Salvinorin A reduces neuropathic nociception in the insular cortex of the rat.

BACKGROUND: Neuropathic pain is one of the most important challenges in public health. The search for novel treatments is important for an adequate relief without adverse effects. In this sense salvinorin A (SA), the main diterpene of the medicinal plant Salvia divinorum is an important antinociceptive compound, which acts as a potent agonist of kappa opioid receptor (KOR) and cannabinoid CB1 receptors. METHODS: We evaluated nociceptive responses in a neuropathic pain model induced by the sciatic nerve ligature (SNL) in the right hind paw, after the microinjection of SA, Salvinorin B (SB), KOR and CB1 antagonists directly in the insular cortex (IC) in male wistar rats. RESULTS: We found a potent antinociceptive effect with the administration of SA. Moreover, this effect was blocked by the administration of a KOR antagonist as well as the administration of a CB1 antagonist. CONCLUSION: Salvinorin A has a potent antinociceptive effect when is administered centrally in the IC by the interaction with KOR and CB1 receptors. SIGNIFICANCE: We show evidence on the effectiveness of the administration of salvinorin A in the IC in a rodent model of neuropathic pain. These results support the use of novel compounds like SA as a therapeutic alternative for neuropathic pain relief.

Modification of pepsinogen I levels and their correlation with gastrointestinal injury after administration of dexibuprofen, ibuprofen or diclofenac: a randomized, open-label, controlled clinical trial.

OBJECTIVE: To assess the effect of a 2-week treatment with dexibuprofen, in comparison with ibuprofen and diclofenac, on pepsinogen plasma concentrations and gastrointestinal mucosa, as well as the correlation of these changes with gastrointestinal mucosal injury. METHODS: 60 patients with rheumatologic disease in chronic therapy with NSAID, were included. After a 7-day run-in period patients were randomly assigned to receive a 14-day treatment with dexibuprofen (Group A; Day 1 - 3 = 400 mg t.i.d; Day 4 - 14 = 400 mg b.i.d.), ibuprofen (Group B; Day 1 - 3 = 800 mg t.i.d; Day 4 -14 = 800 mg b.i.d.) or diclofenac (Group C; Day 1 - 3 = 50 mg t.i.d; Day 4 - 14 = 50 mg b.i.d.). Upper gastrointestinal endoscopy (Day 15), capsule-endoscopy (Day 16, 7 patients of each group) and determination of pepsinogen plasma concentrations were performed (basal and Day 15). A semiquantitative scale was designed for the assessment of the gastrointestinal mucosa. RESULTS: No differences in plasma pepsinogen were found between treatment groups or gastrointestinal injury grades or between basal and post-therapy determinations. Dexibuprofen showed gastroduodenal mucosal injury in fewer patients (42.1%) than was the case with ibuprofen (5%; p = 0.003) and diclofenac (30%; p = N.S.). Dexibuprofen administration was also associated with more patients having no intestinal mucosal damage (42.86% vs. 28.7% in the diclofenac group and 14.29% in the ibuprofen group; p = 0.0175). The rate of clinical adverse events was similar in Groups A, B and C (28%, 38% and 34%). CONCLUSIONS: Dexibuprofen showed a lower rate of gastroduodenal and intestinal mucosal injury. This effect was not mediated by modifications of plasma pepsinogen levels.

Stimulation of the medical preoptic area facilitates sexual behavior but does not reverse sexual satiation.

The aim of the present study was to establish whether electrical and/or drug stimulation of the medial preoptic area/anterior hypothalamus (mPOA/AH) surmounts the sexual behavior inhibition that results from copulation to exhaustion. Thus, intermittent electrical stimulation of the mPOA/AH (alone or combined with the systemic injection of yohimbine or apomorphine, at doses that were subthreshold for reversing sexual exhaustion) or intrapreoptic treatments to block GABAergic transmission were applied to sexually satiated rats. The results suggest that the mPOA/AH is not responsible for male sexual behavior inhibition or for the pharmacologically induced sexual behavior expression in satiated rats. Data are discussed in terms of the roles ascribed to the mPOA/AH, both in the control of sexual behavior expression and in the regulation of the postejaculatory interval.

Habituation and dehabituation of the spinal polysynaptic reflex responses: modification by naloxone and opiates and their anatomical correlates.

