Skip to main content

Advertisement

SpringerLink
Log in

Effect of Naloxone-3-Glucuronide and N-Methylnaloxone on the Motility of the Isolated Rat Colon After Morphine

  • Original Paper
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

The effect of the opioid antagonists naloxone-3-glucuronide and N-methylnaloxone on rat colon motility after morphine stimulation was measured. The rat model consisted of the isolated, vascularly perfused colon. The antagonists (10−4 M, intraluminally) and morphine (10−4 M, intra-arterially) were administered from 20 to 30 and from 10 to 50 min, respectively. Colon motility was determined by the luminal outflow. The antagonist concentrations in the luminal and venous outflow were measured by high-performance liquid chromatography. Naloxone-3-glucuronide and N-methylnaloxone reversed the morphine-induced reduction of the luminal outflow to baseline within 10 and 20 min, respectively. These antagonists were then excreted in the luminal outflow and could not be found in the venous samples. Naloxone, produced by hydrolysis or demethylation, was not detectable. In conclusion, highly polar naloxone derivatives peripherally antagonize the motility-lowering effect of morphine in the perfused isolated rat colon, are stable, and are not able to cross the colon-mucosal blood barrier.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Vanegas G, Ripamonti C, Sbanotto A, De Conno F (1998) Side effects of morphine administration in cancer patients. Cancer Nurs 21:289–297

    Article  PubMed  CAS  Google Scholar 

  2. Grond S, Zech D, Diefenbach C, Bischoff A (1994) Prevalence and pattern of symptoms in patients with cancer pain: a prospective evaluation of 1635 cancer patients referred to a pain clinic. J Pain Symptom Manage 9:372–382

    Article  PubMed  CAS  Google Scholar 

  3. Schug SA, Zech D, Grond S, Jung H, Meuser T, Stobbe B (1992) A long-term survey of morphine in cancer pain patients. J Pain Symptom Manage 7:259–266

    Article  PubMed  CAS  Google Scholar 

  4. Holmes S (1989) Use of a modified symptom distress scale in assessment of the cancer patient. Int J Nurs Stud 26:69–79

    Article  PubMed  CAS  Google Scholar 

  5. Simpkins JW, Smulkowski M, Dixon R, Tuttle R (1988) Evidence for the delivery of narcotic antagonists to the colon as their glucuronide conjugates. J Pharmacol Exp Ther 244:195–205

    PubMed  CAS  Google Scholar 

  6. Pappagallo M (2001) Incidence, prevalence, and management of opioid bowel dysfunction. Am J Surg 182:11S–18S

    Article  PubMed  CAS  Google Scholar 

  7. Fallon MT, Hanks GW (1999) Morphine, constipation and performance status in advanced cancer patients. Palliat Med 13:159–160

    Article  PubMed  CAS  Google Scholar 

  8. De Luca A, Coupar IM (1996) Insights into opioid action in the intestinal tract. Pharmacol Ther 69:103–115

    Article  PubMed  CAS  Google Scholar 

  9. Porreca F, Cowan A, Raffa RB, Tallarida RJ (1983) Ketazocines and morphine: effects on gastrointestinal transit after central and peripheral administration. Life Sci 32:1785–1790

    Article  PubMed  CAS  Google Scholar 

  10. Galligan JJ, Burks TF (1983) Centrally mediated inhibition of small intestinal transit and motility by morphine in the rat. J Pharmacol Exp Ther 226:356–361

    PubMed  CAS  Google Scholar 

  11. Manara L, Bianchi G, Ferretti P, Tavani A (1986) Inhibition of gastrointestinal transit by morphine in rats results primarily from direct drug action on gut opioid sites. J Pharmacol Exp Ther 237:945–949

    PubMed  CAS  Google Scholar 

  12. Yuan CS, Foss JF, Osinski J, Toledano A, Roizen MF, Moss J (1997) The safety and efficacy of oral methylnaltrexone in preventing morphine-induced delay in oral-cecal transit time. Clin Pharmacol Ther 61:467–475

    Article  PubMed  CAS  Google Scholar 

  13. Bartlett SE, Dodd PR, Smith MT (1994) Pharmacology of morphine and morphine-3-glucuronide at opioid, excitatory amino acid, GABA and glycine binding sites. Pharmacol Toxicol 75:73–81

    PubMed  CAS  Google Scholar 

  14. Christrup LL (1997) Morphine metabolites. Acta Anaesthesiol Scand 41:116–122

    PubMed  CAS  Google Scholar 

  15. Ulens C, Baker L, Ratka A, Waumans D, Tytgat J (2001) Morphine-6beta-glucuronide and morphine-3-glucuronide, opioid receptor agonists with different potencies. Biochem Pharmacol 62:1273–1282

    Article  PubMed  CAS  Google Scholar 

  16. Meunier A, Latremoliere A, Mauborgne A, et al. (2005) Attenuation of pain-related behavior in a rat model of trigeminal neuropathic pain by viral-driven enkephalin overproduction in trigeminal ganglion neurons. Mol Ther 11:608–616

    Article  PubMed  CAS  Google Scholar 

  17. Comert M, Sipahi EY, Ustun H, et al. (2005) Morphine modulates inducible nitric oxide synthase expression and reduces pulmonary oedema induced by alpha-naphthylthiourea. Eur J Pharmacol 511:183–189

