Peripheral prostaglandin E2 prolongs the sensitization of nociceptive dorsal root ganglion neurons possibly by facilitating the synthesis and anterograde axonal trafficking of EP4 receptors.

Prostaglandin E2 (PGE2), a well-known pain mediator enriched in inflamed tissues, plays a pivotal role in the genesis of chronic pain conditions such as inflammatory and neuropathic pain. PGE2-prolonged sensitization of nociceptive dorsal root ganglion (DRG) neurons (nociceptors) may contribute to the transition from acute to chronic pain. However, the underlying cellular mechanisms are poorly understood. In this study, we tested the hypothesis that facilitating synthesis and anterograde axonal trafficking of EP receptors contribute to PGE2-prolonged nociceptor sensitization. Intraplantar (i.pl.) injection of a stabilized PGE2 analog, 16,16 dimethyl PGE2 (dmPGE2), in a dose- and time-dependent manner, not only elicited primary tactile allodynia which lasted for 1d, but also prolonged tactile allodynia evoked by a subsequent i.pl. injection of dmPGE2 from 1d to 4d. Moreover, the duration of tactile allodynia was progressively prolonged following multiple sequential i.pl. injections of dmPGE2. Co-injection of the selective EP1 or EP4 receptor antagonist, the inhibitors of cAMP, PKA, PKC, PKCε or PLC as well as an interleukin-6 (IL-6) neutralizing antiserum differentially blocked primary tactile allodynia elicited by the 1st dmPGE2 and the prolonged tactile allodynia evoked by the 2nd dmPGE2, suggesting the involvement of these signaling events in dmPGE2-induced nociceptor activation and sensitization. Co-injection of a selective COX2 inhibitor or two EP4 antagonists prevented or shortened inflammagen-prolonged nociceptor sensitization. I.pl. injection of dmPGE2 or carrageenan time-dependently increased EP4 levels in L4-6 DRG neurons and peripheral nerves. EP4 was expressed in almost half of IB4-binding nociceptors of L4-6 DRG. Taken together, our data suggest that stimulating the synthesis and anterograde axonal trafficking to increase EP4 availability at the axonal terminals of nociceptors is likely a novel mechanism underlying PGE2-prolonged nociceptor sensitization. Blocking COX2/PGE2/EP4 signaling at an earlier stage of inflammation or injury is crucial for preventing the transition from acute pain to a chronic state.

Analysis of 16,16-dimethylprostaglandin E2-induced diarrhea in cecectomized rats.

The 16,16-dimethylprostaglandin E2 (dmPGE2)-induced diarrhea was analyzed in cecectomized rats prepared by resecting the cecum and its vasculature without disturbing the ileocecal junction. dmPGE2 (0.1-1.0 mg/kg, p.o.) dose-dependently increased the number of defecation episodes and induced a soft and watery stool in cecectomized rats. At 0.3 mg/kg, the diarrhea-inducing effects of dmPGE2 were more pronounced in cecectomized than in control rats. When given i.p., dmPGE2 (0.3 mg/kg) induced a watery stool in cecectomized and control rats with the same efficacy, although these effects were short-lasting as compared to oral administration. Castor oil (4 ml/kg, p.o.) also induced diarrhea, but did not produce a watery stool in cecectomized rats. There were no differences between cecectomized and control rats in basal small intestinal transits or in dmPGE2 (0.3 mg/kg, p.o.)-induced enhancements. Moreover, the basal and dmPGE2-induced jejunal net fluid transfers were the same in cecectomized and in control rats. On the other hand, the enhanced secretion of colonic fluid by dmPGE2, given intraluminally, was only half of that in control rats, whereas the colonic transit-enhancing effect of dmPGE2 in cecectomized rats was more pronounced than in control rats at 15 but not at 30 min after its administration. The basal colonic fluid contents and transits were the same in cecectomized and in control rats. Loperamide and morphine (0.1 and 1.0 mg/kg, s.c.) inhibited the dmPGE2 (0.3 mg/kg, p.o.)-induced diarrhea in cecectomized rats. N-methyllevallorphan (5 mg/kg, s.c.) completely antagonized the inhibitory effect of loperamide and partly antagonized the effect of morphine. These results suggest that oral administration of dmPGE2 induces a more pronounced secretory diarrhea in cecectomized than in control rats, probably due to the lack of the reservoir function of the cecum in the operated animals. This secretory diarrhea model is suitable for evaluating the antidiarrheal activity of drugs.

