AJP - GI Add DOIs to your references at manuscript stage!
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Gastrointest Liver Physiol 291: G128-G134, 2006; doi:10.1152/ajpgi.00442.2005
0193-1857/06 $8.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (5)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Noble, M. D.
Right arrow Articles by Liddle, R. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Noble, M. D.
Right arrow Articles by Liddle, R. A.

NEUROREGULATION AND MOTILITY

Local disruption of the celiac ganglion inhibits substance P release and ameliorates caerulein-induced pancreatitis in rats

Marc D. Noble, Joelle Romac, Yu Wang, Jay Hsu, John E. Humphrey, and Rodger A. Liddle

Department of Medicine, Duke University and Durham Veterans Affairs Medical Centers, Durham, North Carolina

Submitted 19 September 2005 ; accepted in final form 14 February 2006


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Primary sensory neurons of the C and A{delta} subtypes express the vanilloid capsaicin receptor TRPV1 and contain proinflammatory peptides such as substance P (SP) that mediate neurogenic inflammation. Pancreatic injury stimulates these neurons causing the release of SP in the pancreas resulting in pancreatic edema and neutrophil infiltration that contributes to pancreatitis. Axons of primary sensory neurons innervating the pancreas course through the celiac ganglion. We hypothesized that disruption of the celiac ganglion by surgical excision or inhibition of C and A{delta} fibers through blockade of TRPV1 would reduce the severity of experimental pancreatitis by inhibiting neurogenic inflammation. Resiniferatoxin (RTX) is a specific TRPV1 agonist that, in high doses, selectively destroys C and A{delta} fibers. Sprague-Dawley rats underwent surgical ganglionectomy or application of 10 µg RTX (vs. vehicle alone) to the celiac ganglion. One week later, pancreatitis was induced by six hourly intraperitoneal injections of caerulein (50 µg/kg). The severity of pancreatitis was assessed by serum amylase, pancreatic edema, and pancreatic myeloperoxidase (MPO) activity. SP receptor (neurokinin-1 receptor, NK-1R) internalization in acinar cells, used as an index of endogenous SP release, was assessed by immunocytochemical quantification of NK-1R endocytosis. Caerulein administration caused significant increases in pancreatic edema, serum amylase, MPO activity, and NK-1R internalization. RTX treatment and ganglionectomy significantly reduced pancreatic edema by 46% (P < 0.001) and NK-1R internalization by 80% and 51% (P < 0.001 and P < 0.05, respectively). RTX administration also significantly reduced MPO activity by 47% (P < 0.05). Neither treatment affected serum amylase, consistent with a direct effect of caerulein. These results demonstrate that disruption of or local application of RTX to the celiac ganglion inhibits SP release in the pancreas and reduces the severity of acute secretagogue-induced pancreatitis. It is possible that selectively disrupting TRPV1-bearing neurons could be used to reduce pancreatitis severity.

TRPV1; endocytosis; resiniferatoxin; neurogenic inflammation; neurokinin-1 receptor

NEUROGENIC INFLAMMATION RESULTS from activation of specific afferent sensory nerves leading to the release of neurotransmitters from nerve terminals that ultimately cause vasodilation, plasma extravasation, and cellular infiltration (11, 14). These effects can lead to mast cell degranulation, neutrophil adhesion, and the production of reactive oxygen species (1, 32, 34). Neurogenic inflammation is a major factor in the inflammatory response to injury in a number of organs including the pancreas. Recent data suggest that activation of primary sensory neurons and release of inflammatory mediators are important in determining the severity of pancreatitis (25).

Substance P (SP) is a neurokinin located within primary afferent sensory neurons and has a substantial role in mediating neurogenic inflammation. SP release causes extravasation of plasma from postcapillary venules in the pancreas as well as other gastrointestinal organs (5). SP is the specific ligand for the neurokinin-1 receptor (NK-1R).

