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Agonist-dependent development of delta opioid receptor tolerance in the colon

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Abstract

The use of opioid analgesics is severely limited due to the development of intractable constipation, mediated through activation of mu opioid receptors (MOR) expressed by enteric neurons. The related delta opioid receptor (DOR) is an emerging therapeutic target for chronic pain, depression and anxiety. Whether DOR agonists also promote sustained inhibition of colonic transit is unknown. This study examined acute and chronic tolerance to SNC80 and ARM390, which were full and partial DOR agonists in neural pathways controlling colonic motility, respectively. Excitatory pathways developed acute and chronic tolerance to SNC80, whereas only chronic tolerance developed in inhibitory pathways. Both pathways remained functional after acute or chronic ARM390 exposure. Propagating colonic motor patterns were significantly reduced after acute or chronic SNC80 treatment, but not by ARM390 pre-treatment. These findings demonstrate that SNC80 has a prolonged inhibitory effect on propagating colonic motility. ARM390 had no effect on motor patterns and thus may have fewer gastrointestinal side-effects.

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Acknowledgments

The authors thank Professors Brigitte Kieffer and Macdonald Christie for DOReGFP mice, Dr Sabatino Ventura for advice with pharmacological analysis and Cameron Nowell for advice on image analysis.

Funding

National Health and Medical Research Council (NHMRC) Australia 1049730 and 1121029 (DPP & MC), 1083480 (DPP); JJD, AB and PR are supported by NHMRC Australian Postgraduate Awards. Research in DPP’s laboratory is funded in part by Takeda Pharmaceuticals. The research presented in this manuscript was not related to this agreement.

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Authors and Affiliations

  1. Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia

    Jesse J. DiCello, Ayame Saito, Pradeep Rajasekhar, Benjamin W. Sebastian, Rachel M. McQuade, Arisbel B. Gondin, Nicholas A. Veldhuis, Meritxell Canals, Simona E. Carbone & Daniel P. Poole

  2. ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Parkville, VIC, Australia

    Jesse J. DiCello, Ayame Saito, Pradeep Rajasekhar, Nicholas A. Veldhuis, Meritxell Canals, Simona E. Carbone & Daniel P. Poole

  3. Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, VIC, Australia

    Daniel P. Poole

  4. The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia

    Rachel M. McQuade

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  1. Jesse J. DiCello
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Contributions

JJD conceived, designed, conducted, analyzed and interpreted experiments, supervised the study and wrote the manuscript. AS conducted and analyzed experiments. BWS and RM conducted experiments. PR assisted with experimental analysis and made Fig. 8. NAV, AB and MC assisted with interpretation of data. SEC conducted experiments, supervised the study, and assisted with drafting of the manuscript. DPP conceived, designed, conducted and analyzed experiments, supervised the study, and wrote the manuscript.

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Correspondence to Jesse J. DiCello or Daniel P. Poole.

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Supplementary material 1 (DOCX 11 kb)

Supplementary Fig. 1

TAN67 acts as a partial DOR agonist in the colon. (a) TAN67 inhibited EFS-evoked contractions in a concentration-dependent manner. (b) TAN67-evoked contractions were desensitized following repeated exposures to agonist. (c) TAN67 (1 nM- 10 µM) only weakly internalized DOReGFP in myenteric neurons (n=21-52 neurons from 3-5 mice). Data are expressed as mean ± s.e.m.; N=5-6 mice for tissue contraction experiments. Statistical comparison performed by one-way repeated measures ANOVA followed by Dunnett’s post-hoc test (*p<0.05 and ***p<0.01)

Supplementary Fig. 2

Prolonged inhibitory effects of DOR and MOR agonists on electrically stimulated contractions of the colon. (a, b) EFS-evoked contractions remained suppressed after each subsequent exposure to SNC80. (c, d) The efficacy at which ARM390 inhibited electrically stimulated contractions significantly increased at the third and fourth addition. (e, f) DAMGO maintained its ability to diminish EFS-evoked contractions at each subsequent exposure. Circles indicate where EFS was applied. Data points are expressed as mean ± s.e.m., n=5-7 mice per treatment. Statistical analyses for the SNC80 and DAMGO data were conducted using a one-way repeated measures ANOVA followed by Dunnett’s post-hoc test. Statistical analyses for the ARM390 data were performed using Friedman’s test followed by Dunn’s post-hoc analysis (*p<0.05 and **p<0.01 compared to 1st addition)

Supplementary Fig. 3

An acute treatment (3 h) with the MOR agonist loperamide reduced CMMC frequency. (a, b) Relatively fewer CMMCs were generated in the loperamide-treated group compared to the equivalent acute SNC80-treated group under basal conditions. The data set presented for the SNC80-pretreated group was taken from Fig. 5d. Yellow arrows indicate representative CMMCs. Data are expressed as mean ± s.e.m., n=8-10 mice per treatment group. Statistical analysis was conducted using the Student’s t test (*p<0.05)

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DiCello, J.J., Saito, A., Rajasekhar, P. et al. Agonist-dependent development of delta opioid receptor tolerance in the colon. Cell. Mol. Life Sci. 76, 3033–3050 (2019). https://doi.org/10.1007/s00018-019-03077-6

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