Neurokinin-1 receptor (NK1R) and delta-opioid receptor (DOR) (NK1R/DOR)

The Neurokinin-1 receptor (NK1R) and delta-opioid receptor (DOR) are G protein-coupled receptors (GPCRs) that play critical, often overlapping roles in the central and peripheral nervous systems. NK1R, encoded by the TACR1 gene, is the primary receptor for Substance P and is heavily involved in the transmission of pain, the vomiting reflex, and neurogenic inflammation (UniProt: P25103). The delta-opioid receptor, encoded by OPRD1, is part of the endogenous opioid system and modulates nociception, mood, and emotional responses (UniProt: P41143). Therapeutic strategies targeting both receptors simultaneously, often through bifunctional ligands, are being developed to treat chronic and neuropathic pain with improved efficacy and fewer side effects compared to traditional opioids (Lee et al., 2016). By antagonizing NK1R and activating DOR, these compounds can synergistically inhibit pain signaling while potentially avoiding the high abuse liability and respiratory depression associated with mu-opioid receptor agonists. Additionally, this dual-target approach is explored in the context of cancer, where NK1R signaling promotes tumor growth and DOR may influence cell proliferation. The interaction between these two pathways is significant because NK1R internalization can be modulated by opioid receptor activity, suggesting a functional crosstalk that can be exploited for drug design (PubMed: 15140414).

Other names

TACR1 and OPRD1Substance P receptor and Delta-type opioid receptorNK-1R and delta-opioid receptor

Dual modulation involving the antagonism of the Neurokinin-1 receptor to inhibit Substance P-mediated pro-nociceptive signaling and the agonism of the delta-opioid receptor to activate inhibitory antinociceptive pathways.