Chronic Morphine Induces IL-18 in Ileum Myenteric Plexus Neurons Through Mu-opioid Receptor Activation in Cholinergic and VIPergic Neurons

Muchhala, Karan H.; Köşeli, Eda; Gade, Aravind R; Woods, Kareem; Minai, S.; Kang, Minho; McQuiston, A. Rory; Dewey, William L.; Akbarali, Hamid I.

doi:10.1007/s11481-021-10050-3

Cited by 6 publications

(9 citation statements)

References 57 publications

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“…Many of these genera have been shown to improve gut integrity and inversely correlate with inflammatory conditions such as inflammatory bowel disease, cardio-metabolic diseases, and neurobiological or neurodegenerative conditions 110,111,113,119,130,137,176,[182][183][184][185][186][187] . The replication of protection from tolerance by diet supplementation of butyrate alone (Figure 6) suggests a mechanism by which the identified taxa could exert their effects and could explain why differential loss of such community members could lead to cytokine-directed inflammation that is a suggested cause of opioid-induced hyperalgesia and tolerance 19,38,41,175 (Supplemental Figure 14), though it does not dictate that other mechanisms are not at play. One possibility is that butyrate palliatively countered the reduced analgesic benefits of morphine as tolerance developed by changing the threshold of pain perception by attenuating inflammation, thereby preventing pain sensitization of nociceptor neurons, rather than preventing homeostatic adaptations from occurring 41,188 (Figure 7; Supplemental Figure 14).…”

Section: Discussionmentioning

confidence: 99%

Gut dysbiosis was inevitable, but tolerance was not: temporal responses of the murine microbiota that maintain its capacity for butyrate production correlate with sustained antinociception to chronic voluntary morphine

Sall,

Foxall,

Felth

et al. 2024

Preprint

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The therapeutic benefits of opioids are compromised by the development of analgesic tolerance, which necessitates higher dosing for pain management thereby increasing the liability for dependence and addiction. Rodent models indicate opposing roles of the gut microbiota in tolerance: morphine-induced gut dysbiosis exacerbates tolerance, whereas probiotics ameliorate tolerance. Not all individuals develop tolerance which could be influenced by differences in microbiota, and yet no study has capitalized upon this natural variation to identify specific features linked to tolerance. We leveraged this natural variation in a murine model of voluntary oral morphine self-administration to elucidate the mechanisms by which microbiota influences tolerance. Although all mice shared similar and predictive morphine-driven microbiota changes that largely masked informative associations with variability in tolerance, our high-resolution temporal analyses revealed a divergence in the progression of dysbiosis that best explained differences in the development in tolerance. Mice that did not develop tolerance also maintained a higher abundance of taxa capable of producing the short-chain fatty acid (SCFA) butyrate, known to bolster intestinal barriers, suppress inflammation, and promote neuronal homeostasis. Furthermore, dietary butyrate supplementation significantly reduced the development of tolerance. These findings could inform immediate therapies to extend the analgesic efficacy of opioids.

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Section: Discussionmentioning

confidence: 99%

Gut dysbiosis was inevitable, but tolerance was not: temporal responses of the murine microbiota that maintain its capacity for butyrate production correlate with sustained antinociception to chronic voluntary morphine

Sall,

Foxall,

Felth

et al. 2024

Preprint

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Section: Discussionmentioning

confidence: 99%

“…Approximately half of the μ-opioid receptor-expressing neurons in the enteric nervous system are cholinergic 25,34 . A subset of μ-opioid receptor-containing neurons also expresses the inhibitory neurotransmitter, vasoactive intestinal peptide (VIP) 25,34 . VIPergic neurons have been shown to regulate the activity of intestinal epithelial cells via crosstalk with innate lymphoid cells, ILC2, and ILC3 [36][37][38] .…”

Section: Discussionmentioning

confidence: 99%

The Role of Morphine-Induced Impairment of Intestinal Epithelial Antibacterial Activity in Dysbiosis and its Impact on the Microbiota-Gut-Brain Axis

