The Possible Role of MOPr-DOPr Heteromers and Its Regulatory Protein RTP4 at Sensory Neurons in Relation to Pain Perception

Abstract

Heteromers between mu opioid receptor (MOPr) and delta opioid receptor (DOPr) (i.e., MOPr-DOPr heteromer) have been found to be expressed in different brain regions, in the spinal cord, and in dorsal root ganglia. Recent studies on this heteromer reveal its important pathophysiological function in pain regulation including neuropathic pain; this suggests a role as a novel therapeutic target in chronic pain management. In addition, receptor transporter protein 4 (RTP4) has been shown to be involved in the intracellular maturation of the MOPr-DOPr heteromers. RTP4 appears to have unique distribution in vivo being highly expressed in sensory neurons and also macrophages; the latter are effector cells of the innate immune system that phagocytose foreign substances and secrete both pro-inflammatory and antimicrobial mediators; this suggests a possible contribution of RTP4 to neuronal immune-related pathological conditions such as neuropathic pain. Although RTP4 could be considered as an important therapeutic target in the management of pain via MOPr-DOPr heteromer, a few reports have supported this. This review will summarize the possible role or functions of the MOPr-DOPr heteromer and its regulatory molecule RTP4 in pain modulation at sensory neurons.

Nerve Growth Factor/Tyrosine Kinase A Receptor Pathway Enhances Analgesia in an Experimental Mouse Model of Bone Cancer Pain by Increasing Membrane Levels of δ-Opioid Receptors

“…8 DOR activation after nerve injury is associated with a protective function that limits nociceptive and affective manifestations of neuropathic pain, whereas MOR activation increases anxiety-like responses involving forebrain γ -aminobutyric acid-mediated neurons and enhances mechanical pain sensitivity, along with DOR expression and spinal cord gliosis in spared nerve injury mice. 9 In various models of chronic pain, DOR agonists have been shown to effectively inhibit inflammation and neuropathic pain 10,11 and may even reduce drug tolerance to MOR agonists. 12 Because DORs are primarily located in the cytoplasm, 13 DOR expression, trafficking, and membrane localization may contribute to their role in alleviating chronic inflammation and neuropathic pain.…”

“…In various models of chronic pain, DOR agonists have been shown to effectively inhibit inflammation and neuropathic pain 10,11 and may even reduce drug tolerance to MOR agonists. 12 Because DORs are primarily located in the cytoplasm, 13 DOR expression, trafficking, and membrane localization may contribute to their role in alleviating chronic inflammation and neuropathic pain.…”

Restriction of SARS-CoV-2 replication by receptor transporter protein 4 (RTP4)

“…In humans, RTP4 belongs to a gene family consisting of four members (RTP1, RTP2, RTP3, and RTP4) that serve as chaperones that facilitate the transport of G protein-coupled receptors to the plasma membrane ( 37 - 39 ). RTP1 and RTP2 are specifically expressed on olfactory neurons where they are involved in the functional expression of odorant receptors ( 39 - 42 ), while RTP3 and RTP4 colocalize with bitter taste receptors ( 43 ) and serve to regulate opioid and taste receptors ( 43 ). Human RTP4 (hRTP4) is a widely expressed ( 7 , 44 , 45 ) 247 amino acid protein consisting of an amino-terminal (N-terminal) zinc finger domain (ZFD), an intrinsic disordered variable region and a single carboxy-terminal (C-terminal) transmembrane domain (TM).…”