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Keywords:

  • cisplatin;
  • emesis;
  • gastric emptying;
  • pica;
  • radiology;
  • rat

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author contributions
  9. Competing interests
  10. Conflict of interest
  11. References

Background  Chemotherapy induces nausea/emesis and gastrointestinal dysmotility. Pica, the ingestion of non-nutritive substances, is considered as an indirect marker of nausea/emesis in non-vomiting species, like the rat. Cisplatin is the most emetogenic antitumoral drug. In the rat, acute cisplatin induces pica and gastric dysmotility in a temporally related manner, but the effects of chronic cisplatin are not well known. This study analyzed the effects of chronic cisplatin on pica and on gastrointestinal motor function in the rat, using radiographic, non-invasive methods.

Methods  Rats received saline or cisplatin (1–3 mg kg−1, i.p.) once a week for four consecutive weeks. Serial X-rays were taken 0–8 h after administration of barium sulfate, which was given intragastrically immediately after the first and last cisplatin administrations and 1 week after treatment finalization. Pica (i.e., kaolin intake) was measured in isolated rats.

Key Results  Cisplatin delayed gastric emptying and induced acute (during the 24 h following each administration) pica. Upon chronic administration, these effects were exacerbated. In addition, basal kaolin intake was enhanced (facilitated) and gastric distension induced. Delayed gastric emptying and gastric distension were not apparent 1 week after treatment, but basal kaolin intake was still elevated.

Conclusions & Inferences  Whereas gastric dysmotility induced by cisplatin is parallel to the development of acute pica and might underlie facilitation of pica throughout chronic treatment, it does not explain its long-term maintenance. These findings should be taken into account in the search for new antiemetic strategies.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author contributions
  9. Competing interests
  10. Conflict of interest
  11. References

Nausea and vomiting are important side effects of chemotherapy, potentially leading to poor quality of life and, as nausea is a highly aversive sensation (it has been argued to be more aversive than pain),1 patient compliance with drug treatment may be affected.2 While both 5-HT3 and NK1 receptor antagonists have had a major impact upon patients’ experience of chemotherapy, they do not completely block nausea and vomiting in all patients and nausea is less well treated than vomiting.2 Furthermore, resistance to antiemetics may develop during chronic chemotherapy.3

Cisplatin is an antineoplastic drug used clinically for a variety of malignancies (ovarian, testicular, lung, colon, and others). It is a very toxic agent capable of inducing nephrotoxicity, ototoxicity, and peripheral sensorial neuropathy. In addition, it induces nausea and emesis, anorexia and weight loss. In fact, it is among the most emetogenic antitumoral drugs4 and serves as a reference for the study of antiemetics in experimental animals.5

In the rat, which does not vomit in response to emetogenic stimuli, indirect markers need to be used. One such marker, pica, consists of the ingestion of non-nutritive substances, i.e., kaolin,6–11 and develops in the rat not only after acute7,8,12 but also upon chronic administration of cisplatin.10,11

Gastric dysrhythmia has also been correlated with malaise in animal models of nausea and vomiting and nausea in humans in a variety of conditions, including chemotherapy.13–17 Alterations in gastric rhythm might also be triggered by emetogenic stimuli in the rat. In fact, together with increased chewing and swallowing, delayed gastric emptying is the main response in the rat to substances that would induce vomiting in other species such as the ferret,5 and it has been argued to be a surrogate marker of vomiting in these non-emetic species.2,18 Interestingly, delayed gastric emptying showed a strict temporal relationship with pica behavior induced by acute cisplatin in the rat.12 In addition to pica and gastric dysmotility, chronic administration of cisplatin might induce motility alterations in other gastrointestinal (GI) regions.

Therefore, the aim of this work was to determine the effects of chronic cisplatin administration, which better mimics the clinical situation,10,11 on GI motility (gastric emptying and intestinal transit) in the rat, using radiographic methods.12 These methods are excellent to non-invasively examine motility alterations in the different GI regions upon acute12 and chronic treatments.19 A parallel pica study was also performed for comparison.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author contributions
  9. Competing interests
  10. Conflict of interest
  11. References

The experiments were designed and performed in strict accordance with the EC regulations for care and use of experimental animals (EEC No. 86/609) and were approved by the Ethical Committee at the Universidad Rey Juan Carlos.

