Inhibition of the phosphoinositide 3-kinase-AKT-cyclic GMP-c-Jun N-terminal kinase signaling pathway attenuates the development of morphine tolerance in a mouse model of neuropathic pain

Okerman, Travis; Jurgenson, Taylor; Moore, Mackenzie; Klein, Amanda H.

doi:10.1177/17448069211003375

Cited by 9 publications

(10 citation statements)

References 15 publications

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“…The gamma catalytic subunit of PIK3 is upregulated by morphine in the periaqueductal gray matter and is involved in morphine‐induced antinociception (Narita et al, 2004) and the development of morphine tolerance (Okerman et al, 2021). In cardiomyocytes, the Pik3 has been involved in opioid‐induced decrease in apoptosis (Yao et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Methadone administered to rat dams during pregnancy and lactation affects the circadian rhythms of their pups

Pačesová

Spišská

Novotný

et al. 2023

J of Neuroscience Research

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The circadian clock is one of the most important homeostatic systems regulating the majority of physiological functions. Its proper development contributes significantly to the maintenance of health in adulthood. Methadone is recommended for the treatment of opioid use disorders during pregnancy, increasing the number of children prenatally exposed to long‐acting opioids. Although early‐life opioid exposure has been studied for a number of behavioral and physiological changes observed later in life, information on the relationship between the effects of methadone exposure and circadian system development is lacking. Using a rat model, we investigated the effects of prenatal and early postnatal methadone administration on the maturation of the circadian clockwork in the suprachiasmatic nucleus (SCN) and liver, the rhythm of aralkylamine N‐acetyltransferase (AA‐NAT) activity in the pineal gland, and gene expression in the livers of 20‐day‐old rats. Our data show that repeated administration of methadone to pregnant and lactating mothers has significant effect on rhythmic gene expression in the SCN and livers and on the rhythm of AA‐NAT in the offspring. Similar to previous studies with morphine, the rhythm amplitudes of the clock genes in the SCN and liver were unchanged or enhanced. However, six of seven specific genes in the liver showed significant downregulation of their expression, compared to the controls in at least one experimental group. Importantly, the amplitude of the AA‐NAT rhythm was significantly reduced in all methadone‐treated groups. As there is a strong correlation with melatonin levels, this result could be of importance for clinical practice.

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Section: Discussionmentioning

confidence: 99%

Methadone administered to rat dams during pregnancy and lactation affects the circadian rhythms of their pups

Pačesová

Spišská

Novotný

et al. 2023

J of Neuroscience Research

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Section: Discussionmentioning

confidence: 99%

“…59 KEGG analysis suggested MAPK signaling pathway, PI3K-Akt signaling pathway, ECM-receptor interaction, and gap junction were enriched, which were related to neuropathic pain. 52,60,61 CircRNAs are non-coding RNAs with covalently closed circular structures with 5' and 3' ends. The sequences of circRNAs are conserved among mammalian species and have higher stability than liner mRNAs because the particular ring structure enables them to escape from RNase degradation.…”

Section: Discussionmentioning

confidence: 99%

Interactions Among Non-Coding RNAs and mRNAs in the Trigeminal Ganglion Associated with Neuropathic Pain