NK-1Rs are located on a variety of cell types including inflammatory cells, smooth muscle cells, vascular endothelial cells, surface epithelia, and pancreatic acinar cells (3, 24, 26, 31). Activation of this receptor has been shown to mediate the release of various proinflammatory agents (24). Further experiments using NK-1R knockout mice have shown that pancreatic inflammation can be significantly attenuated in caerulein-induced pancreatitis (7). Alternatively, local infusion of the NK-1R antagonist CP-96345 into the pancreatic duct has been shown to significantly reduce the severity of pressure-induced pancreatitis (8). These data demonstrate that activation of the NK-1R is an important step in initiating the inflammatory cascade in the pancreas leading to more severe forms of pancreatitis and that blocking this receptor can reduce the severity of pancreatitis. Activation of the vanilloid capsaicin receptor TRPV1 located on C and A{delta} primary sensory neurons has been shown to mediate the release of SP (24). Pancreatic injury stimulates these neurons through the activation of TRPV1. Moreover, blocking TRPV1 significantly reduced SP release and pancreatitis severity (24).

Resiniferatoxin (RTX) is a specific TRPV1 agonist that, in high doses, selectively destroys C and A{delta} fibers by dramatically increasing intracellular calcium concentrations and disrupting vital organelles (28). In the current study, we hypothesized that local denervation of the C and A{delta} neurons innervating the pancreas via surgical ganglionectomy or administration of RTX to the ganglion would reduce the severity of acute secretagogue-induced pancreatitis. The celiac ganglion has nerves coursing it that directly innervate the pancreas, thus making it an attractive target for surgical or pharmacological denervation. We demonstrate that surgical excision or application of RTX to the celiac ganglion inhibits SP release and reduces the severity of secretagogue-induced pancreatitis.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Animal protocol and experimental design. All animal experiments were performed with approval of the Duke University Institutional Animal Care and Use Committee. Male Sprague-Dawley rats, weighing 250–300 g were purchased from Charles River Laboratories (Wilmington, MA) and housed in climate-controlled rooms with a 12:12-h light-dark cycle. All rats were fed standard laboratory diet until an overnight fast before the experiment. Rats were allocated to the following groups (n = 12): control, ganglionectomy, or RTX administration. On the day of the experiment, the rats were anesthetized with xylazine and ketamine in a 1:10 ratio at a dose of 0.1 ml/100 g body wt administered intramuscularly. At laparotomy, the intraperitoneal organs were moved superiorly in the abdominal cavity allowing for exposure of the aorta, superior mesenteric artery, and celiac artery. The technique of celiac ganglionectomy has been described previously (23), but briefly, the celiac ganglion was located within the area between the superior mesenteric artery and celiac artery. For those rats undergoing celiac ganglionectomy, the ganglion was removed. For those rats in the RTX group, 100 µl of RTX at a concentration of 100 µg/ml were applied to the ganglion over 30 min to apply a total dose of 10 µg. For those rats in the sham surgical group, 100 µl of vehicle were applied over 30 min. Rats were observed for 7 days after surgery during which time they were allowed food and water ad libitum. Seven days postoperatively, six rats from each group were designated to receive either caerulein or vehicle.

Caerulein-induced pancreatitis. The CCK analog caerulein was purchased from Bachem California (Torrance, CA) and dissolved in 0.1 M NaHCO3 followed by dilution in isotonic saline. Caerulein was prepared the morning of the experiment and stored on ice. After an overnight fast, caerulein was administered as six hourly intraperitoneal injections at a supramaximal-stimulating dose of 50 µg/kg per injection (15). Control rats received six hourly intraperitoneal injections of isotonic saline. One hour after the last caerulein injection, rats were euthanized in a carbon dioxide precharged chamber. Mixed arteriovenous blood was collected by decapitation for measurement of serum amylase activity. The pancreas was then removed, weighed, and compared with body weight as a measure of edema and divided for histological grading, measurement of tissue myeloperoxidase (MPO), and measurement of NK-1R endocytosis.

Serum amylase concentration. Mixed arteriovenous blood was centrifuged for 10 min at 1,500 g. The serum amylase concentration was measured by using the Procion yellow starch assay as previously described (13). A standard curve was prepared by using crude type VI-B {alpha}-amylase (Sigma, St. Louis, MO), and serum amylase was expressed as milligrams per milliliter.

