M.I. Martín

Enteric neuropathy evoked by repeated cisplatin in the rat

Background  Acute administration of the antitumoral drug cisplatin can induce nausea/emesis and diarrhea. The long‐term effects of cisplatin on gastrointestinal motility, particularly after repeated administration, are not well known. Because cisplatin is highly neurotoxic, myenteric neurons can be affected. Our aim was to study the prolonged effects of repeated cisplatin administration in a rat model, focusing on gastrointestinal motor function and myenteric neurons.

Characterization of the vasorelaxant mechanisms of the endocannabinoid anandamide in rat aorta

Studies in isolated preparations of vascular tissue (mainly resistance vessels) provide evidence that anandamide exerts vasorelaxation. The aim of the present work was to further characterize the mechanisms involved in the vascular response induced by anandamide in a conduit vessel, rat aorta.

Altered feeding behaviour induced by long-term cisplatin in rats.

In animals without the emetic reflex, several emetogenic stimuli induce pica, an altered feeding behaviour consisting of the ingestion of non-nutritive substances. The development of pica in response to an emetogenic stimulus has been proposed to be useful as an indirect marker of nausea in the rat. In fact, like nausea and emesis in humans, it is accompanied by serotonin release from the enterochromaffin cells, increased c-fos labelling in the area postrema and the nucleus tractus solitarius, and a delay in gastric emptying. Furthermore, pica, measured as kaolin intake, is reduced by anti-emetic drugs. Pica has been demonstrated after single doses of cisplatin, the most emetogenic chemotherapeutic drug. However, cisplatin, as other antineoplastic drugs, is generally given in cycles, where conventional anti-emetics tend to lose efficiency. The aim of this work was to evaluate the pica induced by long-term treatment with cisplatin. Saline or cisplatin was administered once a week for 5 consecutive weeks, and temperature, body weight, food ingestion and kaolin intake were measured on a daily basis. The influence of isolation (pica is necessarily studied in isolated animals) and exposure to kaolin (basal kaolin intake could modify pica itself and other parameters) on temperature, body weight and daily food ingestion was negligible in saline-treated rats. Cisplatin administered at 3 mg/kg/week was too toxic: it produced hypothermia, weight drop and anorexia in both grouped and isolated rats, and 50% mortality in isolated animals. Toxicity associated with cisplatin administered at 1 mg/kg/week was acceptable, with a slower rate of weight gain being the major effect. In these rats, each cisplatin injection produced both acute anorexia and rebound hyperphagic responses. In addition, each administration induced both acute pica and an increase in basal kaolin intake, resembling the development of nausea in humans. This model could be useful for studying both the mechanisms leading to nausea associated with a long-term antineoplastic treatment and the efficiency of new anti-emetic drugs.

Selective lack of tolerance to delayed gastric emptying after daily administration of WIN 55,212-2 in the rat.

Abstract  The use of cannabinoids to treat gastrointestinal (GI) motor disorders has considerable potential. However, it is not clear if tolerance to their actions develops peripherally, as it does centrally. The aim of this study was to examine the chronic effects of the cannabinoid agonist WIN 55,212‐2 (WIN) on GI motility, as well as those in the central nervous and cardiovascular systems. WIN was administered for 14 days, at either non‐psychoactive or psychoactive doses. Cardiovascular parameters were measured in anaesthetized rats, whereas central effects and alterations in GI motor function were assessed in conscious animals using the cannabinoid tetrad and non‐invasive radiographic methods, respectively. Tests were performed after first (acute effects) and last (chronic effects) administration of WIN, and 1 week after discontinuing treatment (residual effects). Food intake and body weight were also recorded throughout treatment. Blood pressure and heart rate remained unchanged after acute or chronic administration of WIN. Central activity and GI motility were acutely depressed at psychoactive doses, whereas non‐psychoactive doses only slightly reduced intestinal transit. Most effects were reduced after the last administration. However, delayed gastric emptying was not and could, at least partially, account for a concomitant reduction in food intake and body weight gain. The remaining effects of WIN administration in GI motility were blocked by the CB1 antagonist AM 251, which slightly accelerated motility when administered alone. No residual effects were found 1 week after discontinuing cannabinoid treatment. The different systems show differential sensitivity to cannabinoids and tolerance developed at different rates, with delayed gastric emptying being particularly resistant to attenuation upon chronic treatment.

Cannabinoid/agonist WIN 55,212-2 reduces cardiac ischaemia–reperfusion injury in Zucker diabetic fatty rats: role of CB2 receptors and iNOS/eNOS.

