Although a neurogenic mechanism involving NK-1 receptor activation has been demonstrated for PAR1 agonist-induced paw edema , there is currently no evidence that such a mechanism also occurs in the gut. Contrary to the situation with PAR2, subinflammatory doses of PAR1 agonists did not induce hyperalgesia after intraplantar injection, but they increased nociceptive threshold in rats and significantly inhibited inflammatory hyperalgesia induced by carrageenan . Here again, there is no evidence yet for such a mechanism in the gastrointestinal tract. However, other neurally controlled functions of the gut seem to be regulated by PAR1 activation on enteric neurons.
Buresi and colleagues have recently shown that PAR1 activation in mouse intestinal tissues, mounted in Ussing chambers, decreased secretory responses to neural stimulation. This suggests that PAR1 could contribute to disorders of secretory function associated with the development of colitis. It is interesting to note that PAR2 agonists also regulate intestinal secretion, but, unlike PAR1, PAR2 agonists have been shown to stimulate chloride secretion by a neurogenic process . No studies have yet demonstrated a role for PAR3 or PAR4 in neurally evoked intestinal functions.
This review summarized recent evidence that proteinases, through the activation of PARs, are able to interact with the ENS, thereby affecting neurally evoked intestinal functions. Inflammation and pain perception appear to be two major functions that are regulated by neuronal PARs. There has been considerable interest recently in the development of agents that modify these processes. PARs that are expressed on nerves represent, together with the proteinases that activate them, exciting new targets for therapeutic intervention. Most reliable pharmacy can offer sildenafil online pharmacy always charging you a lot less.
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