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Role of cyclooxygenases 1 and 2 in the modulation of neuromuscular functions in the distal colon of humans and mice
  1. M Fornai1,
  2. C Blandizzi1,
  3. R Colucci1,
  4. L Antonioli1,
  5. N Bernardini2,
  6. C Segnani2,
  7. B Baragatti3,
  8. S Barogi3,
  9. P Berti4,
  10. R Spisni4,
  11. M Del Tacca1
  1. 1Division of Pharmacology and Chemotherapy, Department of Oncology, Transplants and Advanced Technologies in Medicine, University of Pisa, Pisa, Italy
  2. 2Section of Histology, Department of Human Morphology and Applied Biology, University of Pisa, Pisa, Italy
  3. 3Laboratory of Physiological Genomics, Scuola Superiore S Anna and Institute of Clinical Physiology, National Research Council, Pisa, Italy
  4. 4Department of Surgery, University of Pisa, Pisa, Italy
  1. Correspondence to:
    Professor M Del Tacca
    Divisione di Farmacologia e Chemioterapia, Dipartimento di Oncologia, Trapianti e Nuove Tecnologie in Medicina, Università di Pisa, Via Roma, 55, 56126 Pisa, Italy;


Background: Cyclooxygenase isoforms (COX-1, COX-2) may exert differential regulatory actions on enteric motor functions under normal or pathological conditions.

Aims: To examine the occurrence and functions of COX-1 and COX-2 in the neuromuscular compartment of normal distal colon using human and murine tissue.

Methods: Gene expression (human, mouse), protein expression (human), gene deletion (mouse), and the effects of dual and isoform specific COX inhibitors on in vitro motility (human, mouse) were investigated.

Results: Reverse transcription-polymerase chain reaction (RT-PCR) showed mRNA expression of COX-1 and COX-2 in human and wild-type mouse colonic muscle whereas only COX-2 or COX-1 was detected in COX-1 or COX-2 knockout animals. Immunohistochemistry localised both isoforms in neurones of myenteric ganglia, COX-1 in circular layer myocytes, and COX-2 in longitudinal muscle. Indomethacin (COX-1/COX-2 inhibitor), SC-560 (COX-1 inhibitor), or DFU (COX-2 inhibitor) enhanced atropine sensitive electrically induced contractions of human longitudinal muscle. The most prominent actions were recorded with indomethacin or SC-560 plus DFU. These results were confirmed under pharmacological blockade of non-cholinergic nerves. Atropine sensitive contractions evoked by carbachol in the presence of tetrodotoxin were enhanced by indomethacin or DFU but not by SC-560. In wild-type mice, contractile responses to electrical stimulation were enhanced by indomethacin, SC-560, or DFU. SC-560 potentiated electrically induced contractions in COX-2, but not COX-1, knockout mice. In contrast, DFU enhanced the contractions elicited by electrical stimuli in COX-1, but not in COX-2, knockout mice.

Conclusions: These results indicate that COX-1 and COX-2 are expressed in the neuromuscular compartment of normal human colon where they modulate cholinergic excitatory control of colonic motility at prejunctional and postjunctional sites, respectively.

  • COX-1, cyclooxygenase 1
  • COX-2, cyclooxygenase 2
  • RT-PCR, reverse transcription-polymerase chain reaction
  • PBS, phosphate buffered saline
  • dNTP, deoxynucleotide triphosphate mixture
  • HRP, horseradish peroxidase
  • DAB, 3,3′-diaminobenzidine tetrahydrochloride
  • l-NAME, Nω-nitro-l-arginine methylester
  • cyclooxygenase
  • myenteric nerves
  • intestinal motility
  • human colon

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  • Conflict of interest: None declared.