the disease. Most of existing combination drug targets are developed based on clinical experience or text-and-trial strategy, which cannot provide theoretical guidelines for designing and screening effective drug combinations. Therefore, systematic identification of multiple drug targets and optimal intervention strategy needs to be developed. Results We developed a strategy to screen the synergistic combinations of two drug targets in disease networks based on the classification of single drug targets. The method tried to identify the sensitivity of single intervention and then the combination of multiple interventions that can restore the disease network to a desired normal state. In our strategy of screening drug target combinations, we first classified all drug targets into sensitive and insensitive single drug targets. Then, we identified the synergistic and antagonistic of drug target combinations, including the combinations of sensitive drug targets, the combinations of insensitive drug target and the combination of sensitive and insensitive targets. Finally, we applied our strategy to Arachidonic Acid (AA) metabolic network and found 18 pairs of synergistic drug target combinations, five of which have been proven to be viable by biological or medical experiments. Conclusions Different from traditional methods for judging drug synergy and antagonism, we propose the framework of how to enhance the efficiency by perturbing two sensitive targets in a combinatorial way, how to decrease the drug dose and therefore its side effect and cost by perturbing combinatorially a main sensitive target and an auxiliary insensitive target, and how to perturb two insensitive targets to realize the transition from a disease state to a healthy one which cannot be realized by perturbing each insensitive target alone. Although the idea is mainly applied to an AA metabolic network, the strategy holds for more general molecular networks such as combinatorial regulation in gene regulatory networks. Electronic supplementary material The online version of this article (10.1186/s12859-019-2730-8) contains supplementary material, which is available to authorized users.

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“…However, under conditions of inflammation or exposure to inflammatory mediators, peripherally-restricted opioid agonists can produce profound antinociceptive responses (Fields et al, 1980;Chen et al, 1997;Obara et al, 2009;Rowan et al, 2009;Berg et al, 2011Berg et al, , 2012Sullivan et al, 2015a). Similarly, with peripheral sensory neurons in culture, activation of opioid receptors do not activate the Gi-adenylyl cyclase signaling pathway unless cells are first exposed to an inflammatory mediator, such as bradykinin (BK) or arachidonic acid (AA) (Patwardhan et al, 2005;Berg et al, 2007Berg et al, , 2011Berg et al, , 2012Sullivan et al, 2015aSullivan et al, , 2017. Induction of opioid receptor functional competence in peripheral sensory neurons by inflammatory mediators is mediated by cyclooxygenase (COX)-dependent metabolites of AA (Berg et al, 2007(Berg et al, , 2011Sullivan et al, 2015a).…”

Section: Introductionmentioning

confidence: 99%

“…Induction of opioid receptor functional competence in peripheral sensory neurons by inflammatory mediators is mediated by cyclooxygenase (COX)-dependent metabolites of AA (Berg et al, 2007(Berg et al, , 2011Sullivan et al, 2015a). In addition, a second AA-mediated signaling pathway regulates the responsiveness of peripheral opioid receptor systems, however in a negative manner (Sullivan et al, 2015a(Sullivan et al, , 2017. Following the initial induction of functional competence via AA signaling, a prolonged period of non-responsiveness ensues during which responsiveness to agonist cannot be re-induced.…”

Section: Introductionmentioning

confidence: 99%

Signaling characteristics and functional regulation of delta opioid-kappa opioid receptor (DOP-KOP) heteromers in peripheral sensory neurons

et al. 2019

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Receptor heteromers often display distinct pharmacological and functional properties compared to the individual receptor constituents. In this study, we compared the properties of the DOP-KOP heteromer agonist, 6'-guanidinonaltrindole (6'-GNTI), with agonists for DOP ([D-Pen2,5]enkephalin [DPDPE]) and KOP (U50488) in peripheral sensory neurons in culture and in vivo. In primary cultures, all three agonists inhibited PGE 2 -stimulated cAMP accumulation as well as activated extracellular signal-regulated kinase ½ (ERK) with similar efficacy. ERK activation by U50488 was Gi-protein mediated but that by DPDPE or 6'-GNTI was Gi-protein independent (i.e., pertussis toxin insensitive). Brief pretreatment with DPDPE or U50488 resulted in loss of cAMP signaling, however, no desensitization occurred with 6'-GNTI pretreatment. In vivo, following intraplantar injection, all three agonists reduced thermal nociception. The dose-response curves for DPDPE and 6'-GNTI were monotonic whereas the curve for U50488 was an inverted U-shape. Inhibition of ERK blocked the downward phase and shifted the curve for U50488 to the right. Following intraplantar injection of carrageenan, antinociceptive responses to either DPDPE or U50488 were transient but could be prolonged with inhibitors of 12/15-lipoxgenases (LOX). By contrast, responsiveness to 6'-GNTI remained for a prolonged time in the absence of LOX inhibitors. Further, pretreatment with the 12/15-LOX metabolites, 12-and 15hydroxyeicosatetraenoic acid, abolished responses to U50488 and DPDPE but had no effect on 6'-GNTI-mediated responses either in cultures or in vivo. Overall, these results suggest that DOP-KOP heteromers exhibit unique signaling and functional regulation in peripheral sensory neurons and may be a promising therapeutic target for the treatment of pain.

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Regulation of δ Opioid Receptor-Mediated Signaling and Antinociception in Peripheral Sensory Neurons by Arachidonic Acid–Dependent 12/15-Lipoxygenase Metabolites

Cited by 9 publications

References 30 publications

Making Sense of Pharmacology: Inverse Agonism and Functional Selectivity

Making Sense of Pharmacology: Inverse Agonism and Functional Selectivity

Screening drug target combinations in disease-related molecular networks

Signaling characteristics and functional regulation of delta opioid-kappa opioid receptor (DOP-KOP) heteromers in peripheral sensory neurons

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