Animals

Male Wistar rats (250–275 g) were obtained from Harlan Laboratories (Barcelona, Spain). Upon arrival to our laboratory, animals were housed, isolated (for the pica study) or grouped (4–6 per cage, for the radiographic study), in standard transparent cages (60 × 40 × 20 cm) that were furnished with wood shaving bedding, which was changed every 1–2 days. Cages were placed adjacent to each other under environmentally controlled conditions (temperature: 20 °C; humidity: 60%) with a 12 h light/12 h dark cycle (lights on between 08:00 and 20:00 hours). Animals had free access to standard laboratory rat chow (Harlan Laboratories) and tap water. For the pica experiments, pellets of both food (150 ± 1 g) and kaolin (15 ± 0.1 g) were placed in adjacent, separate compartments in a divided food hopper and were continuously available throughout the experiment. Experiments started at least 1 week after arrival of animals to the laboratory.

Experimental protocol

During the first week, rats were habituated to the testing procedures and to daily handling by the investigator. This week of adaptation was considered as a control period and is termed as experimental week 0 (W0) hereafter. In the pica study, isolated rats were habituated also to the presence of kaolin pellets (see below) for an additional week (W0′) prior to the beginning of the experiment. After these periods of adaptation, rats received one intraperitoneal injection once per week for 4 weeks on the first day of each experimental week (W1–W4), of either cisplatin (at 1, 2, or 3 mg kg−1; termed Cispt 1, 2, or 3, 1 mL kg−1) or saline (0.9% w/v, 1 mL kg−1). To prevent eventual nephrotoxicity induced by chronically administered cisplatin, 2 mL of saline was also injected subcutaneously just before intraperitoneal saline or cisplatin injection.20

Evaluation of overall health and neuropathy

All rats were regularly examined throughout the experiment to detect signs of general toxicity.

In the grouped rats, bodyweight gain, nociceptive responses indicative of neuropathy, rectal temperature, and spontaneous locomotion were measured in that sequence, 1 week after treatment finalization (W5), with an interval of 5 min between tests.

The development of peripheral nociceptive neuropathy was evaluated using tests for both mechanical allodynia and heat-hypo/hyperalgesia. For mechanical allodynia, which was measured first, rats were placed individually on an elevated iron mesh in a clear plastic cage and were allowed to adapt to the testing environment for at least 10 min. Habituation to this environment was also performed on 2 days before assessment. Calibrated von Frey hairs ranging from 0.9 to 40 g (0.9, 1.4, 2.1, 2.5, 3, 4, 5.5, 7.5, 8, 10.5, 13, 14, 15, 17, 25, 27, 32, and 40 g) were applied to the plantar aspect of each hindpaw, from below the mesh floor. Each stimulus was applied for a maximum duration of approximately 2 s, and this was repeated five times with 1- to 3-s intervals. Only robust and immediate withdrawal responses to the stimulus were recorded. A positive result was considered when at least three of five responses were obtained (60%) with each filament, and this value was considered as the tactile threshold. If less than three positive responses were noted in any hair trial, the process was repeated with the next higher force hair. Mechanical allodynia was defined as a significant decrease in von Frey hair threshold evoked by mechanical stimuli. The 40 g hair was selected as the upper cut-off limit for testing.

Responses to thermal stimuli were evaluated right after mechanical allodynia, using a 37370 plantar test apparatus (Ugo Basile, Comerio VA, Italy). The withdrawal latency from a focused beam of radiant heat applied to the mid-plantar surface of the hindpaws was recorded. The intensity of the light was adjusted at the beginning of the experiment so that the control average baseline latencies were about 8 s, and a cut-off latency of 25 s was imposed. The withdrawal latency of each paw was measured during three trials separated by 2-min intervals, and the mean of the three readings was used for data analysis.

Core temperatures were measured using a P6 thermometer and a lubricated rectal probe (Cibertec, Madrid, Spain) inserted into the rectum to a constant depth of 5 cm.

