Biased agonism at kappa opioid receptors: Implication in pain and mood disorders

Dogra, Shalini; Yadav, Prem N.

doi:10.1016/j.ejphar.2015.07.018

Cited by 47 publications

(52 citation statements)

References 92 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, it also activates the G protein-independent β-arrestin1 pathway responsible for cutaneous flushing and other adverse effects [86]. Similarly, in kappa opioid receptors, activation of ERK signaling while retaining the G-protein signaling bias over β-arrestin2 pathway is effective in relieving pain without inducing adverse effects such as dysphoria, sedation, and diuresis associated with β-arrestin signaling [87,88]. The pharmacological profiles of specific ligands for other GPCRs, including dopamine [89], glucagon-like peptide [90], opioid [91], and angiotensin II [92] receptors, show selective activation of particular signaling pathway(s) that could potentially support a clinically relevant therapeutic effect vs. inciting other, deleterious signaling cascades.…”

Section: Pharmacotherapeutic Implications Of Biased Signaling At Cbrsmentioning

confidence: 99%

Functional selectivity at G-protein coupled receptors: Advancing cannabinoid receptors as drug targets

Mallipeddi

Janero

Zvonok

et al. 2017

Biochemical Pharmacology

View full text Add to dashboard Cite

The phenomenon of functional selectivity, whereby a ligand preferentially directs the information output of a G-protein coupled receptor (GPCR) along (a) particular effector pathway(s) and away from others, has redefined traditional GPCR signaling paradigms to provide a new approach to structure-based drug design. The two principal cannabinoid receptors (CBRs) 1 and 2 belong to the class-A GPCR subfamily and are considered tenable therapeutic targets for several indications. Yet conventional orthosteric ligands (agonists, antagonists/inverse agonists) for these receptors have had very limited clinical utility due to their propensity to incite on-target adverse events. Chemically distinct classes of cannabinergic ligands exhibit signaling bias at CBRs toward individual subsets of signal transduction pathways. In this review, we discuss the known signaling pathways regulated by CBRs and examine the current evidence for functional selectivity at CBRs in response to endogenous and exogenous cannabinergic ligands as biased agonists. We further discuss the receptor and ligand structural features allowing for selective activation of CBR-dependent functional responses. The design and development of biased ligands may offer a pathway to therapeutic success for novel CBR-targeted drugs.

show abstract

Section: Pharmacotherapeutic Implications Of Biased Signaling At Cbrsmentioning

confidence: 99%

Functional selectivity at G-protein coupled receptors: Advancing cannabinoid receptors as drug targets

Mallipeddi

Janero

Zvonok

et al. 2017

Biochemical Pharmacology

View full text Add to dashboard Cite

show abstract

“…Recent studies have suggested that the analgesic effects of KOR are mediated by G protein regulation of ion channels, including increased G protein gated potassium channel and decreased calcium channel conductance resulting in reduced neuronal excitability; whereas the aversive effects of KOR agonists require G protein-coupled receptor kinase 3 (GRK3)-dependent arrestin activation [5,6]. The concept that functionally selective agonists that preferentially activate one signaling cascade can be developed has re-energized opioid drug development [7,8]. Furthermore the hypothesis that a centrally active G protein biased KOR agonist that does not induce arrestin-dependent signaling might be a safer analgesic has stimulated the field [8,9].…”

Section: Introductionmentioning

confidence: 99%

Nalfurafine is a G-protein biased agonist having significantly greater bias at the human than rodent form of the kappa opioid receptor