MPO activity. Portions of pancreas were immediately frozen. MPO, an enzyme produced by neutrophils, was used as a marker of inflammation associated with neutrophil infiltration, as previously described (4). The assay was performed in microtiter plates using a Safire plate reader from Tecan, with measurement wavelength at 450 nm and reference wavelength at 650 nm. Human MPO (Sigma) was used as standard. Protein concentration of the pancreatic extract was determined using the micro BCA protein assay (Pierce). Results were expressed in MPO units per milligram protein.

Histology. Portions of the pancreas were fixed overnight at room temperature in a pH-neutral, phosphate-buffered, 10% formalin solution. The tissue was then embedded in paraffin, sectioned at 5 µm, and stained with hematoxylin and eosin. Histological severity of pancreatitis was rated by a histologist blinded to the study design using a scale of 0–4 and included parameters of edema, necrosis, and neutrophil infiltration.

Immunocytochemical analysis of SP release. SP release was assessed by analysis of NK-1R endocytosis as described previously (19, 24).

Quantification of NK-1R endocytosis. Immunostained sections were analyzed using a Zeiss LSM-410 inverted krypton-argon confocal laser-scanning system coupled to a Zeiss Axiovert 100 microscope as described (19, 24). Optical sections (0.5 µm) of 512 x 512 pixels were obtained and processed using Adobe PhotoDeluxe. Quantification of NK-1R endocytosis was performed by analyzing 10 NK-1R immunoreactive acinar cells per mouse (n = 5) and determining the number of these cells containing >15 NK-1R-immunoreactive endosomes. Cytoplasmic endosomes were distinguished from plasma membrane-associated NK-1R immunoreactivity by ensuring that the nucleus of the acinar cells was in the same optical section as the NK-1R-immunoreactive endosomes.

Statistical analysis. Results are means ± SE. Statistical comparisons among groups were examined by one-way ANOVA with the Tukey posttest, using GraphPad Prism version 4.02. Statistical significance was set at P < 0.05.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Repeated administration of supramaximal-stimulating doses of caerulein caused pancreatitis as evidenced by elevations in pancreatic edema, MPO activity, and serum amylase. Caerulein-treated, sham-operated rats had a 3.25-fold increase in pancreas-to-body weight ratio (0.004 vs. 0.013, P < 0.001, n = 6) (Fig. 1). As shown in Fig. 2, caerulein substantially increased the size of the gross pancreas. Caerulein-treated, sham-operated rats also demonstrated a 2.8-fold increase in MPO levels (27.5 vs. 76.1 U/mg pancreatic protein, P < 0.01) (Fig. 3) and a 5.5-fold increase in amylase levels (1.2 vs. 6.6 mg/ml, P < 0.001) (Fig. 4) compared with vehicle-treated, sham-operated rats.


Figure 1
View larger version (16K):
[in this window]
[in a new window]
  		Fig. 1. Quantification of pancreatic edema. Pancreatic edema was measured by comparing pancreas:body weight ratios expressed in grams. Caerulein administration significantly increased pancreatic pancreas-to-body weight ratio (****P < 0.0001). This effect was inhibited by both ganglionectomy (GN) and application of resiniferatoxin (RTX) to the celiac ganglion (***P < 0.001) (n = 6).

 

Figure 2
View larger version (101K):
[in this window]
[in a new window]
  		Fig. 2. Effects of caerulein, GN, and RTX treatment on pancreatic size. Photographs are representative of pancreata from rats treated with vehicle alone (A), caerulein alone (B), caerulein + GN (C), and caerulein + RTX (D).

 

Figure 3
View larger version (18K):
[in this window]
[in a new window]
  		Fig. 3. Effect of GN and RTX on caerulein-induced MPO activity. Caerulein administration significantly increased pancreatic MPO activity that was inhibited by RTX pretreatment. (*P < 0.05, **P < 0.01, n = 5 or 6).

 

Figure 4
View larger version (18K):
[in this window]
[in a new window]
  		Fig. 4. Effect of GN and RTX on serum amylase. Caerulein treatment significantly increased serum amylase levels (***P < 0.001, n = 6). These elevated values were unaltered by GN or RTX pretreatment.

 
We hypothesized that primary sensory neuronal function, particularly SP release, was important in the pancreatic response to caerulein-induced injury. To investigate whether SP release occurred in the pancreas following caerulein administration, NK-1R internalization on pancreatic acinar cells was quantified. Caerulein treatment significantly increased NK-1R internalization with only 6% of cells demonstrating ≥15 vesicles per cell under basal conditions compared with 92% of cells following caerulein treatment (P < 0.0001) as shown in Figs. 5 and 6.


