PMID- 35106734
OWN - NLM
STAT- MEDLINE
DCOM- 20221215
LR  - 20230602
IS  - 1557-1904 (Electronic)
IS  - 1557-1890 (Print)
IS  - 1557-1890 (Linking)
VI  - 17
IP  - 1-2
DP  - 2022 Jun
TI  - Chronic Morphine Induces IL-18 in Ileum Myenteric Plexus Neurons Through 
      Mu-opioid Receptor Activation in Cholinergic and VIPergic Neurons.
PG  - 111-130
LID - 10.1007/s11481-021-10050-3 [doi]
AB  - The gastrointestinal epithelium is critical for maintaining a symbiotic 
      relationship with commensal microbiota. Chronic morphine exposure can compromise 
      the gut epithelial barrier in mice and lead to dysbiosis. Recently, studies have 
      implicated morphine-induced dysbiosis in the mechanism of antinociceptive 
      tolerance and reward, suggesting the presence of a gut-brain axis in the 
      pharmacological effects of morphine. However, the mechanism(s) underlying 
      morphine-induced changes in the gut microbiome remains unclear. The 
      pro-inflammatory cytokine, Interleukin-18 (IL-18), released by enteric neurons 
      can modulate gut barrier function. Therefore, in the present study we 
      investigated the effect of morphine on IL-18 expression in the mouse ileum. We 
      observed that chronic morphine exposure in vivo induces IL-18 expression in the 
      ileum myenteric plexus that is attenuated by naloxone. Given that mu-opioid 
      receptors (MORs) are mainly expressed in enteric neurons, we also characterized 
      morphine effects on the excitability of cholinergic (excitatory) and vasoactive 
      intestinal peptide (VIP)-expressing (inhibitory) myenteric neurons. We found 
      fundamental differences in the electrical properties of cholinergic and VIP 
      neurons such that VIP neurons are more excitable than cholinergic neurons. 
      Furthermore, MORs were primarily expressed in cholinergic neurons, although a 
      subset of VIP neurons also expressed MORs and responded to morphine in 
      electrophysiology experiments. In conclusion, these data show that morphine 
      increases IL-18 in ileum myenteric plexus neurons via activation of MORs in a 
      subset of cholinergic and VIP neurons. Thus, understanding the neurochemistry and 
      electrophysiology of MOR-expressing enteric neurons can help to delineate 
      mechanisms by which morphine perturbs the gut barrier.
CI  - (c) 2022. The Author(s), under exclusive licence to Springer Science+Business 
      Media, LLC, part of Springer Nature.
FAU - Muchhala, Karan H
AU  - Muchhala KH
AD  - Department of Pharmacology and Toxicology, School of Medicine, Virginia 
      Commonwealth University, 1112 E. Clay Street, Richmond, VA, 23298, USA.
FAU - Koseli, Eda
AU  - Koseli E
AD  - Department of Pharmacology and Toxicology, School of Medicine, Virginia 
      Commonwealth University, 1112 E. Clay Street, Richmond, VA, 23298, USA.
FAU - Gade, Aravind R
AU  - Gade AR
AD  - Department of Pharmacology and Toxicology, School of Medicine, Virginia 
      Commonwealth University, 1112 E. Clay Street, Richmond, VA, 23298, USA.
FAU - Woods, Kareem
AU  - Woods K
AD  - Department of Pharmacology and Toxicology, School of Medicine, Virginia 
      Commonwealth University, 1112 E. Clay Street, Richmond, VA, 23298, USA.
FAU - Minai, Suha
AU  - Minai S
AD  - Department of Pharmacology and Toxicology, School of Medicine, Virginia 
      Commonwealth University, 1112 E. Clay Street, Richmond, VA, 23298, USA.
FAU - Kang, Minho
AU  - Kang M
AD  - Department of Pharmacology and Toxicology, School of Medicine, Virginia 
      Commonwealth University, 1112 E. Clay Street, Richmond, VA, 23298, USA.
FAU - McQuiston, A Rory
AU  - McQuiston AR
AD  - Department of Anatomy and Neurobiology, School of Medicine, Virginia Commonwealth 
      University, 1101 E. Marshall Street, Richmond, VA, 23298, USA.
FAU - Dewey, William L
AU  - Dewey WL
AD  - Department of Pharmacology and Toxicology, School of Medicine, Virginia 
      Commonwealth University, 1112 E. Clay Street, Richmond, VA, 23298, USA.
FAU - Akbarali, Hamid I
AU  - Akbarali HI
AUID- ORCID: 0000-0003-1423-0774
AD  - Department of Pharmacology and Toxicology, School of Medicine, Virginia 
      Commonwealth University, 1112 E. Clay Street, Richmond, VA, 23298, USA. 
      Hamid.akbarali@vcuhealth.org.
LA  - eng
GR  - P30 DA033934/DA/NIDA NIH HHS/United States
GR  - P30DA033934/NH/NIH HHS/United States
GR  - R25GM090084/NH/NIH HHS/United States
GR  - DA036975/NH/NIH HHS/United States
GR  - R25 GM090084/GM/NIGMS NIH HHS/United States
GR  - R01 DA036975/DA/NIDA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20220202
PL  - United States
TA  - J Neuroimmune Pharmacol
JT  - Journal of neuroimmune pharmacology : the official journal of the Society on 
      NeuroImmune Pharmacology
JID - 101256586
RN  - 76I7G6D29C (Morphine)
RN  - 0 (Interleukin-18)
RN  - 0 (Cholinergic Agents)
RN  - 0 (Receptors, Opioid)
SB  - IM
MH  - Mice
MH  - Animals
MH  - *Myenteric Plexus
MH  - *Morphine/pharmacology
MH  - Interleukin-18
MH  - Cholinergic Agents
MH  - Receptors, Opioid
PMC - PMC9343479
MID - NIHMS1778299
OTO - NOTNLM
OT  - Chronic morphine
OT  - Enteric neurons
OT  - Gut epithelial barrier
OT  - Interleukin-18 (IL-18)
OT  - Mu-opioid receptor
OT  - Neurochemical coding
COIS- Declarations Competing Interest The authors have no competing financial or 
      non-financial interests to declare that are relevant to this manuscript.
EDAT- 2022/02/03 06:00
MHDA- 2022/12/15 06:00
PMCR- 2023/06/01
CRDT- 2022/02/02 05:37
PHST- 2021/12/02 00:00 [received]
PHST- 2021/12/26 00:00 [accepted]
PHST- 2022/02/03 06:00 [pubmed]
PHST- 2022/12/15 06:00 [medline]
PHST- 2022/02/02 05:37 [entrez]
PHST- 2023/06/01 00:00 [pmc-release]
AID - 10.1007/s11481-021-10050-3 [pii]
AID - 10.1007/s11481-021-10050-3 [doi]
PST - ppublish
SO  - J Neuroimmune Pharmacol. 2022 Jun;17(1-2):111-130. doi: 
      10.1007/s11481-021-10050-3. Epub 2022 Feb 2.