Schattauer

Kuhar

Song

et al. 2017

Cellular Signalling

106

102

View full text Add to dashboard Cite

Nalfurafine is a moderately selective kappa opioid receptor (KOR) analgesic with low incidence of dysphoric side effects in clinical development for the treatment of uremic pruritis. The basis for its reduced dysphoric effect compared to other KOR agonists is not clear, but prior studies suggest that the aversive properties of KOR agonists require p38α MAPK activation through an arrestin-dependent mechanism. To determine whether nalfurafine is a functionally selective KOR agonist, we measured its potency to activate the G protein-dependent early phase of Extracellular Signal-Regulated Kinase (ERK1/2) phosphorylation and the arrestin-dependent late phase of p38 MAPK signaling. Nalfurafine was approximately 250 fold more potent for ERK1/2 activation as compared to p38 MAPK activation in human KOR (hKOR) expressing HEK293 cells, and approximately 20 fold more potent for ERK1/2 activation than p38 activation in rodent KOR (rKOR) expressing HEK293 cells. The 10-fold greater G-bias at the hKOR than rKOR was unexpected, however the G protein biased effect of nalfurafine is consistent with its reduced dysphoric effects in human and rodent models. Although nalfurafine is reported to have low receptor selectivity in radio ligand binding assays, its antinociceptive effect was blocked by the selective KOR antagonist norbinaltorphimine. Nalfurafine pretreatment also resulted in a KOR-dependent and mu opioid receptor-independent reduction in scratching induced by 5′-GNTI. These findings suggest that nalfurafine is a functionally selective KOR agonist and that KOR agonists able to selectively activate G protein signaling without activating p38α MAPK may have therapeutic potential as non-dysphoric antipruritic analgesics.

show abstract

“…Similar to prototypical kappa agonists, nalfurafine produces antinociception and diminishes the abuse-related effects of morphine in rodents and primates (Hasebe et al 2004; Ko and Husbands 2009). Additionally, nalfurafine has recently been shown to function as a G-protein-biased agonist at human and, to a lesser degree, rat kappa opioid receptors (Schattauer et al 2017), suggesting that the drug may produce fewer of the p38 MAPK-associated dysphoric effects than the relatively unbiased, traditional kappa agonists (see Dogra and Yadav 2015 for review). Based on these findings, nalfurafine may reduce the reinforcing effects of prescription opioids without causing untoward effects typical of traditional kappa agonists.…”

Section: Introductionmentioning

confidence: 99%

Effects of nalfurafine on the reinforcing, thermal antinociceptive, and respiratory-depressant effects of oxycodone: modeling an abuse-deterrent opioid analgesic in rats

et al. 2017

View full text Add to dashboard Cite

Rationale Strategies to reduce the misuse of mu opioid agonists are critically needed. Previous work has shown that kappa opioid agonists can diminish the abuse-related effects and augment the antinociceptive effects of mu agonists. However, use of traditional kappa agonists is limited by their dysphoric side effects. Objectives The current study examined the effects of nalfurafine, a clinically available atypical kappa agonist, on the reinforcing, thermal antinociceptive, and respiratory depressant effects of oxycodone in male rats. Methods To determine oxycodone:nalfurafine mixture proportions to be examined intravenously across procedures, a progressive-ratio (PR) self-administration procedure compared the reinforcing effects of oxycodone (56 μg/kg/inj) available alone or as a mixture with co-administered nalfurafine (0.32, 1, or 3.2 μg/kg/inj), corresponding to oxycodone:nalfurafine proportions of 175:1, 56:1 and 18:1, respectively. Next, PR and thermal antinociception dose-effect functions were each determined for oxycodone, nalfurafine, and the same oxycodone:nalfurafine mixture proportions. Finally, the respiratory depressant effects of equi-antinociceptive doses of oxycodone, nalfurafine, and the mixtures were compared. Results Nalfurafine decreased the reinforcing effects of oxycodone, and the 18:1 mixture did not function as a reinforcer. Oxycodone and nalfurafine each produced dose-dependent antinociception, and the mixtures produced additive antinociception. In addition, antinociceptive doses of the 56:1 and 18:1 mixtures did not produce respiratory depression. Conclusions These results suggest that nalfurafine may augment the thermal antinociceptive effects while reducing the reinforcing and respiratory depressant effects of oxycodone.

show abstract

Biased agonism at kappa opioid receptors: Implication in pain and mood disorders

Cited by 47 publications

References 92 publications

Functional selectivity at G-protein coupled receptors: Advancing cannabinoid receptors as drug targets

Functional selectivity at G-protein coupled receptors: Advancing cannabinoid receptors as drug targets

Nalfurafine is a G-protein biased agonist having significantly greater bias at the human than rodent form of the kappa opioid receptor

Effects of nalfurafine on the reinforcing, thermal antinociceptive, and respiratory-depressant effects of oxycodone: modeling an abuse-deterrent opioid analgesic in rats

Contact Info

Product

Resources

About