Figure 5
View larger version (16K):
[in this window]
[in a new window]
  		Fig. 5. Quantification of NK-1R endocytotic vesicles in pancreatic acinar cells. The number of acinar cells (n = 10/treatment) containing more than 15 NK-1R-immunoreactive endosomes was used as a measure of the relative amount of substance P released. Caerulein significantly stimulated NK-1R internalization (****P < 0.0001), and both GN and RTX administration significantly inhibited these effects (*P < 0.05, ****P < 0.0001 vs. caerulein).

 

Figure 6
View larger version (133K):
[in this window]
[in a new window]
  		Fig. 6. Confocal microscopic images of pancreatic acinar cells stained for NK-1R immunoreactivity. Acinar cells are stained with specific NK-1R antisera from rats treated with vehicle alone (A), caerulein alone (B), caerulein + GN (C), and caerulein + RTX (D). A single acinar cell is shown in each panel.

 
The axons of primary sensory nerves innervating the pancreas course through the celiac ganglion. To determine whether interruption of these nerves might affect SP release and the inflammatory response following caerulein administration, surgical ganglionectomy was performed. Celiac ganglionectomy caused a 46% reduction in pancreas-to-body weight ratio (0.013 vs. 0.007, P < 0.001) (Fig. 1), indicating a significant reduction in caerulein-induced pancreatic edema. Similarly, NK-1R internalization was reduced by 51% in caerulein-treated rats postceliac ganglionectomy. Although MPO activity was lower in rats that underwent ganglionectomy, this result was not statistically significant. Amylase activity was not statistically different between any of the observed groups, which is consistent with caerulein having a direct effect on the pancreas (24, 25).

To determine whether selective destruction of primary sensory neurons in the celiac ganglion may alter caerulein-induced pancreatitis, RTX was applied to the celiac ganglion. RTX is a selective agonist of TRPV1 that, in high concentrations, selectively destroys C and A{delta} fibers. Importantly, RTX administration to the celiac ganglion reduced caerulein-induced pancreatic edema by 46% (0.013 vs. 0.007 g, P < 0.001) (Fig. 1), MPO activity by 47% (76.1 vs. 40.2 U/mg protein, P < 0.05) (Fig. 3), and NK-1R internalization by 80% (Figs. 5 and 6). To confirm that RTX was acting locally at the ganglion and did not have a systemic effect, an eye-wipe test was performed. The eye-wipe responses to corneal application of 0.1% capsaicin were identical in both RTX- and sham-treated rats, indicating that RTX did not cause systemic destruction of primary sensory neurons (results not shown).

Ganglionectomy and RTX treatments alone had no effect on any pancreas measurements and were not different from rats that had sham surgery (results not shown).

The gross appearances of the pancreas from vehicle- and caerulein-treated rats with and without ganglionectomy or RTX pretreatment are shown in Fig. 2. Both celiac ganglionectomy and RTX substantially reduced the marked edematous enlargement of the pancreas stimulated by caerulein. Figure 7 shows histological sections of pancreas from the same groups. Caerulein treatment caused edema, cellular disruption, acinar cell vacuolization, and necrosis. These parameters were significantly reduced in pancreata from animals treated with celiac ganglionectomy or RTX.


Figure 7
View larger version (78K):
[in this window]
[in a new window]
  		Fig. 7. Effects of caerulein, GN, and RTX treatment on pancreatic histology. A: representative histology sections of pancreas from rats treated with vehicle alone (A), caerulein alone (B), caerulein + GN (C), and caerulein + RTX (D). B: histological severity of pancreatitis was evaluated using a scale of 0–4 (see MATERIALS AND METHODS). ***P < 0.001.

