Challenges and new opportunities for detecting endogenous opioid peptides in reward

Conway, Sineadh M.; Mikati, Marwa O.; Al‐Hasani, Ream

doi:10.1016/j.addicn.2022.100016

Cited by 13 publications

(15 citation statements)

References 107 publications

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“…Here we describe the engineering, characterization, and application of a novel geneticallyencoded sensor (NOPLight) for monitoring the opioid neuropeptide N/OFQ in vitro, ex vivo, and in vivo. Endogenous opioid peptides represent one of the largest classes of neuropeptide families, yet detecting their release, dynamics, and properties in vitro and in vivo has been a challenge for over 60 years since their discovery [57][58][59] . We sought to develop a sensor which could detect: 1) evoked release, 2) endogenous release during naturalistic behavior, and 3) exogenous ligands in vivo to inform brain localization of pharmacological agents.…”

Section: Discussionmentioning

confidence: 99%

Development of a genetically encoded sensor for probing endogenous nociceptin opioid peptide release

Zhou

Stine

Prada

et al. 2023

Preprint

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Nociceptin/orphanin-FQ (N/OFQ) is a recently appreciated critical opioid peptide with key regulatory functions in several central behavioral processes including motivation, stress, feeding, and sleep. The functional relevance of N/OFQ action in the mammalian brain remains unclear due to a lack of high-resolution approaches to detect this neuropeptide with appropriate spatial and temporal resolution. Here we develop and characterize NOPLight, a genetically encoded sensor that sensitively reports changes in endogenous N/OFQ release. We characterized the affinity, pharmacological profile, spectral properties, kinetics, ligand selectivity, and potential interaction with intracellular signal transducers of NOPLight in vitro. Its functionality was established in acute brain slices by exogeneous N/OFQ application and chemogenetic induction of endogenous N/OFQ release from PNOC neurons. In vivo studies with fiber photometry enabled a direct recording of binding by N/OFQ receptor ligands, as well as the detection of natural or chemogenetically-evoked endogenous N/OFQ release within the paranigral ventral tegmental area (pnVTA). In summary, we show that NOPLight can be used to detect N/OFQ opioid peptide signal dynamics in tissue and freely-behaving animals.

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Section: Discussionmentioning

confidence: 99%

Development of a genetically encoded sensor for probing endogenous nociceptin opioid peptide release

Zhou

Stine

Prada

et al. 2023

Preprint

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“…Exogenous CART(62-76) inhibits carrageenan-induced hyperalgesia, which can be decreased by CTAP and eliminated by general opioid or KOR specific antagonists. Endogenous opioid peptides (except for nociceptin) share a common N-terminal tyrosine-glycine-glycine-phenylalanine amino acid sequence [ 73 ], bind to TLR4, and non-stereoselectively activate TLR4 signalling [ 74 ]. Although the first two amino acids of the N-terminal region of CART(62-76) are tyrosine-glycine, we showed that this CART fragment has no affinity to specific opioid receptors.…”

Section: Discussionmentioning

confidence: 99%

Unique, Specific CART Receptor-Independent Regulatory Mechanism of CART(55-102) Peptide in Spinal Nociceptive Transmission and Its Relation to Dipeptidyl-Peptidase 4 (DDP4)

