Ligand-Free Signaling of G-Protein-Coupled Receptors: Comparison
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Please note this is a comparison between Version 1 by Wolfgang Sadee and Version 3 by Lindsay Dong.

Numerous G-protein-coupled receptors (GPCRs) display ligand-free basal signaling with potential physiological functions, a target in drug development. As an example, the μ opioid receptor (MOR) signals in ligand-free form (MOR-μ*), influencing opioid responses. In addition, agonists bind to MOR but can dissociate upon MOR activation, with ligand-free MOR-μ* carrying out signaling. Opioid pain therapy is effective but incurs adverse effects (ADRs) and risk of opioid use disorder (OUD). Sustained opioid agonist exposure increases persistent basal MOR-μ* activity, which could be a driving force for OUD and ADRs. Antagonists competitively prevent resting MOR (MOR-μ) activation to MOR-μ*, while common antagonists, such as naloxone and naltrexone, also bind to and block ligand-free MOR-μ*, acting as potent inverse agonists. A neutral antagonist, 6β-naltrexol (6BN), binds to but does not block MOR-μ*, preventing MOR-μ activation only competitively with reduced potency. 

  • basal receptor signaling
  • GPCR
  • μ opioid receptor
  • C

1. Introduction

Receptors have evolved to sense environmental and cellular stimuli with exquisite sensitivity. Often existing in large aggregates of proteins and other components, receptors respond to minute forces that trigger conformational changes, aggregate remodeling, and subsequent signaling processes. Maintaining receptors in their silent state requires intricate mechanisms to balance quiescence with responsiveness. If this restraint is incomplete, the receptor ‘leaks’, i.e., partially signals with ligand-free basal activity observed with numerous receptor classes [1][2][3][1,2,3]. Several factors can enhance basal signaling, for example, high receptor expression, mutations, including single nucleotide polymorphisms, membrane lipids, ions, and environmental conditions [4]. Pathophysiological consequences include neoplastic transformation occurring when mutations or overexpression activate basal signaling of growth factor receptors [4]. 
In contrast to causing pathogenic effects, basal activity can also serve physiological functions. For example, the ghrelin receptor, a GPCR, signals at ~50% of maximal capacity in a ligand-free form, leading to inverse agonists (antagonists that block ligand-free basal signaling) as treatment for eating disorders [5][6][6,7]. Therapy of psychoses involves inverse agonists of 5HT2A, also endowed with basal signaling [7][8]. Among opioid receptors, the δ opioid receptor (DOR) was the first discovered to display basal activity [8][9], followed by the μ opioid receptor (MOR) [9][10]. Assuming basal activity has a physiological role, one must ask whether and how basal activity is regulated—an area requiring more research. Another unresolved question asks whether agonists continue to bind to the activated receptor or dissociate after activation to generate ligand-free receptors, which could carry out part or all of the signaling, involving multiple downstream pathways.
Opioid analgesics are highly effective, but the risk of addiction, respiratory depression, bowel dysfunction, hyperalgesia, pruritis, cognitive impairment, and other adverse effects limit clinical utility. While OUD risk might be lower when analgesics are used therapeutically, for example, against cancer pain, a high risk of developing opioid use disorder (OUD) [10][11] has resulted in an epidemic of opioid overdose deaths [11][12] and millions in the US are non-medical or illicit opioid users [12][13]. Multiple strategies have been developed to treat or prevent OUD and adverse effects, some targeting the complexity of opioid receptor functions [13][14], but none have yet markedly curbed the opioid epidemic [12][13]. For example, positive allosteric MOR modulators [14][15] and ‘biased agonists’ acting via G proteins or β-arrestins [15][16][17][16,17,18] can cause analgesia with reduced adverse effects, as receptors exist in multiple conformations and signaling complexes that can be differentially activated [4]. Current OUD therapies (e.g., methadone, buprenorphine, or naltrexone maintenance) are effective but remain sub-optimal [18][19]. Effective therapies that break or prevent the vicious circle of OUD are urgently needed.

2. Physiological Role and Regulation of Basal MOR Signaling

2.1. Regulation and Influence in Pain and Dependence

The ground-state MOR-μ appears to be in an equilibrium with basally active MOR-μ* [19][20]. While the physiological regulation of the MOR-μ–MOR-μ* equilibrium remains enigmatic, β-arrestin-2 and c-Src appear to be involved, down-regulating G protein coupling while also mediating alternative signaling processes [20][21][21,22]. Diverse studies have demonstrated a role of basal MOR signaling in affecting pain perception, for example, counteracting post-surgical pain sensitization [22][23][23,24]. Following repeated opioid dosing, for pain therapy or with illicit use, MOR-μ* displays enhanced and sustained basal activity, involved in analgesia and dependence [24][25][26][27][28][29][30][31][25,26,27,28,29,30,31,32], which can differ between tissue type and brain regions [30][31]. Similarly, increased exposure through enkephalin release during withdrawal was shown to enhance MOR basal signaling, thereby ameliorating withdrawal symptoms [27][28]. In an opioid-dependent state, reversal of MOR-μ* to MOR-μ appears to be slow and MOR-μ* may be a driving force underlying dependence [29][30]. Dependence can last for days and weeks and compulsive drug-seeking behavior much longer, both elements of opioid use disorder (OUD) [32][33].