    Article  PubMed  CAS  Google Scholar 

  18. Lewanowitsch T, Irvine RJ (2002) Naloxone methiodide reverses opioid-induced respiratory depression and analgesia without withdrawal. Eur J Pharmacol 445:61–67

    Article  PubMed  CAS  Google Scholar 

  19. Maslov LN, Lishmanov YB, Solenkova NV, Gross GJ, Stefano GB, Tam SW (2003) Activation of peripheral delta opioid receptors eliminates cardiac electrical instability in a rat model of post-infarction cardiosclerosis via mitochondrial ATP-dependent K+ channels. Life Sci 73:947–952

    Article  PubMed  CAS  Google Scholar 

  20. Menendez L, Lastra A, Meana A, Hidalgo A, Baamonde A (2005) Analgesic effects of loperamide in bone cancer pain in mice. Pharmacol Biochem Behav 81:114–121

    Article  PubMed  CAS  Google Scholar 

  21. Herrmann C, Cuber JC, Dakka T, Bernard C, Chayvialle JA (1991) Bombesin potentiates taurocholic acid-induced neurotensin release in rats. Endocrinology 128:2853–2857

    Article  PubMed  CAS  Google Scholar 

  22. Herrmann-Rinke C, Eissele R, Arnold R, Goke B (1996) Studies on the viability of the isolated vascularly perfused rat colon. Digestion 57:349–355

    Article  PubMed  CAS  Google Scholar 

  23. Reber PU, Patel AG, Lewis MP, Ashley SW, Reber HA (1998) Stenting does not decompress the pancreatic duct as effectively as surgery in experimental chronic pancreatitis. Surgery 124:561–567

    PubMed  CAS  Google Scholar 

  24. Scheurer U, Drack E, Halter F (1985) Cyclooxygenase inhibitors affect Met-enkephalin- and acetylcholine-stimulated motility of the isolated rat colon. J Pharmacol Exp Ther 234:742–746

    PubMed  CAS  Google Scholar 

  25. Scheurer U, Wenger F, Caliezi A, Drack E, Varga L, Halter F (1990) Different motor actions of dynorphins and nonpeptide kappa opioid receptor agonists in the isolated rat colon. J Pharmacol Exp Ther 252:1324–1330

    PubMed  CAS  Google Scholar 

  26. Lenard L Jr., Halmai V, Bartho L (1999) Morphine contracts the guinea pig ileal circular muscle by interfering with a nitric oxide mediated tonic inhibition. Digestion 60:562–566

    Article  PubMed  CAS  Google Scholar 

  27. Meissner W, Schmidt U, Hartmann M, Kath R, Reinhart K (2000) Oral naloxone reverses opioid-associated constipation. Pain 84:105–109

    Article  PubMed  CAS  Google Scholar 

  28. Sykes NP (1996) An investigation of the ability of oral naloxone to correct opioid-related constipation in patients with advanced cancer. Palliat Med 10:135–144

    PubMed  CAS  Google Scholar 

  29. Jurna I, Kaiser R, Kretz O, Baldauf J (1992) Oral naloxone reduces constipation but not antinociception from oral morphine in the rat. Neurosci Lett 142:62–64

    Article  PubMed  CAS  Google Scholar 

  30. Bianchi G, Fiocchi R, Tavani A, Manara L (1982) Quaternary narcotic antagonists' relative ability to prevent antinociception and gastrointestinal transit inhibition in morphine-treated rats as an index of peripheral selectivity. Life Sci 30:1875–1883

    Article  PubMed  CAS  Google Scholar 

  31. Yuan CS, Foss JF, O'Connor M, Toledano A, Roizen MF, Moss J (1996) Methylnaltrexone prevents morphine-induced delay in oral-cecal transit time without affecting analgesia: a double-blind randomized placebo-controlled trial. Clin Pharmacol Ther 59:469–475

    Article  PubMed  CAS  Google Scholar 

  32. Yuan CS, Foss JF, O'Connor M, Osinski J, Roizen MF, Moss J (1999) Effects of intravenous methylnaltrexone on opioid-induced gut motility and transit time changes in subjects receiving chronic methadone therapy: a pilot study. Pain 83:631–635

    Article  PubMed  CAS  Google Scholar 

  33. Yuan CS, Foss JF, O'Connor M, et al. (2000) Methylnaltrexone for reversal of constipation due to chronic methadone use: a randomized controlled trial. JAMA 283:367–372

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

This study was supported by Grant 3200–066693.01 from the Swiss National Science Foundation.

Author information

Authors and Affiliations

  1. Department of Vascular Surgery, Lindenhof Hospital, Bern, Switzerland

    Peter Reber

  2. Department of Clinical Research, University of Bern, Murtenstrasse 35, CH-3010, Bern, Switzerland

    Rudolf Brenneisen & Catarina Batista

  3. Clinic for Gastroenterology, University Hospital, Bern, Switzerland

    Beatrice Flogerzi, Peter Netzer & Ulrich Scheurer

Authors
  1. Peter Reber
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rudolf Brenneisen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Beatrice Flogerzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Catarina Batista
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Peter Netzer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ulrich Scheurer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rudolf Brenneisen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Reber, P., Brenneisen, R., Flogerzi, B. et al. Effect of Naloxone-3-Glucuronide and N-Methylnaloxone on the Motility of the Isolated Rat Colon After Morphine. Dig Dis Sci 52, 502–507 (2007). https://doi.org/10.1007/s10620-006-9563-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-006-9563-9

Keywords

Search

Navigation