Diabetes increases cardiac damage after myocardial ischaemia. Cannabinoids can protect against myocardial ischaemia/reperfusion injury. The aim of this study was to examine the cardioprotective effect of the cannabinoid agonist WIN 55,212‐2 (WIN) against ischaemia/reperfusion injury in an experimental model of type 2 diabetes. We performed these experiments in the Zucker diabetic fatty rat, and focused on the role of cannabinoid receptors in modulation of cardiac inducible nitric oxide synthase (iNOS)/endothelial‐type nitric oxide synthase (eNOS) expression.

Contributions of peripheral and central opioid receptors to antinociception in rat muscle pain models

Administration of hypertonic saline (HS) is an accepted model to study muscular pain. HS-induced nociceptive responses were tested in masseter, already described, and in two new pain models of spinally innervated muscles (gastrocnemius and triceps) developed in rats at our laboratory. HS administration in the masseter induced vigorous hindpaw shaking and in the gastrocnemius or triceps, paw withdrawal or flexing. Participation of the central and peripheral opioid receptors in HS-induced pain is compared in these muscles: masseter, innervated by trigeminal nerve, and gastrocnemius and triceps by spinal nerves. Morphine and loperamide were used to reveal peripheral and central components of opioid analgesia. Both agonists reduced HS-induced nociceptive behaviours in the masseter and were antagonised by the opioid antagonist naloxone and by naloxone methiodide, an opioid receptor antagonist that poorly penetrates the blood-brain barrier. Unexpectedly, in the gastrocnemius and triceps, morphine, but not loperamide, decreased the nociceptive behaviour and this effect was only reversed by naloxone. So, peripheral opioid receptors seem to participate in HS-induced masseter pain, whereas only central opioid receptors reduced the nociception in gastrocnemius and triceps. Our results suggest that the use of peripheral opioids can be more advantageous than central opioids for treatment of orofacial muscular pain.

The cannabinoid antagonist SR144528 enhances the acute effect of WIN 55,212‐2 on gastrointestinal motility in the rat

Background  In the absence of pathology, cannabinoid‐induced depression of gastrointestinal (GI) motility is thought to be mediated primarily by CB1 receptors, whereas the role of CB2 receptors is still unclear. The aim of this work was to radiographically analyze the acute effect of the mixed cannabinoid agonist WIN 55,212‐2 (WIN) on GI motor function in the rat, focusing on the involvement of CB1 and CB2 receptors.

Cannabinoids may worsen gastric dysmotility induced by chronic cisplatin in the rat

Background  Although cannabinoids have traditionally been used for the treatment and/or prevention of nausea and/or emesis, anorexia and weight loss induced by clinical use of antineoplastic drugs, their efficacy and safety in long‐term treatments are still controversial. Our aim was to analyze the effects of the non‐selective cannabinoid agonist WIN 55 212‐2 (WIN) on gastrointestinal (GI) dysmotility and other adverse effects induced by repeated cisplatin administration in the rat.

The involvement of 5-HT3 and 5-HT4 receptors in two models of gastrointestinal transit in mice.

Our aim was to study the involvement of 5-hydroxytryptamine (5-HT)(3) and 5-HT(4) receptors in two models of gastrointestinal transit (GIT) in mice: the 5-hydroxytryptophan (5-HTP)-induced diarrhea and intestinal inflammation produced by an irritant agent, croton oil (CO). 5-HTP (10 mg/kg) produced diarrhea that was significantly inhibited after pretreatment with ondansetron (5-HT(3) antagonist) or RS 39604 (5-HT(4) antagonist) (1-5 mg/kg). The GIT speed was increased after CO and 5-HTP administration. 5-HT(3-4) antagonists decreased GIT after 5-HTP-treatment but not after CO-treatment. Our results show that 5-HT(3) and 5-HT(4) receptors are involved in 5-HTP-induced diarrhea. This may be the reason why 5-HT(3-4) antagonists could be useful in the treatment of carcinoid syndrome diarrhea. 5-HT(3-4) antagonists were not effective in the modifications of GIT; nevertheless, they could be useful in the treatment of inflammatory bowel diseases because some symptoms as abdominal pain, discomfort or abnormal bowel function are modulated via 5-HT(3).

Vascular toxicity of chemotherapeutic agents.

Cancer chemotherapy is not free of undesirable side effects. With respect to the cardiovascular system, cardiotoxicity is a well-described and potentially lethal side effect of certain chemotherapeutic agents, such as anthracyclines. However, in the last few years, several clinical studies have taken into account the fact that some non-anthracycline chemotherapy treated-patients also have a significantly increased risk of cardiovascular events. The exact mechanism of this toxicity is not known, and several possibilities, including vascular autonomic neuropathy and vascular damage, have been proposed. The aim of the present review was to collate information on the clinical and experimental evidence regarding vascular toxicity for each of the different groups of chemotherapeutic agents. The mechanisms proposed to underlie this toxicity are also discussed.