Behavioral toxicity of selected radioprotectors.

Effective radioprotection with minimal behavioral disruption is essential for the selection of protective agents to be used in manned spaceflight. This overview summarizes the studies on the behavioral toxicity of selected radioprotectors classified as phosphorothioates (WR-2721, WR-3689), bioactive lipids (16, 16 dimethylprostaglandin E2(DiPGE2), platelet activating factor (PAF), leukotriene C4), and immunomodulators (glucan, synthetic trehalose dicorynomycolate, and interleukin-1). Behavioral toxicity was examined in laboratory mice using a locomotor activity test. For all compounds tested, there was a dose-dependent decrease in locomotor behavior that paralleled the dose-dependent increase in radioprotection. While combinations of radioprotective compounds (DiPGE2 plus WR-2721) increased radioprotection, they also decreased locomotor activity. The central nervous system stimulant, caffeine, was able to mitigate the locomotor decrement produced by WR-3689 or PAF.

Dimethyl-prostaglandin E2 prevents stress ulceration with minimal complications.

Gastric mucosal damage produced by topical application of necrotizing agents is diminished by topical or systemic pretreatment with a variety of E and F prostaglandins. The rat restraint model of gastric mucosal injury is more analogous to clinical stress ulceration than are models using intragastric application of toxic solutions; however, previous use of prostaglandin E1 in the restraint model resulted in a prohibitive incidence of GI morbidity. The current study used the restraint model of stress ulceration to compare the effects of a more potent prostaglandin analogue, 16,16-dimethyl prostaglandin E2, with hyperosmolar glucose and antacids. All three agents afforded significant protection from grossly apparent mucosal lesions, alone and in combination. Although other physiologic effects of each agent differed, the only effect which correlated with prevention of mucosal lesions was suppression of gastric acidity. Since effective doses of cytoprotective prostaglandins did not produce notable morbidity in comparison with other agents, they may prove to be a useful adjunct to stress ulcer prophylaxis in clinical settings.

Protection of mice against mixed fission neutron-gamma (n: gamma = 1:1) irradiation by WR-2721, 16,16-dimethyl PGE2, and the combination of both agents.

The survival of mice after whole-body exposure to a modified fission neutron-gamma field (n: gamma = 1:1) was used to examine radiation protection by WR-2721, 16,16-dimethyl PGE2(DiPGE2), and the combination of both agents. Administration of WR-2721 (453 mg/kg) increased the LD50/30 from 5.24 to 7.17 Gy (DMF = 1.37), whereas pretreatment with DiPGE2 (1.6 mg/kg) increased the LD50/30 to 5.77 Gy (dose modification factor (DMF) = 1.10). The combination of 453 mg/kg WR-2721 and 0.4 mg/kg DiPGE2 resulted in an LD50/30 of 7.33 Gy, yielding a DMF of 1.39. However, no significant difference in protection was obtained with the combination of the two agents compared to that seen with WR-2721 alone.

Interactions between cyclosporin A, indomethacin and 16,16-dimethyl prostaglandin E2: effects on renal, hepatic and gastrointestinal toxicity in the rat.

