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Involvement of central opioid receptors in protective effects of methadone on experimental colitis in rats

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Abstract

Purpose

There are several lines of evidence on the protective roles of opioids in gastrointestinal inflammatory conditions. This study aims to distinguish the central and peripheral roles of methadone, a non-selective opioid receptor agonist, in an acute model of ulcerative colitis in male rats.

Methods

Ulcerative colitis was induced by intrarectal administration of acetic acid 4%. Methadone was injected subcutaneously (s.c.), 5 and 10 mg/kg, and intracerebroventricular (i.c.v.), 50 and 300 ng/rat. Opioid antagonists were employed. Methylnaltrexone (MNTX; 5 mg/kg, i.p.), a peripherally acting opioid receptor antagonist, and naltrexone (NTX; 5 mg/kg, i.p. and 10 ng/rat, i.c.v.), a peripherally and centrally acting opioid receptor antagonist were injected before methadone (10 mg/kg, s.c. and or 300 ng/rat, i.c.v.) administration. NTX (5 mg/kg, i.p. and 10 ng/rat, i.c.v.) were administered 30 min prior to administration of methadone (10 mg/kg, s.c. and 300 ng/rat, i.c.v.), respectively. MNTX (5 mg/kg, i.p.) was injected 30 min prior to methadone (10 mg/kg, s.c.). Seventy-two hours following colitis induction, macroscopic and microscopic mucosal lesions, and the colonic levels of tumor necrosis factor-alpha (TNF-α) and interleukin-1β (IL-1β) were determined.

Results

Methadone (300 ng/rat, i.c.v.) and Methadone (5 and 10 mg/kg, s.c.) improved the macroscopic and microscopic scores through opioid receptors. Also, a significant reduction in TNF-α and IL-1β was observed. Peripherally and centrally injected NTX significantly reversed methadone 10 mg/kg s.c. anti-inflammatory effects while MNTX could not completely reverse this effect. Moreover, centrally administered methadone (300 ng/rat) showed the anti-inflammatory effect which was reversed by central administration of NTX (10 ng/rat).

Conclusions

The opioid receptors mainly the central opioid receptors may mediate the protective actions of methadone on the experimental model of inflammatory bowel disease in rat.

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Acknowledgements

The study was supported by a Grant from Tehran University of Medical Sciences, Tehran, Iran (No. 16555-15-04-90).

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Author notes

  1. Nahid Fakhraei and Nina Javadian contributed equally in the study.

Authors and Affiliations

  1. Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran

    Nahid Fakhraei, Nina Javadian & Ahmad Reza Dehpour

  2. Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran

    Nina Javadian, Nastaran Rahimi & Ahmad Reza Dehpour

  3. Department of Pathology, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran

    Fatemeh Nili

  4. Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Reza Rahimian, Nastaran Rahimi & Ahmad Reza Dehpour

  5. Department of Psychiatry and Neuroscience, Faculty of Medicine, CERVO Brain Research Centre, Laval University, Quebec, G1J 2G3, Canada

    Reza Rahimian

  6. Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Shiva Hashemizadeh

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  1. Nahid Fakhraei
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Fakhraei, N., Javadian, N., Rahimian, R. et al. Involvement of central opioid receptors in protective effects of methadone on experimental colitis in rats. Inflammopharmacol 26, 1399–1413 (2018). https://doi.org/10.1007/s10787-018-0538-1

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