Kozsurek

Király

Gyimesi

et al. 2023

IJMS

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Cocaine- and amphetamine-regulated transcript (CART) peptides are involved in several physiological and pathological processes, but their mechanism of action is unrevealed due to the lack of identified receptor(s). We provided evidence for the antihyperalgesic effect of CART(55-102) by inhibiting dipeptidyl-peptidase 4 (DPP4) in astrocytes and consequently reducing neuroinflammation in the rat spinal dorsal horn in a carrageenan-evoked inflammation model. Both naturally occurring CART(55-102) and CART(62-102) peptides are present in the spinal cord. CART(55-102) is not involved in acute nociception but regulates spinal pain transmission during peripheral inflammation. While the full-length peptide with a globular motif contributes to hyperalgesia, its N-terminal inhibits this process. Although the anti-hyperalgesic effects of CART(55-102), CART(55-76), and CART(62-76) are blocked by opioid receptor antagonists in our inflammatory models, but not in neuropathic Seltzer model, none of them bind to any opioid or G-protein coupled receptors. DPP4 interacts with Toll-like receptor 4 (TLR4) signalling in spinal astrocytes and enhances the TLR4-induced expression of interleukin-6 and tumour necrosis factor alpha contributing to inflammatory pain. Depending on the state of inflammation, CART(55-102) is processed in the spinal cord, resulting in the generation of biologically active isoleucine-proline-isoleucine (IPI) tripeptide, which inhibits DPP4, leading to significantly decreased glia-derived cytokine production and hyperalgesia.

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“…The studies described in this review used a multitude of techniques to probe the role of enkephalin, and each technique has limitations that can influence interpretations of results. Limitations of enkephalin measurement techniques (Conway et al, 2022) are due, in part, to the complexity of the endogenous enkephalinergic system. Opioid peptides are highly homologous peptides that are rapidly degraded and bind to multiple opioid receptor types.…”

Section: Discussionmentioning

confidence: 99%

“…There are different methods and techniques to evaluate enkephalinergic involvement in reward-related pathways and behaviors. Methods for measuring enkephalin release are limited (for review, see: Conway et al, 2022); therefore, studies often measure enkephalin concentrations in various brain regions as indirect measures of releasable peptide or a releasable pools. Peptide expression and release are likely related, such that if there is increased peptide synthesized, packaged in vesicles, and available for release (intracellular expression), then more peptide is actually released (either tonically or during stimulated release).…”

Section: Methods Used To Evaluate Enkephalinmentioning

confidence: 99%

The role of enkephalinergic systems in substance use disorders

Rysztak

Jutkiewicz

2022

Front. Syst. Neurosci.

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Enkephalin, an endogenous opioid peptide, is highly expressed in the reward pathway and may modulate neurotransmission to regulate reward-related behaviors, such as drug-taking and drug-seeking behaviors. Drugs of abuse also directly increase enkephalin in this pathway, yet it is unknown whether or not changes in the enkephalinergic system after drug administration mediate any specific behaviors. The use of animal models of substance use disorders (SUDs) concurrently with pharmacological, genetic, and molecular tools has allowed researchers to directly investigate the role of enkephalin in promoting these behaviors. In this review, we explore neurochemical mechanisms by which enkephalin levels and enkephalin-mediated signaling are altered by drug administration and interrogate the contribution of enkephalin systems to SUDs. Studies manipulating the receptors that enkephalin targets (e.g., mu and delta opioid receptors mainly) implicate the endogenous opioid peptide in drug-induced neuroadaptations and reward-related behaviors; however, further studies will need to confirm the role of enkephalin directly. Overall, these findings suggest that the enkephalinergic system is involved in multiple aspects of SUDs, such as the primary reinforcing properties of drugs, conditioned reinforcing effects, and sensitization. The idea of dopaminergic-opioidergic interactions in these behaviors remains relatively novel and warrants further research. Continuing work to elucidate the role of enkephalin in mediating neurotransmission in reward circuitry driving behaviors related to SUDs remains crucial.

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Challenges and new opportunities for detecting endogenous opioid peptides in reward

Cited by 13 publications

References 107 publications

Development of a genetically encoded sensor for probing endogenous nociceptin opioid peptide release

Development of a genetically encoded sensor for probing endogenous nociceptin opioid peptide release

Unique, Specific CART Receptor-Independent Regulatory Mechanism of CART(55-102) Peptide in Spinal Nociceptive Transmission and Its Relation to Dipeptidyl-Peptidase 4 (DDP4)

The role of enkephalinergic systems in substance use disorders

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