Crosstalk between Opioid and Anti-Opioid Systems: An Overview and Its Possible Therapeutic Significance

Abstract

Opioid peptides and receptors are broadly expressed throughout peripheral and central nervous systems and have been the subject of intense long-term investigations. Such studies indicate that some endogenous neuropeptides, called anti-opioids, participate in a homeostatic system that tends to reduce the effects of endogenous and exogenous opioids. Anti-opioid properties have been attributed to various peptides, including melanocyte inhibiting factor (MIF)-related peptides, cholecystokinin (CCK), nociceptin/orphanin FQ (N/OFQ), and neuropeptide FF (NPFF). These peptides counteract some of the acute effects of opioids, and therefore, they are involved in the development of opioid tolerance and addiction. In this work, the anti-opioid profile of endogenous peptides was described, mainly taking into account their inhibitory influence on opioid-induced effects. However, the anti-opioid peptides demonstrated complex properties and could show opioid-like as well as anti-opioid effects. The aim of this review is to detail the phenomenon of crosstalk taking place between opioid and anti-opioid systems at the in vivo pharmacological level and to propose a cellular and molecular basis for these interactions. A better knowledge of these mechanisms has potential therapeutic interest for the control of opioid functions, notably for alleviating pain and/or for the treatment of opioid abuse.

Exploring pharmacological inhibition of Gq/11 as an analgesic strategy

“…One attractive area with significant potential for explaining how routing of μ receptor signals can be biased is its signalling crosstalk with other receptor systems that converge on common effectors to allow differential programming of cellular responses. Several signalling systems impacting processing of μ receptor signals and in vivo opioid actions have been described (Gibula‐Tarlowska & Kotlinska, 2020 ). Interestingly, studying one of these systems, we found that blockade of the G q/11 ‐coupled orphan receptor GPR139 exerted augmentation of opioid signalling via the μ receptor and dissociated analgesia from withdrawal at the behavioural level (Wang et al, 2019 ).…”

Transcriptomic Changes in Mouse Bone Marrow-Derived Macrophages Exposed to Neuropeptide FF

“…NPFF affected the opioid signaling pathway ( Figure 6 A), which provided clues to the reported regulation of opioid analgesic activity by the NPFF system [ 58 , 59 ]; NPFF inhibited osteoclast activity ( Figure 6 A), which was consistent with the report that NPFF suppresses the differentiation of monocytes into osteoclasts [ 60 , 61 ]; NPFF regulated fatty acid metabolism ( Figure 6 C), which provided basis for the modulatory function of NPFF on lipid metabolism [ 22 ]; NPFF adjusted the cell checkpoints of macrophages ( Figure 6 E), which was consistent with the recent study that NPFF modulates the cell checkpoints-related gene ( PDL1 ) of RAW 264.7 macrophages [ 33 ]; NPFF modulated the Toll-like receptor signaling pathway ( Figure 6 B and Figure 7 C), which might explain the previous report that NPFF inhibits the TLR4-induced inflammatory response of macrophages [ 31 , 32 ]. Besides, NPFF regulated the nitric oxide signaling pathway of macrophages ( Figure 7 A), which might provide a basis for the previous report that NPFF suppresses the nitric oxide level of macrophages [ 31 , 32 ].…”

The Potential of Methocinnamox as a Future Treatment for Opioid Use Disorder: A Narrative Review

“…MOR, KOR and DOR belong to the largest membrane receptor family called the trimeric GPCR superfamily. Opioids activate the inhibitory (Gi) signaling pathway to initiate analgesic functions [ 54 , 55 , 56 , 57 ]. GPCRs are known for their trimeric subunits consisting of alpha (Gα), beta (Gβ), and gamma (Gγ) [ 58 ].…”