Contribution of mu and delta opioid receptors to the pharmacological profile of kappa opioid receptor subtypes

Abstract

Molecular cloning has identified three opioid receptors: mu (MOR), delta (DOR) and kappa (KOR). Yet, cloning of these receptor types has offered little clarification to the diverse pharmacological profiles seen within the growing number of novel opioid ligands, which has led to the proposal of multiple subtypes. In the present study, utilizing in vitro and in vivo methods including the use of opioid receptor knockout mice, we find that certain antinociceptive effects of the KOR-1 and KOR-2 subtype-selective ligands (+)-(5α,7α,8β)-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-benzene-acetamide (U69, 593) and 4-[(3,4-Dichlorophenyl)acetyl]-3-(1-pyrrolidinylmethyl)-1-piperazine-carboxylic acid methyl ester fumarate (GR89, 696), respectively, are potentiated by antagonism of MOR and DOR receptors. We believe that our findings can be best explained by the existence of KOR-DOR and KOR-MOR heteromers. We only find evidence for the existence of these heteromers in neurons mediating mechanical nociception, but not thermal nociception. These findings have important clinical ramifications as they reveal new drug targets that may provide avenues for more effective pain therapies.

Role of endogenous opioid peptides in the infarct size-limiting effect of adaptation to chronic continuous hypoxia

“…Transactivation of G-protein coupled receptors can occur via their heterodimerization on cell membrane that is a formation of a complex of two receptors (Rediger et al, 2009;Pasternak and Pan, 2011). Such heterodimers can be formed between various types of receptors including μ-and δ-ORs (Law et al, 2005;Décaillot et al, 2008;Liu et al, 2009;Kabli et al, 2010;Sarkar et al, 2012) or κ-and δ-ORs (Ansonoff et al, 2010;Brissett et al, 2012). It has been shown, for example, that selective blocking of δ-OR in HEK293 cells co-expressed both μ-and δ-ORs promotes transinhibition of μ-OR via interaction of δ-OR antagonist with μ-δ-OR heterodimer (Yekkirala et al, 2012).…”

A Review of the Therapeutic Potential of Recently Developed G Protein-Biased Kappa Agonists

“…In 2012, using BRET assays, Rives et al (2012) found that 6′-GNTI is a partial G protein agonist (Table 1), with no detectable β-arrestin 2 recruitment. The κOR agonist GR89,696 has been suggested to also interact with κOR-δOR heteromers (Brissett et al, 2012), however, in contrast to 6′-GNTI, GR89,696 reportedly displays β-arrestin2 bias (White et al, 2014), giving pause to a hypothesis that the κOR-δOR heteromer adopts a G protein biased conformation. Similar to HS666, 6′GNTI was not significantly aversive in male C57BL/6 mice in the CPA paradigm, nor was it sedative (Zangrandi et al, 2016).…”

Comprehensive overview of biased pharmacology at the opioid receptors: biased ligands and bias factors

“…206 It had also been suggested that GR89696 could interact with KOR/DOR heterodimers to mediate antinociception. 223 A bias factor for GR89696 of 0.67 towards β-arrestin-2 was calculated by White et al (Sal A as a reference ligand, using the operational model for quantification; Equation 2) which produces an unfavorable bias for GR89696, 200 which was also reported by Kenakin et al 224 6. U50,488 U50,488 is a compound developed by Van Voigtlander et al in the search for opioid analgesics.…”