Muchhala

Kang

Köşeli

et al. 2023

Preprint

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Recent evidence suggests that chronic exposure to opioid analgesics such as morphine disrupt the intestinal epithelial layer and cause intestinal dysbiosis. Inhibiting opioid-induced dysbiosis can preclude the development of tolerance to opioid-induced antinociception, suggesting an important role of the gut-brain axis in mediating opioid effects. However, the mechanism underlying opioid-induced dysbiosis remains unclear. Host-produced antimicrobial peptides (AMPs) are critical for the integrity of the intestinal epithelial barrier as they prevent the pathogenesis of the enteric microbiota. Here, we report that chronic morphine exposure reduces expression of the antimicrobial peptide, Regenerating islet-derived 3 gamma (Reg3γ), in the ileum resulting in reduced intestinal antimicrobial activity against Gram-positive bacteria, L. reuteri. Fecal samples from morphine-treated mice had reduced levels of the phylum, Firmicutes, concomitant with reduced levels of short-chain fatty acid, butyrate. Fecal microbial transplant (FMT) from morphine-naïve mice restored the antimicrobial activity, the expression of Reg3γ, and prevented the increase in intestinal permeability and the development of antinociceptive tolerance in morphine-dependent mice. Similarly, oral gavage with sodium butyrate dose-dependently reduced the development of antinociceptive tolerance, and prevented the downregulation of Reg3γ and the reduction in antimicrobial activity. The alpha diversity of the microbiome was also restored by oral butyrate in morphine-dependent mice. These data implicate impairment of the antimicrobial activity of the intestinal epithelium as a mechanism by which morphine disrupts the microbiota-gut-brain axis.

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“…Chemogenetic activation of cholinergic enteric neurons altered the intestinal transcriptome, including the expression of genes responsible for mucosal immunity and antimicrobial responses, and produced effects on the gut microbiome and metabolome 32 . Approximately half of the µ-opioid receptor-expressing neurons in the enteric nervous system are cholinergic 31,33 . A subset of µ-opioid receptor-containing neurons also expresses the inhibitory neurotransmitter, vasoactive intestinal peptide (VIP) 31,33 .…”

Section: Discussionmentioning

confidence: 99%

“…RNA samples were treated with DNase 1 (RNasefree, ThermoFisher Scienti c, Waltham, MA) to remove DNA contamination. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed on a Mini-Opticon real-time PCR system (Bio-Rad, Hercules, CA) by using the iTaq Universal SYBR Green One-Step kit (Bio-Rad, Hercules, CA) as described previously 33 . Gapdh was used as the internal control.…”

Section: Bactericidal Activity Assaymentioning

confidence: 99%

The Role of Morphine-Induced Impairment of Intestinal Epithelial Antibacterial Activity in Dysbiosis and its Impact on the Microbiota-Gut-Brain Axis

Akbarali

Muchhala

Kang

et al. 2023

Preprint

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Host-produced antimicrobial peptides (AMPs) are critical for the integrity of the gut epithelial barrier as they prevent the pathogenesis of the enteric microbiota. Here, we report that intestinal antimicrobial activity is reduced, and epithelial permeability is increased in a morphine-dependent mouse model. Antimicrobial activity and permeability are restored by fecal transplant (FMT) from morphine-naïve mice or by oral gavage of sodium butyrate. Butyrate levels are reduced in the fecal samples of morphine-treated mice concomitant with a reduction in the phylum, Firmicutes. The alpha diversity of the microbiome is also restored by oral butyrate in morphine-dependent mice. FMT or sodium butyrate prevents downregulation of the antimicrobial peptide, Regenerating islet-derived 3 gamma (Reg3γ), and the development of antinociceptive tolerance in morphine-dependent mice. These data implicate impairment of the antimicrobial activity of the intestinal epithelium as a mechanism by which morphine disrupts the microbiota-gut-brain axis.

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Chronic Morphine Induces IL-18 in Ileum Myenteric Plexus Neurons Through Mu-opioid Receptor Activation in Cholinergic and VIPergic Neurons

Cited by 6 publications

References 57 publications

Gut dysbiosis was inevitable, but tolerance was not: temporal responses of the murine microbiota that maintain its capacity for butyrate production correlate with sustained antinociception to chronic voluntary morphine

Gut dysbiosis was inevitable, but tolerance was not: temporal responses of the murine microbiota that maintain its capacity for butyrate production correlate with sustained antinociception to chronic voluntary morphine

The Role of Morphine-Induced Impairment of Intestinal Epithelial Antibacterial Activity in Dysbiosis and its Impact on the Microbiota-Gut-Brain Axis

The Role of Morphine-Induced Impairment of Intestinal Epithelial Antibacterial Activity in Dysbiosis and its Impact on the Microbiota-Gut-Brain Axis

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