Experimental models of pancreatic pain have focused almost exclusively on the chemical initiation of pancreatitis. One such model involves the intraperitoneal injection of rats with 20% L-arginine twice at an interval of one hour (32). This model produces an increase in sensitivity to mechanical stimulation of the upper abdomen (lower threshold to probing with von Frey filaments), indicative of referred pain, during the first week (33). The same model produces an increase in EMG activity (and, therefore, abdominal contractions) of the abdominal muscles that correlates with the severity of pancreatic inflammation and the expression of c-fos in the thoracolumbar spinal cord (34). This, and similar, models have an advantage over many of the others we review here in that surgical manipulation is not required, thus avoiding any possible complication arising from tissue damage or manipulation. Pancreatitis can also be induced in rats by the injection of 8mgkg_1 dibutyltin dichloride (dissolved in two parts ethanol and then mixed with three parts glycerol) into the tail vein (35). Treated rats show hypersensitivity to abdominal probing with von Frey filaments and significantly shorter withdrawal latencies for thermal stimuli at three and seven days (and one day in the case of thermal stimulation) following initiation of pancreatitis (36). These responses were dose-dependently inhibited by morphine treatment.
An alternative method to introduce chemicals into the pancreas is the surgical cannula-tion of the common bile (biliopancreatic) duct (37). Studies show that introduction of capsaicin or agonists for the proteinase-activated receptor 2 (trypsin or its selective activating peptide) will produce increased EMG activity in the acromiotrapezius muscle (38). Administration of the hapten 2,4,6-trinitrobenzenesulfonic acid (TNBS) (see section "The Large Intestine, Rectum, and Anus'' for more information) in the same manner (37) will produce referred abdominal mechanical sensitivity for as long as six weeks postinstillation, and rats show significant hypersensitivity to all forces of von Frey filament tested (2.75-120 mN) three weeks after instillation (Fig. 3) (39).
An extension of these intraductal delivery models is the intraperitoneal injection of the Cholecystokinin analogue caerulein (to accelerate the contraction of the bile system) alongside infusion of a bile salt, glycodeoxycholic acid, into the pancreas. Pancreatitis [described as moderately severe; (40)] develops after 12 hours, and experimental animals show significantly reduced activity (40,41), a measure that has been used to grade visceral pain.
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