Efficacy as a Vector: the Relative Prevalence and Paucity of Inverse Agonism

Kenakin, Terry

doi:10.1124/mol.65.1.2

Cited by 201 publications

(162 citation statements)

References 127 publications

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“…Such uncovering of the inverse agonist properties of naloxone by morphine pretreatment is predicted, since morphine would be expected to increase the number of constitutively active mu receptors (for a review, see Kenakin, 2004). Therefore, the possibility that constitutively active mu receptors, formed after morphine treatment, mediate the heightened naloxone-precipitated 'motivational' withdrawal was examined in the current study.…”

Section: Introductionmentioning

confidence: 95%

Constitutively Active Mu Opioid Receptors Mediate the Enhanced Conditioned Aversive Effect of Naloxone in Morphine-Dependent Mice

Shoblock

Maidment

2005

Neuropsychopharmacol

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Naloxone administration produces a robust conditioned place aversion (CPA) in opiate-naive rodents by blocking the action of enkephalins at mu opioid receptors. This aversive response is potentiated by prior exposure to morphine. In vitro studies indicate that morphine treatment may promote constitutive activity of mu opioid receptors. We hypothesized that such enhanced constitutive activity in vivo may underlie the increased aversive property of naloxone by uncovering the inverse agonist property of this drug. The CPA produced by naloxone was compared with that produced by the neutral antagonists 6-alpha-and 6-beta-naloxol in mice with and without prior morphine exposure. While all three drugs produced CPA, only naloxone CPA was enhanced by morphine given 20 h prior to each naloxone injection. Furthermore, only naloxone produced withdrawal jumping when given 20 h after morphine, even though 6-alpha-naloxol was able to produce jumping when given 4 h after morphine. These data suggest that morphine may enhance naloxone CPA by increasing levels of constitutively active mu receptors and further support the role of such constitutive activity in mediating naloxone-precipitated physical withdrawal. Such long-term changes in constitutive activity of the mu receptor induced by exogenous opiate exposure may thus be an important factor in hedonic homeostatic dysregulation proposed to underlie the addictive process.

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Section: Introductionmentioning

confidence: 95%

Constitutively Active Mu Opioid Receptors Mediate the Enhanced Conditioned Aversive Effect of Naloxone in Morphine-Dependent Mice

Shoblock

Maidment

2005

Neuropsychopharmacol

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“…However, a considerable number of GPCRs, either wild-type or pathologically relevant mutants, display significant constitutive activity both in vitro and in vivo (de Ligt et al, 2000;Morisset et al, 2000): the equilibrium between inactive and active receptor conformations is shifted toward activation even in the absence of agonist ligands, leading to measurable basal activation of intracellular signaling pathways (Milligan, 2003). Antagonist ligands that inhibit this basal activation by stabilizing inactive receptor conformations are termed inverse agonists (Milligan and Bond, 1997), whereas true "neutral" antagonists inhibit binding of both agonists and inverse agonists without favoring the equilibrium between active or inactive conformations (Kenakin, 2004). Interesting consequences of constitutive activity were reported recently for GPCRs such as the type 1 cannabinoid receptor (CB1R), the 5-HT 2C serotonin receptor, or the ␣ 1a adrenergic receptor (Leterrier et al, 2004;Marion et al, 2004;Morris et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Constitutive Activation Drives Compartment-Selective Endocytosis and Axonal Targeting of Type 1 Cannabinoid Receptors

Leterrier¹,

Lainé²,

Darmon³

et al. 2006

J. Neurosci.

183

208

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The type 1 cannabinoid receptor (CB1R) is one of the most abundant G-protein-coupled receptors (GPCRs) in the brain, predominantly localized to axons of GABAergic neurons. Like several other neuronal GPCRs, CB1R displays significant in vitro constitutive activity (i.e., spontaneous activation in the absence of ligand). However, a clear biological role for constitutive GPCR activity is still lacking. This question was addressed by studying the consequences of constitutive activation on the intracellular trafficking of endogenous or transfected CB1Rs in cultured hippocampal neurons using optical and electron microscopy. We found that constitutive activity results in a permanent cycle of endocytosis and recycling, which is restricted to the somatodendritic compartment. Thus, CB1Rs are continuously removed by endocytosis from the plasma membrane in the somatodendritic compartment but not in axons, where CB1Rs accumulate on surface. Blocking constitutive activity by short-term incubation with inverse agonist 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-morpholinyl-1H-pyrazole-3-carboxamide (AM281) results in sequestration of recycled CB1Rs on the somatodendritic plasma membrane. Long-term inhibition of endocytosis by cotransfection of dominant-negative proteins results in impaired axonal polarization of surface-bound CB1Rs. Kinetic analysis shows that the majority of newly synthesized CB1Rs arrive first to the somatodendritic plasma membrane, from where they are rapidly removed by AM281-sensitive constitutive endocytosis before being delivered to axons. Thus, constitutive-activity driven somatodendritic endocytosis is required for the proper axonal targeting of CB1R, representing a novel, conformation-dependent targeting mechanism for axonal GPCRs.