2.2. Neutral Antagonists and Inverse Agonists

Basal receptor activity can be revealed with the use of neutral antagonists and inverse agonists [33][36]. In vitro and in vivo methods have yielded multiple compounds with a range of effects on basal MOR activity, including diverse neutral MOR antagonists [34][35][36][37][37,38,39,40] and DOR signaling [38][39][41,42]. Naltrexone and naloxone act largely as neutral antagonists at spontaneously signaling MOR-μ* under opioid-naive conditions, whereas both turn into inverse MOR-μ* agonists after morphine pretreatment [40][34]. The same conversion of antagonists into inverse agonists upon agonist exposure has been demonstrated with DOR [41][43]. Studies on biased agonist ligands have shown that MOR exists in multiple conformations that trigger distinct signaling pathways [15][16][17][16,17,18]. One can, thus, hypothesize that the dependent MOR-μ* state differs from MOR-μ* signaling under opioid-naïve conditions, with naloxone changing from a neutral antagonist to an inverse agonist. In a similar fashion, the antipsychotic pimavanserin acts as an inverse agonist at 5HT2A when coupling to Gαi1 but as a neutral antagonist with Gαq/11 [42][44], suggesting that MOR sensitivity could also depend on the signaling pathway. As observed with opioid agonists, treatment with antagonists also affects the MOR-μ–MOR-μ* equilibrium. Generally, treatment with inverse agonists tends to sensitize MOR and enhance the active state (MOR-μ*) while neutral antagonists favor the MOR-μ ground state [43][45].

2.3. Ligand-Free Signaling of Opioid Receptors in Peripheral Nociceptors

Basal MOR and DOR signaling in peripheral nociceptors also plays a role in neuropathic pain. Jeske [44][47] summarizeviewed the existence of distinct MOR conformations of varying relative abundance as a function of cellular environment and in the periphery compared to the CNS. In peripheral afferent nociceptors, both MOR and DOR maintain a silent status that cannot be readily activated by opioid agonists, possibly because of interactions with GRK2 and β-arrestin [20][23][45][21,24,48], representing, again, a different form of MOR-μ. Inflammatory stimuli lead to activation, both spontaneously to generate basal signaling and restoration of response to agonists for both MOR and DOR. Thus, nociceptive stimuli generate active MOR-μ* as a physiological countermeasure, leading to abatement of neuropathic pain [23][46][24,49]. However, if such basal MOR activity fails to be reversed, or is maintained by opioid drug exposure, it can contribute to chronic neuropathic pain and hyperalgesia, supported by the finding that the peripheral antagonist methylnaltrexone prevents opioid tolerance, dependence, and hyperalgesia [45][48]. 

3. Model of μ Opioid Receptor Signaling

3.1. MOR Activation by Agonists

The model in Figure 1 raises the question of which form of MOR elicits signaling, agonist-bound or ligand-free MOR-μ*, or both. Upon binding, an agonist induces a subtle conformational change that overcomes restraints keeping MOR-μ in its ground state, triggering remodeling of the composite receptor aggregate, subsequently, to engage signaling factors, such as G proteins. Each sequential step can cause conformational changes in the receptor, leading to altered agonist affinity to MOR. Diverse evidence supports the hypothesis that some agonists dissociate rapidly after MOR activation. Proposed in Figure 1, agonists, such as etorphine and morphine, appear to bind MOR-μ with high affinity in rodent brains but rapidly dissociate after activation to ligand-free MOR-μ*, which would then carry out the signaling [19][47][20,50]. Etorphine’s dissociation half-life in vivo is ~50 s, whereas in vitro, it increases to ~40 min (depending on incubation conditions), presumably because the receptor aggregate and coupling to downstream signaling factors are altered. 