Spontaneous locomotor activity was evaluated using individual photocell activity chambers (Cibertec). Rats were placed in the recording chambers (55 × 40 cm, with a 3-cm spacing between beams), and the number of interruptions of photocell beams was recorded over a 10-min period. The mean number of crossings of the photocell beams was used for comparison.

Evaluation of gastrointestinal motility (radiographic study)

Gastrointestinal motility was analyzed in grouped rats using radiological non-invasive methods as recently described.12 Briefly, 2.5 mL of a suspension of barium sulfate (2 g mL−1, temperature = 22 °C, Barigraf® AD; Juste SAQF, Madrid, Spain) were orally administered, and serial X-rays were taken immediately and 1, 2, 4, 6, and 8 h after contrast administration. The contrast medium was given three times throughout the experiment: immediately after the first (W1: acute effect) and last (W4: chronic effect) cisplatin administrations and 1 week after treatment finalization (W5: residual effect). Gastrointestinal motor function was semiquantitatively determined from the images by assigning a compounded value to the organ (stomach, small intestine, cecum, and colorectum), from 0 to 12 points, taking into consideration the following parameters:12 percentage of the organ filled by contrast (0–4 points); intensity of contrast (0–4 points); homogeneity of contrast (0–2 points); and sharpness of the GI region profile (0–2 points). This analysis was performed in a blinded fashion by a trained investigator.

Evaluation of feeding behavior (pica study)

Food ingestion and pica (i.e., kaolin intake) were determined in isolated rats as previously described,10,11 by subtracting the amount of food/kaolin remaining from the amount provided the day before, for each cage. Care was taken to collect all particles, which were weighed to correct for the values of food and kaolin consumption to the nearest 1 and 0.01 g, respectively. These parameters were measured at least 4 days a week (including the day before and 3 days after cisplatin or saline administration), throughout the whole experiment: W0′ (week of adaptation to kaolin exposure), W1–W4 (weeks in which cisplatin or saline was administered), and W5 (1 week after the last administration). In this study, only the effects of Cispt 1 and 2 were tested, because in a previous study the dose of 3 mg kg−1 was too toxic and induced mortality in some isolated rats.10

Kaolin, compounds, and drugs

Kaolin pellets were prepared as previously described.10 Briefly, pharmaceutical-grade kaolin (hydrated aluminum silicate; 98.5%) was mixed with 0.5% carmine and 1% gum arabic in distilled water to form a thick paste. Pellets of the resulting kaolin mixture were shaped to resemble the dimensions of the rats’ normal laboratory diet. The pellets were completely dried at room temperature for up to 48 h.

Barium sulfate (Barigraf® AD; Juste SAQF) was suspended in tap water and continuously hand-stirred until administration. Kaolin, carmine, gum arabic, and cisplatin were purchased from Sigma-Aldrich (Spain). Cisplatin was dissolved in saline (sonicated for about 15 min).

Statistical analysis

Data are presented as the mean values ± SEM. For a more accurate comparison, bodyweight gain is shown as percentage of change vs the average obtained for W0. Differences were analyzed using either Student’s t-test, with Welch’s correction where appropriate, or two-way anova followed by post hoc Bonferroni multiple comparison test. Values of P < 0.05 were regarded as being significantly different.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author contributions
  9. Competing interests
  10. Conflict of interest
  11. References

Irrespective of the dose used, 1 week after finalization of chronic treatment with cisplatin (W5), neither spontaneous locomotor activity (Fig. 1A), nor the withdrawal latency in the plantar test (Fig. 1D) was significantly altered. However, a dose-dependent decrease of core temperature (Fig. 1B) and a reduction of the threshold for mechanical allodynia (Fig. 1C) were found. Bodyweight gain was also reduced in a dose-dependent manner, and at the highest dose tested (3 mg kg−1), rats actually lost weight as compared to saline-treated animals.

image

Figure 1.  Effect of chronic cisplatin on overall health and nociceptive responses indicative of neuropathy in the rat. Spontaneous locomotor activity (A), rectal temperature (B), threshold for mechanical allodynia (C), withdrawal latency from a heat beam (plantar test, D) and bodyweight gain (E) were measured 1 week after treatment finalization. Either saline (1 mL kg−1) or cisplatin (Cispt) at 1, 2, or 3 mg kg−1 was administered once a week for 4 weeks. Bars show mean values ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 vs saline; ###P < 0.001 vs Cispt 1; +vs Cispt 2 (unpaired t-test with Welch’s correction). n ≥ 8 for all groups.

