Facilitating mGluR4 activity reverses the long-term deleterious consequences of chronic morphine exposure
Preprint posted on 29 June 2020 https://www.biorxiv.org/content/10.1101/2020.06.27.174771v1
Article now published in Neuropsychopharmacology at http://dx.doi.org/10.1038/s41386-020-00927-x
Opiate addiction has become a growing problem in the developed countries, especially in the U.S. in the past decade , thus, the development of novel drugs preventing relapses are highly desired. Animal studies are still indispensable parts of the discovery of novel targets for treating morphine dependence.
In previous animal studies, the potential therapeutic actions of metabotropic glutamate receptor subtype 4 (mGluR4, product of Grm4 gene) agonists were reported. For example, the activation of mGluR4 proved to be a promising approach to attenuate the behavioral deficits in mu opioid receptor (Oprm1) knock-out mice, a model of autism . Intracerebroventricular (i.c.v.) administration of a mGluR4 agonist had beneficial effects in rodent models of Parkinson’s disease (PD) , due to the inhibition of GABA release by indirect, D2 receptor-expressing medium spiny neurons (D2-MSNs) .
The aim of the discussed preprint was to clarify if the facilitation of mGluR4 activity could alleviate the detrimental effects of chronic morphine and cocaine treatment in mice.
Very different transcriptional changes are involved in morphine and cocaine abstinence
In the present work, mice were intraperitoneally (i.p.) injected twice daily with saline or morphine or cocaine. After the 3 weeks’ drug-free period, the chronic daily treatment with saline or VU0155041 (partial agonist and positive allosteric modulator of mGluR4) was started. Mice were treated with saline or VU0155041 for 18 days.
The expression of 76 genes were evaluated in four regions, caudate putamen (CPu), central amygdala (CeA), nucleus accumbens (NAc), and bed nucleus of the stria terminalis (BNST).
The mRNA transcription pattern of these genes were highly different between cocaine and morphine abstinent mice, especially in the CPu. In the CPu, NAc and CeA. Huntingtin (HTT)-related genes were up-regulated or unaffected under chronic cocaine exposure whilst their expression was down-regulated in morphine abstinent mice.
Four marker genes (Arpp21, Pde10a, Hpca and Grm4) of MSNs were down-regulated after chronic morphine, but not chronic cocaine exposure. The authors then presumed that the activation of mGluR4 might also reverse the undesired behavioral actions of morphine withdrawal in mice as well.
Behavioral effects of mGluR4 agonist VU0155041 in morphine abstinent mice
Morphine abstinent mice showed a marked deficit in the direct social interaction test (e.g. time in nose contact, number of nose contacts, etc.) and three chamber test compared with vehicle-treated groups. These deficits were fully reversed by 5mg/kg VU0155041. Both 2.5 and 5 mg/kg VU0155041 normalized the latency to eat in the arena and food intake of morphine abstinent mice in the novelty-suppressed feeding test.
Mild hyperalgesia was detected in the morphine abstinent group, in the tail immersion test. VU0155041 had a significant analgesic effect in morphine abstinent mice, but not in vehicle-treated and cocaine abstinent mice.
Transcriptional changes evoked by VU0155041 in the NAc, CeA, CPu
Altogether, mRNA levels of 36 candidate genes (markers of HTT, oxytocin/vasopressin system, striatal MSNs) were measured. In line with the social interaction data, the mRNA expression of Bdnf and 3 out of 4 marker genes of MSNs, including Grm4 were restored after VU0155041 treatment. Overall, VU0155041 successfully reversed the transcriptional changes evoked by morphine abstinence, mainly in the CPu and NAc.
Why I liked this preprint
Pharmaceutical products containing morphine are indispensable in postoperative pain management. In this study, several in vivo behavioral methods were applied to support the transcriptional data. Route of administration of a novel drug is a critical aspect of the assessment of future applications. VU0155041 proved to be effective in treatment of morphine withdrawal in mice via i.p., not i.c.v. injection, therefore, it could be a promising molecule for translational medicine.
Questions for the authors
- Several behavioral tests were performed for this work, which is great, but anxiety-like behavior of mice were assessed by novelty-suppressed feeding test only. My question is, why were elevated plus maze and open-field, the widely accepted methods not applied to assess anxiety-like behavior of mice?
- VU0155041 demonstrated analgesic effect in morphine abstinent mice, but only at 48 o. I think an explanation or hypothesis should be inserted, why VU0155041 was not effective at 50 oC and 52 oC. Moreover, I did not find this 3-different-temperature-approach in the original studies, which was done by researchers who developed tail immersion test for mice [4, 5]. I think the tissue damage and inflammation which is evoked by the first session at 48 oC might have an influence on the second and third session, 50 oC and 52 oC.
- In a previous study, subtype‐selective mGluR antagonists attenuated the morphine withdrawal symptoms induced by naloxone in rats . It would be great if you discuss this contradiction between the literature and your results.