Molecules 27 05826 g001 550
Figure 1. Model of μ opioid receptor (MOR) conformations. MOR-μ* is reversibly activated by both spontaneous conversion and agonists to ligand-free active MOR-μ*. Opioid agonists appear to dissociate from MOR-μ* by losing high-affinity binding. The inverse agonist naltrexone potently blocks ligand-free MOR-μ*, whereas the neutral antagonist 6BN binds to MOR-μ* but does not suppress signaling. Both naltrexone and 6BN block agonist activation competitively at MOR-μ with lower potency. Continued opioid agonist stimulation shifts the equilibrium to persistent MOR-μ* signaling, leading to a dependent state. In contrast to naltrexone, 6BN is proposed to potently accelerate reversal of the equilibrium back to MOR-μ in the opioid-naïve state. Adapted from [19][20].
The proposed role of MOR-μ*, as the active signaling molecule, has several implications that require attention. Structural analyses have defined MOR as being either in the active state when bound to an agonist or in an inactive state bound to an antagonist. As MOR-μ* is active without any ligand, one should reconsider assigning active and inactive MOR states for structural analyses. An activated MOR-μ* bound to a neutral antagonist could provide further insight into receptor-folding dynamics. In addition, if ligand-free MOR-μ*carries out signaling, the response duration is determined by the MOR-μ* lifetime. Assuming a short duration of agonist stimulation (short elimination half-life of the agonist), duration of analgesia should be similar for full agonists with short half-lives. Implicated in numerous overdose deaths, fentanyl is nearly 100-times more potent than morphine, but also a full agonist compared to morphine and is, therefore, assumed to generate more MOR-μ*, causing lasting respiratory depression, even when the agonist rapidly declines in the brain. Full and lasting activation to MOR-μ*, possibly endowed with distinct signaling pathways, could account for reported cases of complete short-term memory loss associated with bilateral destruction of the hippocampus (opioid-related amnestic syndrome [48][52]) in survivors of a near-lethal fentanyl overdose.

3.2. Blocking MOR Activation and Signaling by Antagonists

Following the logic in the MOR model (Figure 1), antagonists can block signaling through two distinct mechanisms: competitively preventing MOR-μ activation to MOR-μ* by agonists or by acting as ‘inverse agonists’ that block ligand-free MOR-μ* signaling, inducing yet another conformational MOR change. Typical MOR antagonists tend to act as full inverse agonists (e.g., BNTX), while naloxone and naltrexone turn into inverse agonists at the elevated basal MOR-μ* state in the dependent state [40][34], suggesting differences between MOR-μ* states. This finding raises the question whether naloxone and naltrexone also act as inverse agonists at MOR-μ* acutely generated by an agonist. Binding to ligand-free MOR-μ*, inverse agonists are expected to reduce signaling, blocking analgesia and causing withdrawal with equal potency, regardless of the agonist load in the body—this appears to be the case for naloxone and naltrexone [49][50][51][35,54,55]. Minute doses of naloxone (0.05–0.1 mg i.v.) cause perceptible withdrawal in methadone-maintenance patients (typically on 50–100 mg methadone per day), while the antinociceptive IC50 of naltrexone in mice is only 0.007 mg/kg against a large dose of 30 mg/kg morphine [40][34]—likely a direct effect on ligand-free MOR-μ*, accounting for extreme naltrexone potency. Conversely, even lethal doses of morphine cannot displace 3H-naloxone labeling of MOR sites in rat brain as morphine is expected to have low affinity to MOR-μ* [52][56].

3.3. Differences between the New MOR Model and Classical GPCR Multistate Models

The main classical multistate GPCR model proposes a ternary complex between agonist, receptor, and G protein, representing the active signaling state [53][58], with some modification, including a binary complex of receptor and G protein deemed inactive. The ternary complex undergoes several conformational steps in the activation process, but any effect on agonist affinity was been considered. Inherent to the MOR model in Figure 1 is an initial conformational change triggered by agonist binding that leads to a substantial reorganization of the receptor complex into a persistent active signaling state, during which the agonist loses affinity and dissociates, generating an active binary receptor complex carrying out the signaling. Persistent receptor signaling after dissociation of the agonist has been demonstrated for rhodopsin, suggested to have wider implications for GPCRs [54][59]. Thereby, ligand-free signaling can occur both with spontaneous activation (basal signaling) or upon agonist activation (these signaling complexes may differ in composition). In the classical model of GPCRs with basal ligand-free signaling, inverse agonists are thought to drive the basally active receptor state back to the resting state, whereas neutral antagonists do not [53][58].

4. Properties of 6β-Naltrexol (6BN)

4.1. 6BN Pharmacology

As a main metabolite of naltrexone in humans (40–50% of the dose) (Figure 2) [51][55], 6BN has a solid safety record in humans [12][13], is stable, orally bioavailable in mice (~25%) [28][29] and in guinea pigs (~30% [55][61]), and has a half-life of ~12 h in humans [56][62], rendering 6BN highly ‘druggable’. Further, 6BN’s in vitro binding affinity to MOR, DOR, and KOR (κ opioid receptor) is 1.4, 29, and 2 nM, respectively, similar to naltrexone’s affinity profile (0.5, 7, and 1 nM, respectively; all Ki values) [51][57][55,63]. As an inverse MOR agonist, naltrexone blocks opioid analgesia and causes withdrawal in dependent subjects with equally high potency [50][51][54,55] so that it can be administered only 1–2 weeks after complete opioid detoxification. In contrast to naltrexone, 6BN blocks analgesia and elicits withdrawal only at much higher doses than naltrexone [19][51][58][20,55,64]. As a result, 6BN as a metabolite was considered not to contribute to naltrexone’s actions in opioid maintenance therapies [59][65], even though 6BN exceeds naltrexone’s blood levels because of its longer half-life.
Molecules 27 05826 g002 550
Figure 2. Pharmacological properties of naltrexone and 6β-naltrexol.
 Pharmacological properties of naltrexone and 6β-naltrexol.