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
It has previously been shown that SP mediates many of the changes that are characteristic of neurogenic inflammation (5). Through interaction with the NK-1R, SP induces plasma extravasation from postcapillary venules and neutrophil infiltration (22). Mice with genetic deletion of NK-1R are protected against secretagogue-induced pancreatitis (2) and choline-deficient, ethionine-supplemented diet-induced hemorrhagic pancreatitis (18), suggesting that blocking the effects of SP mitigates neurogenic inflammation, which appears to be important in the pathogenesis of acute pancreatitis. Conversely, it has been shown that preventing the degradation of SP by inhibition of the membrane protease, neutral endopeptidase, causes a relative increase in SP and can increase plasma extravasation (17). These studies suggest that SP through its interaction with the NK-1R is instrumental in the pathogenesis of neurogenic inflammation.

Primary sensory neurons of the C and A{delta} subtype synthesize SP, which is released from nerve endings upon stimulation (9, 10, 29). It has been demonstrated in secretagogue and obstructive models of pancreatitis that primary sensory denervation reduces the severity of pancreatic inflammation (25). This finding supported a role for these neurons being a common pathway for the development of neurogenic inflammation. TRPV1 is a nonselective cation channel that resides on C and A{delta} fibers, which when activated causes the release of SP. Systemic administration of the TRPV1 inhibitor capsazepine has been shown to reduce the severity of secretagogue-induced pancreatitis (24). However, local denervation of primary sensory neurons of the pancreas as a means to reduce neurogenic inflammation has not been reported previously. We hypothesized that selective disruption of the nerves that directly innervate the pancreas could decrease the severity of secretagogue-induced pancreatitis. Innervation of the pancreas by primary sensory neurons originates from dorsal root ganglion cells (35). The axons of these nerve fibers course through the celiac ganglion making it a possible target for pharmacological or surgical manipulation.

In this study, we sought to compare surgical vs. pharmacological denervation of pancreatic primary sensory neurons. RTX is a member of the vanilloid family but is more potent than capsaicin for activating the TRPV1 receptor (30). When RTX is applied to TRPV1-expressing cells, a significant and prolonged increase in free intracellular calcium occurs (33). The resultant calcium toxicity destroys only the TRPV1-expressing cells (28). In the present study, we applied RTX to the celiac ganglion to selectively eliminate TRPV1-expressing primary sensory neurons. To confirm that the effect of RTX administration to the celiac ganglion was local rather than systemic, we evaluated chemogenic pain perception by forepaw eye-wiping movements in response to application of 0.1% capsaicin (16). Previous studies have shown that systemic denervation of primary sensory nerves attenuates the eye-wipe response (12). Our finding that the eye-wipe response was similar in RTX and sham groups indicates that animals did not have systemic denervation.

Both in vitro and in vivo studies have demonstrated that after binding SP, the NK-1R is rapidly internalized by endocytosis and eventually recycled to the plasma membrane after degradation of bound SP (3, 20, 21). In the current study, we used quantification of NK-1R-immunoreactive endosomes in pancreatic acinar cells to provide an estimate of endogenous SP release. This is a measure of dynamic SP release (rather than total SP content in the pancreas, which may not reflect SP release) and has been used in a number of other studies for evaluating SP release (3, 6, 19, 20, 21). In the current study, we demonstrated that caerulein-induced pancreatitis was associated with an increase in NK-1R internalization, which was reduced by both surgical celiac ganglionectomy and RTX treatment to the celiac ganglion. We believed that both of these maneuvers interrupt primary sensory nerve signaling, thereby reducing SP release in the pancreas. Both RTX administration and ganglionectomy reduced NK-1R internalization. The magnitude of this reduction was similar to the decline in other parameters of inflammation such as decreases in pancreatic MPO levels and edema. It is not surprising that RTX application to the celiac ganglion was not identical to celiac ganglionectomy. Treatment with RTX selectively destroys TRPV1-bearing neurons, which, in turn, prevents the subsequent release of SP and other transmitters of C and A{delta} fibers (e.g., CGRP). Therefore, RTX treatment would be expected to have some actions similar to administration of an SP antagonist. Ganglionectomy, on the other hand, destroys the nerves and axons of the celiac ganglion. Because of this, ganglionectomy affects multiple types of neurons, some of which may even play a protective role against pancreatitis.