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“…However, it is theoretically reasonable to suppose that receptor structures are sufficiently flexible and dynamic to permit assumption of active states in the absence of agonist, and a growing body of research conducted primarily using neurochemical measures in transfected cell lines has provided compelling evidence to suggest that this can occur. These studies have led to the "extended ternary complex" model [2][3][4]14], which can be diagrammed as follows:…”

Section: Tone Due To Constitutive Receptor Activitymentioning

confidence: 99%

“…This model (and more sophisticated derivatives) have been described in detail elsewhere [2,3], but for the purposes of this commentary, two features of the extended ternary complex model are especially relevant. First, as noted above, it allows for active receptor states that can bind to and activate G-proteins in the absence of drug or endogenous ligand.…”

Section: Tone Due To Constitutive Receptor Activitymentioning

confidence: 99%

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Some implications of receptor theory for in vivo assessment of agonists, antagonists and inverse agonists

Negus

2006

Biochemical Pharmacology

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Drug effects can be classified into three major phenotypes: agonist, antagonist and inverse agonist. Agonist and inverse agonist effects are associated with receptor activation and inactivation, respectively, whereas antagonism implies that a drug produces no effect when administered alone but blocks the effects of agonists and inverse agonists. Attention has only recently begun to focus on the theoretical and clinical implications of inverse agonists, and studies of inverse agonism have also stimulated revisions in receptor theory. This commentary addresses two specific issues related to the application of receptor theory to studies of inverse agonists in vivo. First, principles of receptor theory suggest that increasing drug doses produce a graded pharmacological stimulus that is transduced by receptor-containing tissue into a biological response. However, assays vary in their ability to detect those responses, and any given assay provides only a narrow window on the full range of underlying drug effects. Consequently, in vivo assessment of inverse agonists will benefit from development of assays sensitive to graded inverse agonist effects. Second, detection of inverse agonist effects requires some preexisting level of receptor activity (or tone). This tone can result from at least two sources: (a) endogenous ligands for the receptor, or (b) constitutive receptor activity. Strategies for discriminating these two sources of tone will also contribute to the in vivo assessment of inverse agonist effects. Studies with intermediate efficacy ligands may be especially helpful in this regard, because their effects are differentially influenced by endogenous agonist tone versus constitutive receptor tone. KeywordsInverse agonist; Agonist; Antagonist; Receptor theory; In vivo; Constitutive activityThe terms "agonist", "antagonist", and most recently, "inverse agonist" have evolved to describe different profiles of drug effects. By convention, an agonist is considered to be a drug that activates receptors to produce a measurable effect in some assay. A full agonist produces a maximal effect under a given set of conditions, whereas a partial agonist produces a detectable but submaximal effect. Conversely, an inverse agonist produces an effect opposite to that of an agonist, and inverse agonists can also be "full" or "partial". An antagonist produces no effect on its own but blocks the effects of both agonists and inverse agonists. In the first study to demonstrate inverse agonist activity at a G-protein-coupled receptor (the delta opioid receptor), the delta opioid [D-Ala-2 -D-Leu-5 ]enkephalin increased GTPase activity in membranes from a cell line that expresses delta receptors (i.e. an agonist effect), whereas ICI174864 reduced GTPase activity below basal levels (i.e. an inverse agonist effect), and the effects of both drugs were blocked by MR2266 (an antagonist effect) [1].

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Efficacy as a Vector: the Relative Prevalence and Paucity of Inverse Agonism

Cited by 201 publications

References 127 publications

Constitutively Active Mu Opioid Receptors Mediate the Enhanced Conditioned Aversive Effect of Naloxone in Morphine-Dependent Mice

Constitutively Active Mu Opioid Receptors Mediate the Enhanced Conditioned Aversive Effect of Naloxone in Morphine-Dependent Mice

Constitutive Activation Drives Compartment-Selective Endocytosis and Axonal Targeting of Type 1 Cannabinoid Receptors

Some implications of receptor theory for in vivo assessment of agonists, antagonists and inverse agonists

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