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As expected, after its first administration, cisplatin induced a dose-dependent delay in gastric emptying, as compared with saline-treated rats (Fig. 2A). When the radiographic analysis was carried out right after the last cisplatin administration, the effect of cisplatin, particularly at 2 mg kg−1, was enhanced (Fig. 2B). Thus, the maximum effect was seen with 3 mg kg−1 upon acute injection, and this effect was also achieved by the dose of 2 mg kg−1 but only after repeated administration. In addition, the size of the stomach was increased (Fig. 2G), and this effect was visible at least for the first 2 h after the last dose of cisplatin (Fig. 4G). However, 1 week after treatment finalization, no significant differences in gastric emptying (Fig. 2C) or size (Fig. 2H,I) were detected.

image

Figure 2.  Effect of cisplatin on motor function of the stomach (gastric emptying) in the rat. Gastric emptying was measured by radiological methods (see text). Either saline (1 mL kg−1) or cisplatin at 1, 2, or 3 mg kg−1 was administered once a week for 4 weeks. Barium sulfate (2.5 mL, 2 g mL−1) was intragastrically administered either immediately or 1 week after drug administration. (A–C) Acute (after first administration, A), chronic (after last administration, B) and residual (1 week after treatment finalization, C) effects are shown. X-rays were taken 0, 1, 2, 4, 6, and 8 h after barium administration. Data represent mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 vs saline (two-way anova followed by Bonferroni post hoc test). (D–I) Representative X-rays of rats treated with saline or cisplatin at 3 mg kg−1 (Cispt 3) taken 1 h after barium administration (D, E for acute, F, G for chronic, and H, I for residual effects). n ≥ 6 for all groups.

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image

Figure 4.  Effect of cisplatin on motor function of the cecum in the rat. Motor function was measured by radiological methods (see text). Either saline (1 mL kg−1) or cisplatin at 1, 2, or 3 mg kg−1 was administered once a week for 4 weeks. Barium sulfate (2.5 mL, 2 g mL−1) was intragastrically administered either immediately or 1 week after drug administration. (A–C) Acute (after first administration, A), chronic (after last administration, B) and residual (1 week after treatment finalization, C) effects are shown. X-rays were taken 0, 1, 2, 4, 6, and 8 h after barium administration. Data represent mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 vs saline (two-way anova followed by Bonferroni post hoc test). (D–I) Representative X-rays of rats treated with saline or cisplatin at 3 mg kg−1 (Cispt 3) taken 2 h after barium administration (D, E for acute, F, G for chronic, and H, I for residual effects). n ≥ 6 for all groups.

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The curve for small intestinal motility was not significantly different from the control curve after the first administration of cisplatin (Fig. 3A). However, slight but significant reductions of small intestinal transit were found both right after the last administration of the drug and 1 week after treatment (see emptying phase of the corresponding curves in Fig. 3B,C). Irrespective of the treatment received, clustered circular contractions of a ‘beading’ appearance were found throughout the small intestine (Figs 3E,I, 4G and 5E,G,I), suggesting that peristalsis and segmentation were scarcely affected by cisplatin.

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Figure 3.  Effect of cisplatin on motor function of the small intestine in the rat. Motor function was measured by radiological methods (see text). Either saline (1 mL kg−1) or cisplatin at 1, 2, or 3 mg kg−1 was administered once a week for 4 weeks. Barium sulfate (2.5 mL, 2 g mL−1) was intragastrically administered either immediately or 1 week after drug administration. (A–C) Acute (after first administration, A), chronic (after last administration, B) and residual (1 week after treatment finalization, C) effects are shown. X-rays were taken 0, 1, 2, 4, 6, and 8 h after barium administration. Data represent mean ± SEM. *P < 0.05, **P < 0.01 vs saline (two-way anova followed by Bonferroni post hoc test). (D–I) Representative X-rays of rats treated with saline or cisplatin at 3 mg kg−1 (Cispt 3) taken 4 h after barium administration (D, E for acute, F, G for chronic, and H, I for residual effects). n ≥ 6 for all groups.