Although the application of RTX to the celiac ganglion and celiac ganglionectomy both appear to decrease the severity of pancreatitis as demonstrated by reductions in MPO activity, edema, and histological scoring, they do not completely prevent pancreatitis. These findings suggest that these interventions are affecting only one pathway that contributes to the development of pancreatitis. Extensive cellular injury can produce inflammation that involves other mediators that may not have a neurogenic component. Although it is unknown whether inhibition of other neural pathways could further reduce the severity of pancreatitis, we expect that neurogenic influences represent only one of several important processes in the pathogenesis of the disease.

Similar to other studies, reduction of pancreatitis severity was not accompanied by a decrease in serum amylase levels, which is consistent with direct hypestimulation of the pancreas by caerulein (25). Even in experimental pancreatitis, hyperamylasemia is not synonymous with pancreatitis, and we believe that the hyperamylasemia observed in the current study is consistent with caereulein-induced pancreatic injury that does not necessarily lead to pancreatitis. Previous studies have also found that the levels of amylase in the disease course of pancreatitis can be variable and do not correlate accurately with the severity of pancreatitis (25, 27).

In conclusion, caerulein-induced pancreatitis is associated with an increase in NK-1R internalization, consistent with local release of SP; marked pancreatic edema and neutrophil infiltration; and changes in pancreatic histology, indicative of acute pancreatitis. Surgical disruption or local application of RTX to the celiac ganglion reduced NK-1R internalization and reduced the severity of acute secretagogue-induced pancreatitis. These findings indicate that activation of primary sensory nerves is involved in the pancreatic response to injury. It is possible that selectively disrupting TRPV1-bearing neurons could be used to reduce pancreatitis severity.


   FOOTNOTES
 

Address for reprint requests and other correspondence: R. A. Liddle, Box 3913, Duke Univ. Medical Center, Durham, NC 27710