Fang¹,

Liao²,

Tang³

et al. 2022

JPR

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Background Recent studies have demonstrated the contribution of non-coding RNAs (ncRNAs) to neuropathic pain. However, the expression profile of ncRNAs in the trigeminal ganglion (TG) and their functional mechanism underlying trigeminal neuropathic pain are still unclear. Methods In the present study, the trigeminal neuropathic pain model induced by chronic constriction injury of the infraorbital nerve (CCI-ION) was used to study the expression profile and potential regulatory mechanism of miRNAs, lncRNAs, circRNAs, and mRNAs in the TG by RNA-sequencing (RNA-seq) and bioinformatics analysis. CCI-ION mice suffered from mechanical allodynia from 3 days to 28 days after surgery. Results The RNA-seq results discovered 67 miRNAs, 216 lncRNAs, 14 circRNAs, 595 mRNAs, and 421 genes were differentially expressed (DE) in the TG of CCI-ION mice 7 days after surgery. And 39 DEGs were known pain genes. Besides, 5 and 35 pain-related DE mRNAs could be targeted by 6 DE miRNAs and 107 DE lncRNAs, respectively. And 23 pain-related DEGs had protein–protein interactions (PPI) with each other. GO analysis indicated membrane-related cell components and binding-related molecular functions were significantly enriched. KEGG analysis showed that nociception-related signaling pathways were significantly enriched for DE ncRNAs and DEGs. Finally, the competing endogenous RNA (ceRNA) regulatory network of DE lncRNA/DE circRNA-DE miRNA-DE mRNA existed in the TG of mice with trigeminal neuropathic pain. Conclusion Our findings demonstrate ncRNAs are involved in the development of trigeminal neuropathic pain, possibly through the ceRNA mechanism, which brings a new bright into the study of trigeminal neuropathic pain and the development of novel treatments targeting ncRNAs.

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“…Despite this, morphine-mediated changes in metabolites could also influence tolerance development, but there is paucity of information about the impact of morphine administration on plasma metabolites following chronic or acute use in the context of morphine tolerance [ 23 , 24 ]. Various rodent models of morphine tolerance were developed, such as subcutaneous or intraperitoneal injection of morphine for 4–14 days [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ] and morphine pellet implantation [ 25 , 33 , 34 , 35 ]. C57/6B mice were subjected to a well-established tolerance regimen in which mice were subcutaneously administered either saline or morphine for 4 days.…”

Section: Introductionmentioning

confidence: 99%

Changes in Plasma Metabolic Signature upon Acute and Chronic Morphine Administration in Morphine-Tolerant Mice

Kutchy

Palermo

et al. 2023

Metabolites

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Morphine administration causes system-level metabolic changes. Here, we show that morphine-tolerant mice exhibited distinct plasma metabolic signatures upon acute and chronic administration. We utilized a mouse model of morphine tolerance by exposing mice to increasing doses of the drug over 4 days. We collected plasma samples from mice undergoing acute or chronic morphine or saline injections and analyzed them using targeted GC–MS-based metabolomics to profile approximately 80 metabolites involved in the central carbon, amino acid, nucleotide, and lipid metabolism. Our findings reveal distinct alterations in plasma metabolite concentrations in response to acute or chronic morphine intake, and these changes were linked to the development of tolerance to morphine’s analgesic effects. We identified several metabolites that had been differentially affected by acute versus chronic morphine use, suggesting that metabolic changes may be mitigated by prolonged exposure to the drug. Morphine-tolerant mice showed a restoration of amino acid and glycolytic metabolites. Additionally, we conducted reconstructed metabolic network analysis on the first 30 VIP-ranked metabolites from the PLSDA of the saline, acute, and morphine-tolerant mice groups, which uncovered four interaction networks involving the amino acid metabolism, the TCA cycle, the glutamine-phenylalanine-tyrosine pathway, and glycolysis. These pathways were responsible for the metabolic differences observed following distinct morphine administration regimens. Overall, this study provides a valuable resource for future investigations into the role of metabolites in morphine-induced analgesia and associated effects following acute or chronic use in mice.

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Inhibition of the phosphoinositide 3-kinase-AKT-cyclic GMP-c-Jun N-terminal kinase signaling pathway attenuates the development of morphine tolerance in a mouse model of neuropathic pain

Cited by 9 publications

References 15 publications

Methadone administered to rat dams during pregnancy and lactation affects the circadian rhythms of their pups

Methadone administered to rat dams during pregnancy and lactation affects the circadian rhythms of their pups

Interactions Among Non-Coding RNAs and mRNAs in the Trigeminal Ganglion Associated with Neuropathic Pain

Changes in Plasma Metabolic Signature upon Acute and Chronic Morphine Administration in Morphine-Tolerant Mice

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