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image

Figure 5.  Effect of cisplatin on motor function of the colorectum in the rat. Motor function was measured by radiological methods (see text). Either saline (1 mL kg−1) or cisplatin at 1, 2, or 3 mg kg−1 was administered once a week for 4 weeks. Barium sulfate (2.5 mL, 2 g mL−1) was intragastrically administered either immediately or 1 week after drug administration. (A–C) Acute (after first administration, A), chronic (after last administration, B) and residual (1 week after treatment finalization, C) effects are shown. X-rays were taken 0, 1, 2, 4, 6, and 8 h after barium administration. Data represent mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 vs saline (two-way anova followed by Bonferroni post hoc test). (D–I) Representative X-rays of rats treated with saline or cisplatin at 3 mg kg−1 (Cispt 3) taken 8 h after barium administration (D, E for acute, F, G for chronic, and H, I for residual effects). n ≥ 6 for all groups.

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The curves showing arrival to and filling of cecum (small intestinal transit), showed no significant differences after the first administration (Fig. 4A), but a slight, significant delay for cisplatin- vs saline-treated rats was evident after the last administration (Fig. 4B) and 1 week after treatment (Fig. 4C).

Finally, the curve for colorectal motility was slightly delayed after acute cisplatin administration (Fig. 5A), and this effect was enhanced to some extent after the last dose (Fig. 5B). However, motility 1 week after treatment was similar to that in the control group (Fig. 5C).

With regard to the pica study, food intake in saline-treated animals was initially 22.5 ± 1.1 g and did not significantly change throughout the experiment (W0–W5). Cisplatin at either dose induced a significant decrease in food ingestion in the 24 h immediately after administration (acute anorexia), and, for Cispt 2, this difference was enhanced with each administration. In addition, Cispt 2 (but not Cispt 1) induced some reduction in basal food ingestion (i.e., facilitated anorexia) throughout treatment. A week after treatment finalization (W5), basal food intake in the rats treated with Cispt 2 was similar to that in saline- or Cispt 1-treated animals (Fig. 6A).

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Figure 6.  Day-by-day analysis of food ingestion and pica (kaolin intake) in cisplatin-treated rats. Daily food ingestion (A) and daily kaolin intake (B) were measured in isolated rats exposed to kaolin and injected either with saline (1 mL kg−1 week−1, i.p., closed circles, n = 11) or cisplatin at 1 (open triangles, n = 11) or 2 mg kg−1 week−1 (closed triangles, n = 10) on the first day of experimental weeks 1, 2, 3, and 4. Data represent the mean ± S.E.M. *P < 0.05, **P < 0.01, ***P < 0.001 vs saline (two-way anova followed by Bonferroni test).

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After the first day of exposure to kaolin in the saline-treated rats, kaolin intake was lower than 0.2 g and remained around those values for the rest of the experiment (W0–W5). Cispt 2 (but not Cispt 1) induced significant kaolin intake in the 24 h after administration (acute pica), and basal kaolin intake increased throughout treatment, confirming that chronic treatment with cisplatin, at a sufficiently high dose, is associated with facilitation of pica. One week after treatment finalization, the levels of kaolin intake were still significantly elevated in the rats treated with Cispt 2 in comparison with saline- or Cispt 1-treated animals (Fig. 6B).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author contributions
  9. Competing interests
  10. Conflict of interest
  11. References

In this work, we studied the alterations induced by chronic cisplatin in GI motility in the rat. Gastric emptying was dose-dependently delayed by cisplatin. Chronic administration exacerbated this effect and also induced gastric distension, with only minor alterations in intestinal motility. However, delayed gastric emptying and gastric distension were not apparent 1 week after treatment finalization. In a parallel study in isolated rats, chronic cisplatin induced both acute (for the first 24 h after each administration) pica (i.e., kaolin intake, an indirect marker of nausea or visceral malaise) and an increase in basal kaolin intake (facilitated pica), which remained elevated during the week after treatment finalization. Whereas gastric dysmotility encountered in the few hours after cisplatin administration is parallel to the development of acute pica and might underlie facilitation of pica, it does not explain long-term maintenance of this alteration in feeding behavior. These findings might have important implications in the search for new antiemetics.