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Baluk P, Bertrand C, Geppetti P, McDonald DM, and Nadel JA. NK1 receptors mediate leukocyte adhesion in neurogenic inflammation in the rat trachea. Am J Physiol Lung Cell Mol Physiol 268: L263–L269, 1995.[Abstract/Free Full Text]
  2. Bhatia M, Saluja AK, Hofbauer B, Frossard JL, Lee HS, Castagliuolo I, Wang CC, Gerard N, Pothoulakis C, and Steer ML. Role of substance P and the neurokinin 1 receptor in acute pancreatitis and pancreatitis-associated lung injury. Proc Natl Acad Sci USA 95: 4760–4765, 1998.[Abstract/Free Full Text]
  3. Bowden JJ, Garland AM, Baluk P, Lefevre P, Grady EF, Vigna SR, Bunnett NW, and McDonald DM. Direct observation of substance P-induced internalization of neurokinin 1 (NK1) receptors at sites of inflammation. Proc Natl Acad Sci USA 91: 8964–8968, 1994.[Abstract/Free Full Text]
  4. Bradley PP, Priebat DA, Christensen RD, and Rothstein G. Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker. J Invest Dermatol 78: 206–209, 1982.[CrossRef][ISI][Medline]
  5. Figini M, Emanueli C, Grady EF, Kirkwood K, Payan DG, Ansel J, Gerard C, Geppetti P, and Bunnett N. Substance P and bradykinin stimulate plasma extravasation in the mouse gastrointestinal tract and pancreas. Am J Physiol Gastrointest Liver Physiol 272: G785–G793, 1997.[Abstract/Free Full Text]
  6. Grady EF, Garland AM, Gamp PD, Lovett M, Payan DG, and Bunnett NW. Delineation of the endocytic pathway of substance P and its seven-transmembrane domain NK1 receptor. Mol Biol Cell 6: 509–524, 1995.[Abstract]
  7. Grady EF, Yoshimi SK, Maa J, Valeroso D, Vartanian RK, Rahim S, Kim EH, Gerard C, Gerard N, Bunnett NW, and Kirkwood KS. Substance P mediates inflammatory oedema in acute pancreatitis via activation of the neurokinin-1 receptor in rats and mice. Br J Pharmacol 130: 505–512, 2000.[CrossRef][ISI]
  8. He ZJ, Winston JH, Yusuf TE, Micci MA, Elfert A, Xiao SY, and Pasricha PJ. Intraductal administration of an NK1 receptor antagonist attenuates the inflammatory response to retrograde infusion of radiological contrast in rats: implications for the pathogenesis, and prevention of ERCP-induced pancreatitis. Pancreas 27: e13–e17, 2003.[CrossRef][ISI][Medline]
  9. Hokfelt T, Kellerth JO, Nilsson G, and Pernow B. Experimental immunohistochemical studies on the localization, and distribution of substance P in cat primary sensory neurons. Brain Res 100: 235–252, 1975.[CrossRef][ISI][Medline]
  10. Hokfelt T, Kellerth JO, Nilsson G, and Pernow B. Substance p: localization in the central nervous system, and in some primary sensory neurons. Science 190: 889–890, 1975.[Abstract/Free Full Text]
  11. Holzer P. Local effector functions of capsaicin-sensitive sensory nerve endings: involvement of tachykinins, calcitonin gene-related peptide, and other neuropeptides. Neuroscience 24: 739–768, 1988.[CrossRef][ISI][Medline]
  12. Jancso G. Selective degeneration of chemosensitive primary sensory neurones induced by capsaicin: glial changes. Cell Tissue Res 195: 145–152, 1978.[ISI][Medline]
  13. Jung DH. Preparation, and application of Procion Yellow starch for amylase assay. Clin Chim Acta 100: 7–11, 1980.[CrossRef][ISI][Medline]
  14. Kenins P. Identification of the unmyelinated sensory nerves which evoke plasma extravasation in response to antidromic stimulation. Neurosci Lett 25: 137–141, 1981.[CrossRef][ISI][Medline]
  15. Lampel M and Kern HF. Acute interstitial pancreatitis in the rat induced by excessive doses of a pancreatic secretagogue. Virchows Arch A Pathol Anat Histol 373: 97–117, 1977.[CrossRef][Medline]
  16. Lundberg JM and Saria A. Capsaicin-induced desensitization of airway mucosa to cigarette smoke, mechanical, and chemical irritants. Nature 302: 251–253, 1983.[CrossRef][Medline]
  17. Maa J, Grady EF, Kim EH, Yoshimi SK, Hutter MM, Bunnett NW, and Kirkwood KS. NK1 receptor desensitization, and neutral endopeptidase terminate SP-induced pancreatic plasma extravasation. Am J Physiol Gastrointest Liver Physiol 279: G726–G732, 2000.[Abstract/Free Full Text]
  18. Maa J, Grady EF, Yoshimi SK, Drasin TE, Kim EH, Hutter MM, Bunnett NW, and Kirkwood KS. Substance P is a determinant of lethality in diet-induced hemorrhagic pancreatitis in mice. Surgery 128: 232–239, 2000.[CrossRef][ISI][Medline]
  19. Mantyh CR, Pappas TN, Lapp JA, Washington MK, Neville LM, Ghilardi JR, Rogers SD, Mantyh PW, and Vigna SR. Substance P activation of enteric neurons in response to intraluminal Clostridium difficile toxin A in the rat ileum. Gastroenterology 111: 1272–1280, 1996.[CrossRef][ISI][Medline]
