Within 2 h after their intracolonic administration, PAR2 agonists (PAR2-activating peptides and trypsin) also caused nociceptor activation at a spinal level, as demonstrated by increased fos protein expression in the superficial laminae of the spinal dorsal horn . Subinflammatory doses of PAR2 agonists from the colonic lumen provoked a significant increase in the number of abdominal contractions in response to rectal distension, which is characteristic of visceral hyperalgesia . Here again, these experiments could not unequivocally show that these pronociceptive and hyperalgesic effects of PAR2 agonists were due to a direct activation of PAR2 on the ENS. The study by Reed and colleagues , however, showed that transient exposure of enteric submucosal neurons to PAR2 agonists evoked long term hyperexcitability. Similar hyperexcitability of extrinsic afferent neurons could be responsible for the PAR2-induced hyperalgesia we observed in vivo in a rat model of visceral nociception .
Recent studies have shown that patients with the irritable bowel syndrome (IBS) exhibit an increased spontaneous release of mast cell tryptase from colonic tissues . It could be hypothesized that tryptase-induced PAR2 activation of enteric sensory nerves induces a long term hyperexcitability of these neurons, resulting in the visceral pain and hyperalgesia experienced by IBS patients. Although a clear role for PAR2 activation has been demonstrated in the establishment of mast cell degranulation-induced somatic hyperalgesia, using PAR2-deficient mice , such a role in visceral hyperalgesia has yet to be demonstrated. You can be sure your pharmacy offers sale viagra online delivering fast internationally.
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