In agreement with previous reports from our laboratory10–12 and others,20 cisplatin induced a decrease in rectal temperature and nociceptive tactile threshold (mechanical allodynia). These effects were relatively persistent, as they were found 1 week after treatment finalization. In comparison, at that same time point, spontaneous locomotor activity and nociceptive thermal withdrawal response were not different from those obtained in saline-treated rats, suggesting that alterations in these parameters, which have been detected in previous studies,20 either require higher doses (either acute or cumulative) or are not as persistent as the ones mentioned above. In both grouped (this study10,20) and isolated10,11,21,22 rats, chronic cisplatin also induced a dose-dependent decrease in bodyweight gain, likely due to a decrease in food ingestion (see below).

It has been suggested that clays like kaolin may alter GI transit and absorption or serve to bind or dilute a toxin in the GI tract, thus reducing its adverse effects.23–25 In fact, the occurrence of pica seems to protect the animals against cisplatin toxicity to some extent,10,26 and this is probably the reason why rodents have developed this behavior in the absence of an emetic reflex to get rid of ingested toxic substances. Interestingly, pica is sensitive to conventional antiemetics.5,21 Although it could be interesting to determine the effect of kaolin intake on GI motility, kaolin, like barium, is radio-opaque (unpublished observations), and both substances used together would mix throughout the GI tract, impairing radiographic analysis. Therefore, the pica study and the radiographic experiments were performed in separate groups of animals.

As in previous works using the same cisplatin doses (1 and 2 mg kg−1) and pattern of chronic administration (once a week10,11), pica developed both immediately after each administration (acute effect) and throughout treatment (facilitated effect). Interestingly, with Cispt 1, which did not induce significant effects on motility, pica values were relatively low (generally <1 g), and significant differences with the control group were difficult to find (present results10,11). In comparison, Cispt 2 induced a delay in gastric emptying, which was enhanced throughout treatment. The effect of this dose was also much more robust in the pica study, and it induced an increase in both acute and basal kaolin intake (facilitated pica) throughout chronic treatment (present results11). Thus, cisplatin-induced pica behavior and gastric dysmotility are triggered and enhanced in a parallel manner upon chronic administration, suggesting that these effects are related and, probably, mediated by similar mechanisms.27

The effect on pica behavior of Cispt 3 was not studied because this dose was too toxic in isolated animals.10 However, in the radiographic analysis, this dose delayed gastric emptying and induced an increase in gastric size after chronic (but not acute12) administration. These effects were also confirmed by densitometric analysis (data not shown). It is generally thought that nausea and vomiting are associated and could be at least partly due to gastric distension.28 Like pica, gastric distension seems to be dependent on the use of relatively high (either acute or cumulative) cisplatin doses (present results12,21). In fact, it developed in parallel to delayed pica (occurring at least 24 h after administration) induced by acute administration of cisplatin at 6 mg kg−112 and might also mediate delayed (facilitated) pica throughout chronic treatment (present results). Interestingly, in a preliminary study, vincristine, another antitumoral drug that does not induce emesis in the clinic or pica in rodents,29 delayed gastric emptying but did not induce gastric distension,30 suggesting that both parameters might be relatively independent and that gastric distension might be more related to nausea/vomiting/pica than gastric stasis. This hypothesis needs to be confirmed by testing other emetogenic and non-emetogenic drugs.