  20. Mantyh PW, Allen CJ, Ghilardi JR, Rogers SD, Mantyh CR, Liu H, Basbaum AI, Vigna SR, and Maggio JE. Rapid endocytosis of a G protein-coupled receptor: substance P evoked internalization of its receptor in the rat striatum in vivo. Proc Natl Acad Sci USA 92: 2622–2626, 1995.[Abstract/Free Full Text]
  21. Mantyh PW, DeMaster E, Malhotra A, Ghilardi JR, Rogers SD, Mantyh CR, Liu H, Basbaum AI, Vigna SR, Maggio JE, and Simone DA. Receptor endocytosis and dendrite reshaping in spinal neurons after somatosensory stimulation. Science 268: 1629–1632, 1995.[Abstract/Free Full Text]
  22. McDonald DM, Bowden JJ, Baluk P, and Bunnett NW. Neurogenic inflammation. A model for studying efferent actions of sensory nerves. Adv Exp Med Biol 410: 453–462, 1996.[Medline]
  23. Nakao K, Takahashi T, Utsunomiya J, and Owyang C. Extrinsic neural control of nitric oxide synthase expression in the myenteric plexus of rat jejunum. J Physiol 507: 549–560, 1998.[Abstract/Free Full Text]
  24. Nathan JD, Patel AA, McVey DC, Thomas JE, Prpic V, Vigna SR, and Liddle RA. Capsaicin vanilloid receptor-1 mediates substance P release in experimental pancreatitis. Am J Physiol Gastrointest Liver Physiol 281: G1322–G1328, 2001.[Abstract/Free Full Text]
  25. Nathan JD, Peng RY, Wang Y, McVey DC, Vigna SR, and Liddle RA. Primary sensory neurons: a common final pathway for inflammation in experimental pancreatitis in rats. Am J Physiol Gastrointest Liver Physiol 283: G938–G946, 2002.[Abstract/Free Full Text]
  26. O'Connor TM, O'Connell J, O'Brien DI, Bennett MW, Goode T, Burke L, Bredin CP, and Shanahan F. Upregulation of neurokinin-1 receptor expression in the lungs of patients with sarcoidosis. J Clin Immunol 23: 425–435, 2003.[CrossRef][ISI][Medline]
  27. Ohshio G, Saluja A, and Steer ML. Effects of short-term pancreatic duct obstruction in rats. Gastroenterology 100: 196–202, 1991.[ISI][Medline]
  28. Olah Z, Szabo T, Karai L, Hough C, Fields RD, Caudle RM, Blumberg PM, and Iadarola MJ. Ligand-induced dynamic membrane changes, and cell deletion conferred by vanilloid receptor 1. J Biol Chem 276: 11021–11030, 2001.[Abstract/Free Full Text]
  29. Pernow B. Substance P: its distribution, pharmacological actions, and possible physiological role in sensory neurons. Clin Physiol 1: 235–251, 1981.[ISI][Medline]
  30. Ralevic V, Jerman JC, Brough SJ, Davis JB, Egerton J, and Smart D. Pharmacology of vanilloids at recombinant, and endogenous rat vanilloid receptors. Biochem Pharmacol 65: 143–151, 2003.[CrossRef][ISI][Medline]
  31. Renzi D, Pellegrini B, Tonelli F, Surrenti C, and Calabro A. Substance (neurokinin-1) P, and neurokinin A (neurokinin-2) receptor gene and protein expression in the healthy and inflamed human intestine. Am J Pathol 157: 1511–1522, 2000.[Abstract/Free Full Text]
  32. Saban MR, Saban R, Bjorling D, and Haak-Frendscho M. Involvement of leukotrienes, TNF-alpha, and the LFA-1/ICAM-1 interaction in substance P-induced granulocyte infiltration. J Leukoc Biol 61: 445–451, 1997.[Abstract]
  33. Szallasi A and Blumberg PM. Resiniferatoxin, a phorbol-related diterpene, acts as an ultrapotent analog of capsaicin, the irritant constituent in red pepper. Neuroscience 30: 515–520, 1989.[CrossRef][ISI][Medline]
  34. Tanabe T, Otani H, Bao L, Mikami Y, Yasukura T, Ninomiya T, Ogawa R, and Inagaki C. Intracellular signaling pathway of substance P-induced superoxide production in human neutrophils. Eur J Pharmacol 299: 187–195, 1996.[CrossRef][ISI][Medline]
  35. Won MH, Park HS, Jeong YG, and Park HJ. Afferent innervation of the rat pancreas: retrograde tracing, and immunohistochemistry in the dorsal root ganglia. Pancreas 16: 80–87, 1998.[ISI][Medline]



This article has been cited by other articles:


Home page
 GutHome page
M D Noble, J Romac, S R Vigna, and R A Liddle
A pH-sensitive, neurogenic pathway mediates disease severity in a model of post-ERCP pancreatitis
Gut, November 1, 2008; 57(11): 1566 - 1571.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Gastrointest. Liver Physiol.Home page
M. Yamamoto, J. R. Reeve Jr., and G. M. Green
Supramaximal CCK-58 does not induce pancreatitis in the rat: role of pancreatic water secretion
Am J Physiol Gastrointest Liver Physiol, April 1, 2007; 292(4): G964 - G974.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (5)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Noble, M. D.
Right arrow Articles by Liddle, R. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Noble, M. D.
Right arrow Articles by Liddle, R. A.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2006 by the American Physiological Society.