P. A. Cabezos

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.

Cisplatin-induced gastrointestinal dysmotility is aggravated after chronic administration in the rat. Comparison with pica.

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.

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.

Characterization of cannabinoid-induced relief of neuropathic pain in a rat model of cisplatin-induced neuropathy

Clinical use of antineoplastic drugs is associated with the development of numerous adverse effects that many patients find intolerable, including peripheral neuropathy. Cannabinoids have relieved neuropathic pain in different animal models. But their therapeutic activities could be affected by their psychoactive properties. The aim of this work was to determine the effect of cannabinoids in cisplatin-evoked neuropathy. For this purpose, the non-selective agonist WIN 55,212-2 (WIN), the CB1-selective agonist ACEA or the CB2-selective agonist JWH133 (or their vehicle) was either systemically administered at a non-psychoactive dose or locally injected in cisplatin-treated rats. Selective CB1 and CB2 cannabinoid antagonists (AM251 and SR144528, respectively) were used to characterize cannabinoid effects. Cisplatin-treated rats showed mechanical allodynia but not thermal hyperalgesia. Cannabinoid agonists alleviated mechanical allodynia. This effect was mediated by both CB1 and CB2 cannabinoid receptors when the cannabinoid was systemically applied. At the dose used, cannabinoid agonists had no psychoactive effect. The local effect of the drug involved the activation of peripheral CB1 receptors whereas involvement of CB2 receptors was less clear. In a rat model of cisplatin-induced neuropathy, cannabinoids have an antinociceptive effect, but the cannabinoid receptors involved could be different depending on the route of administration. Non-psychoactive doses of cannabinoid agonists are capable of alleviating the signs of peripheral neuropathy when systemically applied. Interestingly, local administration of selective CB1 agonists or systemic administration of CB2 agonists, which are non-psychoactive, may serve as new therapeutic alternatives for symptom management in painful neuropathy associated with cisplatin treatment.

Cannabinoid-induced delayed gastric emptying is selectively increased upon intermittent administration in the rat: role of CB1 receptors

Background  Cannabinoids acutely administered depress central, cardiovascular and gastrointestinal functions. These effects might be modified upon repeated administration. Compared to the effects induced by daily administration, those induced by intermittent administration are less known. The effect of intermittent treatment with the CB1/CB2 cannabinoid agonist WIN55,212‐2 (WIN) was studied in the rat.

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.

213 THE CANNABINOID AGONIST WIN 55,212 2 PREVENTS THE DEVELOPMENT OF MECHANICAL ALLODYNIA INDUCED BY CHRONIC CISPLATIN IN THE RAT

of protein gene product 9.5 (PGP 9.5), a marker of nerve tissue, was utilized to detect the nerve growth in scar tissue under electron microscopy. Results: Results illustrate that the whirl body and the detachment of plasmalemma could be found in Schwann cells of large myelinated fibers. Neurotubule disruption and neurofilament disorganization also developed in small myelinated or unmyelinated fibers. In addition, numerous nerve fibers labeled by PGP 9.5 were observed in scar tissue on light or electron microscopy after 3 months lumbar laminectomy. These small fibers frequently accompany vessels and spread from periphery to central connective tissue of scar. Conclusions: We conclude that the dysmyelination and axonopathy in roots, and the nerve ingrowth in scar tissue could induce neuropathic pain, which might be the main causes of pain syndrome after spine operation.

282 THE CANNABINOID AGONIST WIN 55,212-2 BOTH REVERTS AND PREVENTS SIGNS OF PERIPHERAL NEUROPATHY INDUCED BY CHRONIC CISPLATIN IN THE RAT

patients with neuropathic pain. Results. Ten of 12 male Fabry patients had an isolated and uniform small fiber loss with an extraordinary increase of cold detection threshold and pathological raised warm detection threshold and thermal sensory limen. The remaining 2 patients had large fiber participation due to long lasting renal failure. Conclusions. We have shown a characteristic sensory profile in heterozygous Fabry patients which differs significantly from the sensory profile of painful sensory neuropathies and of painful small-fiber neuropathies of other origin. As a result of these findings, it is possible to establish a simplified neurological testing procedure to detect Fabry disease in an early stage of the disease.