Facilitating mGluR4 activity reverses the long-term deleterious consequences of chronic morphine exposure

Background

Opiate addiction has become a growing problem in the developed countries, especially in the U.S. in the past decade [1], 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 [2]. Intracerebroventricular (i.c.v.) administration of a mGluR4 agonist had beneficial effects in rodent models of Parkinson’s disease (PD) [3], due to the inhibition of GABA release by indirect, D2 receptor-expressing medium spiny neurons (D2-MSNs) [3].

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.

 

Key findings

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

1. 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?
2. 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.

3. In a previous study, subtype‐selective mGluR antagonists attenuated the morphine withdrawal symptoms induced by naloxone in rats [6]. It would be great if you discuss this contradiction between the literature and your results.

 

 

References

 

1. 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.
2. 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.
3. Valenti, O., et al., Group III metabotropic glutamate receptor-mediated modulation of the striatopallidal synapse. J Neurosci, 2003. 23(18): p. 7218-26.
4. 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.
5. 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.
6. 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.

 

doi: https://doi.org/10.1242/prelights.23150

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