Gastric dysmotility and pica developed upon treatment with cisplatin only at relatively high doses (2–3 mg kg−1), whereas low doses (1 mg kg−1) were capable of inducing significant acute reductions in food ingestion (although anorexia was not facilitated by Cispt 1). It is likely that gastric dysmotility (decrease in gastric emptying and induction of gastric distension) underlies the alterations in feeding behavior (decrease in food ingestion, increase in kaolin intake) upon acute12 and chronic cisplatin administration (present results10,11), as these involve more complex tasks. Anorectic signals originating from the stomach may occur almost exclusively in response to volumetric distension of the organ.31,32 Remarkably, this ‘distension-induced anorexia’ is mediated by both gastric and hepatic vagal branches,33 whereas cisplatin-induced pica and anorexia involve only the common hepatic branch of the vagus nerve.34 However, the mechanisms involved in the development of pica and anorexia might not be identical, as anorexia required lower doses than pica to be induced. Besides, no significant anorexia was evident 1 week after treatment finalization, but basal kaolin intake was still well above control levels (present results11), suggesting that recovery of food intake might be more easily achievable than recovery from the malaise state (nausea/emesis/pica).

Our results indicate that visceral malaise increases throughout chronic treatment and is still present 1 week after its finalization. However, no radiographic evidence of delayed gastric emptying or gastric distension was found at that time point (Fig. 2C,H,I), suggesting that the long-term maintenance of pica is not necessarily due to gastric dysmotility; rather, other factors, still to be determined might be involved and exert a major role. It is known that cisplatin induces the release of serotonin, dopamine, and substance P in the brain and selective portions of the small intestine.35 This seems to be involved in the development of nausea/emesis (and pica in the rat) because antagonists of the corresponding receptors are useful antiemetics36 and reduce pica in the rat.5,21 Further studies will be helpful to determine the precise mechanisms involved in the enhancement of pica and gastric dysmotility throughout chronic treatment and their maintenance after treatment finalization and whether these alterations might contribute to the loss of efficacy of antiemetics commonly encountered during chronic chemotherapy.3

Finally, transit in the small and large intestines remained practically unchanged after the first cisplatin administration, but was delayed after the last dose. Although this was probably due to the exacerbated delayed gastric emptying, chronic cisplatin might induce subtle alterations in the intestine that are not detectable radiographically. Thus, several authors have reported that cisplatin might induce significant effects in the intestine in the few hours after administration (either acute or repeated), such as significant histopathological changes of the intestinal mucosa,37 retropropagation of intestinal contents38 or stimulation of intestinal motility.39 One week after the last dose of cisplatin, the motility curves for the small and large intestine were practically the same as in control, saline-treated animals. However, at the same time point, upper intestinal transit, measured with the more precise but invasive charcoal method, was lower in animals chronically treated with cisplatin than in those receiving saline (P. A. Cabezos, G. Vera, M. I. Martín-Fontelles and R. Abalo, unpublished observations). Thus, other experimental methods might be necessary to detect more subtle, persistent alterations in gut function after chronic chemotherapy.

Concluding remarks

We found that gastric dysmotility is exacerbated upon chronic administration of cisplatin in the rat, in parallel with enhanced pica. One week after treatment finalization, no sign of gastric dysmotility remained, but basal kaolin intake was still higher than in saline-treated rats. As pica might be protective against cisplatin toxicity in the rat, further research is necessary to determine whether kaolin intake improves GI motility as well in comparison with animals that have no access to kaolin. Whatever the case may be, the alterations described here might contribute to the commonly encountered reduced effect of antiemetics during chronic chemotherapy, and they should be taken into account in the search for new antiemetic strategies.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author contributions
  9. Competing interests
  10. Conflict of interest
  11. References

This work was supported by Ministerio de Educación y Ciencia (SAF2006-13391-C03-01; SAF2009-12422-C02-01), Universidad Rey Juan Carlos – Comunidad de Madrid (URJC-CM-2006-BIO-0604), and Comunidad de Madrid (S-SAL/0261/2006).

Author contributions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author contributions
  9. Competing interests
  10. Conflict of interest
  11. References

PAC and GV performed the research and analyzed the data. MIMF revised the paper critically and obtained funding. RFP contributed essential tools for the research. RA designed the research study and wrote the paper.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author contributions
  9. Competing interests
  10. Conflict of interest
  11. References