4.2. Potent Suppression of Opioid Dependence with Low-Dose 6BN (LD-6BN)

Oberdick et al. [60][67] determined that 6BN given together with morphine to juvenile mice prevents subsequent withdrawal jumping, with an EC50 of ~0.03 mg/kg. This result indicated high potency in a centrally mediated effect, unexpected even when accounting for the immature BBB in mice until day 20 post-partum, allowing rapid access of 6BN to the brain. Safa et al. then showed that 6BN co-administered with methadone potently suppresses withdrawal behavior in adult guinea pigs (IC50 ~ 0.01 mg/kg) [55][61]. Moreover, LD-6BN given s.c. to pregnant guinea pigs together with methadone suppressed withdrawal behavior in the newborn pups, with an ED50 ~ 0.025 mg/kg 6BN [55][61], without deleterious effects and well below the IC50 against methadone antinociception (estimated ~1.0 mg/kg) [55][61].

4.3. Role of 6β-Naltrexol in the Effects of Very-Low-Dose Naltrexone

Because its low potency as an antagonist (64,65], 6BN was not thought to contribute to naltrexone’s effects, even though its affinity to MOR is similar. On the other hand, very-low doses of naltrexone (VLD–naltrexone, defined as 0.001–1.0 mg total oral dose in humans, below the threshold causing withdrawal in dependent subject [61][69]) have been tested in a variety of indications. For example, VLD–naltrexone is proposed to improve analgesic efficacy, reduce relapse [61][62][63][69,70,71], and facilitate weaning (maximally tolerated dose not causing withdrawal symptoms: 0.25 mg naltrexone [62][70]), by yet poorly defined mechanisms. Further, VLD–naltrexone reduced drug craving after opioid weaning [62][70].

4.4. Potential Clinical Uses of 6b-Naltrexol

The unique properties of LD-6BN support its clinical potential as an ‘retrograde addiction modulator’ in multiple applications, including safety and utility of opioid analgesics and OUD therapies. Further, 6BN acts in three distinct ways as a function of dose [19][55][64][20,61,66]: 1. modulating elements of addiction at low doses; 2. in addition, selectively blocking peripheral opioid effects at intermediate doses; and 3. antagonizing antinociception at high doses. Moreover, intermediate 6BN doses can be selected such that 6BN accumulation in the body reaches levels that blunt central effects upon high-frequency dosing of opioid agonists with shorter half-lives than 6BN, reducing OUD risk [19][20]. ItWe proposes that 6BN is a candidate drug that can improve opioid pain therapy, reduce OUD risk, facilitate opioid-weaning detoxification, treat neonatal opioid withdrawal syndrome [55][61], and improve the safety of opioid maintenance therapies.

5. Conclusion

A prominent role of ligand-free MOR-μ* signaling further implies distinct roles for inverse agonists and neutral antagonists. On thermodynamic grounds, ligands can stabilize the MOR receptor conformation towards those with the highest affinity for the ligand, while that process may trigger further remodeling of the receptor aggregate to either initiate signaling or block it (agonists, neutral agonist, and inverse agonist). The proposed novelty of the MOR model in Figure 1 is the hypothesis that a neutral antagonist has the potential to accelerate gradual reversal of MOR-μ* in the dependent state to the resting state—thereby, reversing dependence, captured by the term ‘retrograde addiction modulation’. Reversal of ligand-free signaling of a two-state receptor-signaling complex by a neutral antagonist is opposite to the assumptions made in classical GPCR models [53][58]. Retrograde addiction modulators as clinical agents must also be neutral antagonists to allow opioid analgesia and avoid acute withdrawal. These combined properties could lead to a new class of drugs for OUD and pain therapy, exemplified by 6BN and analogs shown to be neutral MOR antagonists [3[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83][84][85][86][87][88][89][90][91][92][93][94][95][96][97][98][99][100][101][102][103][104][105][106][107][108][109][110][111][112][113][114][115][116][117][118][119][120][121][122]4,37,38,39,72,73]. The MOR model proposed in  Figure 1 serves as a guide for further study, according to the motto ‘no model is perfect but some are useful’, potentially applicable to many GPCRs.

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