- Kertesz, S.G. and A.J. Gordon, A crisis of opioids and the limits of prescription control: United States. Addiction, 2019. 114(1): p. 169-180.
- Becker, J.A., et al., Autistic-like syndrome in mu opioid receptor null mice is relieved by facilitated mGluR4 activity. Neuropsychopharmacology, 2014. 39(9): p. 2049-60.
- Valenti, O., et al., Group III metabotropic glutamate receptor-mediated modulation of the striatopallidal synapse. J Neurosci, 2003. 23(18): p. 7218-26.
- Sewell, R.D.E. and P.S.J. Spencer, Antinociceptive Activity of Narcotic Agonist and Partial Agonist Analgesics and Other Agents in Tail-Immersion Test in Mice and Rats. Neuropharmacology, 1976. 15(11): p. 683-688.
- Sewell, R.D. and P.S. Spencer, Proceedings: Modification of the antinociceptive activity of narcotic agonists and antagonists by intraventricular injection of biogenic amines in mice. Br J Pharmacol, 1974. 51(1): p. 140P-141P.
- Fundytus, M.E., J. Ritchie, and T.J. Coderre, Attenuation of morphine withdrawal symptoms by subtype-selective metabotropic glutamate receptor antagonists. Br J Pharmacol, 1997. 120(6): p. 1015-20.
Posted on: 16 July 2020 , updated on: 25 January 2021Read preprint
Also in the animal behavior and cognition category:
The unique synaptic circuitry of specialized olfactory glomeruli in Drosophila melanogaster
Subchronic alteration of vestibular hair cells in mice: implications for multisensory gaze stabilization
Sucrose overconsumption impairs feeding circuit dynamics and promotes palatable food intake
Also in the biochemistry category:
Glutamate helps unmask the differences in driving forces for phase separation versus clustering of FET family proteins in sub-saturated solutions
Mechano-dependent sorbitol accumulation supports biomolecular condensate
Proteasome condensate formation is driven by multivalent interactions with shuttle factors and K48-linked ubiquitin chains
preListsanimal behavior and cognition category:in the
9th International Symposium on the Biology of Vertebrate Sex Determination
This preList contains preprints discussed during the 9th International Symposium on the Biology of Vertebrate Sex Determination. This conference was held in Kona, Hawaii from April 17th to 21st 2023.
|List by||Martin Estermann|
A list of preprints dealing with the ecology, evolution and behavior of bats
|List by||Baheerathan Murugavel|
A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020
|List by||Ana Dorrego-Rivas|
Also in the biochemistry category:
Preprint Peer Review – Biochemistry Course at UFRJ, Brazil
Communication of scientific knowledge has changed dramatically in recent decades and the public perception of scientific discoveries depends on the peer review process of articles published in scientific journals. Preprints are key vehicles for the dissemination of scientific discoveries, but they are still not properly recognized by the scientific community since peer review is very limited. On the other hand, peer review is very heterogeneous and a fundamental aspect to improve it is to train young scientists on how to think critically and how to evaluate scientific knowledge in a professional way. Thus, this course aims to: i) train students on how to perform peer review of scientific manuscripts in a professional manner; ii) develop students' critical thinking; iii) contribute to the appreciation of preprints as important vehicles for the dissemination of scientific knowledge without restrictions; iv) contribute to the development of students' curricula, as their opinions will be published and indexed on the preLights platform. The evaluations will be based on qualitative analyses of the oral presentations of preprints in the field of biochemistry deposited in the bioRxiv server, of the critical reports written by the students, as well as of the participation of the students during the preprints discussions.
|List by||Marcus Oliveira|
CellBio 2022 – An ASCB/EMBO Meeting
This preLists features preprints that were discussed and presented during the CellBio 2022 meeting in Washington, DC in December 2022.
|List by||Nadja Hümpfer et al.|
20th “Genetics Workshops in Hungary”, Szeged (25th, September)
In this annual conference, Hungarian geneticists, biochemists and biotechnologists presented their works. Link: http://group.szbk.u-szeged.hu/minikonf/archive/prg2021.pdf
|List by||Nándor Lipták|
The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!
|List by||Osvaldo Contreras|
ASCB EMBO Annual Meeting 2019
A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)
|List by||Madhuja Samaddar et al.|
EMBL Seeing is Believing – Imaging the Molecular Processes of Life
Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019
|List by||Dey Lab|
A curated list of preprints related to cellular metabolism at Biorxiv by Pablo Ranea Robles from the Prelights community. Special interest on lipid metabolism, peroxisomes and mitochondria.
|List by||Pablo Ranea Robles|
This list of preprints is focused on work expanding our knowledge on mitochondria in any organism, tissue or cell type, from the normal biology to the pathology.
|List by||Sandra Franco Iborra|