Rats were treated for 3 or 14 days with cyclosporin A (CsA, 50 mg/kg) or indomethacin (2 or 5 mg/kg) either alone or in combination, or with CsA plus 16,16-dimethylprostaglandin E2 (DMPGE2, 0.25 mg/kg). Hepatic and renal function were unaffected by treatment with indomethacin at either dose and only at the higher dose was severe intestinal ulceration observed. CsA caused renal and hepatic toxicity, evidenced by increased urine N-acetyl-beta-D-glucosaminidase activity, serum urea, creatinine and bilirubin and decreased serum albumin and total protein. In rats cotreated with CsA and either dose of indomethacin the increases in serum urea and creatinine and decreases in serum albumin and total protein were accentuated, but serum bilirubin was not further increased. Intestinal lesions were present in rats treated for 14 days with CsA plus the lower dose of indomethacin, but not in rats treated with either drug alone. In rats treated with DMPGE2 plus CsA, serum urea and creatinine were normal and urine N-acetyl-beta-D-glucosaminidase activity was reduced compared to rats treated with CsA alone, but DMPGE2 cotreatment had no effect on the CsA induced hyperbilirubinaemia. Hepatic microsomal cytochrome P-450 concentration and aminopyrine N-demethylase activity were lower in rats treated with CsA plus indomethacin than in untreated rats or those treated with either drug alone. Coadministration of indomethacin or DMPGE2 had no effect on serum trough CsA levels. The results are interpreted as showing an exacerbation by CsA of the intestinal toxicity of indomethacin, an increase by indomethacin in the renal toxicity of CsA and a protection by DMPGE2 against CsA renal toxicity. Possible mechanisms involving drug interactions and either hepatic cytochrome P-450, renal cyclooxygenase or other renal sites are discussed.

Pathogenic mechanisms involved in mepirizole-induced duodenal damage in the rat.

Mepirizole (60 and 200 mg/kg) administered s.c. induced damage in the surface epithelial cells of the rat proximal duodenum as early as 2 hr after the treatment. 16,16-Dimethyl prostaglandin E2 (dmPGE2, 30 micrograms/kg) administered s.c. significantly protected the duodenal mucosa against mepirizole-induced damage for up to 6 hr. Gastric acid secretion in acute fistula preparations was significantly reduced 1 hr after administration of mepirizole (60 and 200 mg/kg). The secretion reverted to the control level 2 hr later. In the 60 mg/kg-treated group, however, there was a significant increase in the acid output for up to 6 hr. Duodenal HCO3- secretion, stimulated with 10 mM HCl was significantly inhibited with mepirizole (60 and 200 mg/kg). Mepirizole (60 and 200 mg/kg) significantly increased the amount of acid in the duodenum for 2 to 6 hr after the treatment. dmPGE2 (30 micrograms/kg) significantly inhibited gastric acid secretion, stimulated duodenal HCO3- secretion, and reduced the increased amount of acid in the duodenum in response to mepirizole. Endogenous prostaglandin E2 and 6-keto prostaglandin F1 alpha in the duodenal mucosa were significantly reduced by mepirizole (200 mg/kg) 1 to 2 hr later. Mepirizole-induced duodenal damage appears to be caused by the increased amount of acid in the duodenum.

Evaluation of meteneprost potassium (a PGE2 analogue) for cervical dilation and side effects in nonpregnant women.

Meteneprost potassium, a PGE2 analogue, was evaluated in thirty non-pregnant women for use as a prospective cervical dilator and softening agent. No significant change in cervical dilation was noted. A significant relationship between obesity and side effects was observed.

A model of hemorrhagic pancreatitis in cats--role of 16,16-dimethyl prostaglandin E2.

Acute edematous pancreatitis was induced in cats by perfusing activated pancreatic enzymes through their pancreatic ducts. The ducts had been made permeable to large molecules by one of two techniques. The cats either received ethanol (2 ml/kg every 8 h) and aspirin (25 mg/kg every 8 h) orally for 48 h or had their pancreatic ducts perfused for 1 h with 7.5 mM glycodeoxycholate. When the same procedure was followed, but using 16,16-dimethyl prostaglandin E2 (dmPGE2) (2 micrograms/kg X h infused intravenously for 1 h before and during ductal perfusion with activated enzymes), hemorrhagic pancreatitis developed instead. To investigate whether an increase in pancreatic blood flow or microvascular permeability (both caused by dmPGE2) was important in this phenomenon, we tested the effects of isoproterenol (which increased blood flow) and histamine (which increased microvascular permeability) in the model. Thus in similar experiments, either isoproterenol (0.3 micrograms/kg . min) or histamine phosphate (2 micrograms/kg . min) was infused instead of dmPGE2. The animals that received histamine also developed hemorrhagic pancreatitis. Those that received isoproterenol did not. These observations suggested that an increase in microvascular permeability in the pancreas converted edematous pancreatitis to hemorrhagic pancreatitis. These findings suggest also that clinical studies using prostaglandins to treat patients with pancreatitis should be approached with caution.