The sustained inhibitory action of spinal endorphins could be responsible for the habituation of polysynaptic responses in the spinal cord. To test this hypothesis, acute spinalized unanesthetized cats (decerebrated and curarized) were used. Sural nerve electrical stimulation (0.2 Hz) was provided and a progressive decrease in the reflex response was found. Conversely, the field potential (lamina V) progressively increased during stimulation, reaching its maximum amplitude when ventral root response showed maximum habituation. The administration of naloxone (0.8-10.0 mg/kg) produced dehabituation or prevented habituation. The immunohistological results showed leu-enkephalin-like immunoreactive dot-like structures in close proximity to neurons of laminae VII, VIII and IX in the lumbo-sacral segment of the spinal cord. Our results suggest an involvement of opioid peptides in the habituation process.

Effect of red peppers (Capsicum frutescens) intake during gestation on thermonociceptive response of rat offspring.

Oral administration of aqueous red pepper (Capsicum frutescens, Cf) solution and low capsaicin (8-methyl-N-vanillyl-6-nonenamide) doses during gestation produces an increase in the latency of the thermonociceptive escape response of rat offspring. The present work shows that different amounts of Cf (10%, 25% and 50%) incorporated to normal food of gestating rats modify in a dose-dependent manner the flexion reflex latency (R), as well as the latency of appearance of antialgesic behaviours expressed as paw lick (P) and escape response (E) using the hot plate test (53 degrees C+/-0.5 degrees C). The latency of the same parameters was tested in the same subjects 55 days later to determine the persistence of this effect. Results show an increase in latency of the three parameters R, P and E in all experimental groups with respect to controls. Animals (Cf, 25% group) tested 55 days after the first test exhibited latencies similar to controls, which suggests that the process is reversible.

Toluene increases acute thermonociception in mice.

Toluene is an abused solvent widely used in several commercial products. Recent evidence indicates that this solvent is a non-competitive inhibitor of NMDA receptors. Since NMDA receptors have been implicated in pain, this paper describes studies of the effects of increasing concentrations of inhaled toluene on nociception. Swiss Webster mice were exposed to toluene (500-8000 ppm) in static exposure chambers for 30 min. After completing the exposure period, animals were tested for nociception using the hot plate test. Toluene dose-dependently increased nociception as reflected by shorter latencies for the reflex, paw-lick and escape responses in toluene-treated mice with respect to their controls (animals exposed to air). In order to determine the possible role of opioids in this response, morphine (1-10 mg/kg) was injected before toluene inhalation. Toluene was not able to block morphine-induced antinocieption, however, it produced a shift of the morphine dose-response curve to lower effects, suggesting a physiological antagonism. No potentiation was seen when toluene was administered in combination with naloxone. Present results suggest that toluene increases nociception via neurotransmitter systems others than the glutamatergic.

Lesion and electrical stimulation of the ventral tegmental area modify persistent nociceptive behavior in the rat.

The ventral tegmental area (VTA) has been traditionally related with the control of motor responses. However, some studies show that this area is also involved in the processing of nociceptive information. It has been reported that this nucleus participates in the dissociative analgesia phenomenon. In the few works where electrical stimulation and lesion of the VTA have been performed, evaluated with persistent or chronic pain related behaviors, contradictory results have been obtained. Thus, a more detailed analysis of the role of the VTA in persistent pain is needed. Two series of experiments were performed: lesions of this nucleus were done with radiofrequency, (bilaterally at two points per side using a temperature range from 50 to 80 degrees C), and the VTA was electrically stimulated (10 min daily over 5 days, 2 ms rectangular pulses at 100 Hz during 1 s every 5 s) using two different schemes:10 min before the induction of the nociceptive stimulus and 90 min after the induction of the nociceptive stimulus. The latter allowed us to distinguish if the VTA electrical stimulation had a distinctive antinociceptive effect when applied before or after the induction of the nociceptive stimulus on a persistent pain related behavioral response in the rat, the self injury behavior (SIB). Our results showed that VTA lesions enhanced the occurrence of SIB; while activation of this same nucleus by electrical stimulation after the nociceptive stimulus, but not before, facilitates the analgesic process, expressed as a 1 day delay in SIB onset. These results indicate that the VTA is a brain structure that plays a key role in the processing and modulation of persistent pain information. Data are discussed in terms of the relationship of the VTA with the affective component of pain.

Distribution of NADPH-diaphorase in the perioesophageal ganglia of the snail, Helix aspersa.

In this paper we discuss the anatomical localization of NADPH-diaphorase using Nitroblue tetrazolium in perioesophageal ganglia of Helix aspersa. Our results show that the reaction is present in neurons and fibers of the procerebrum, some positive neurons are found in mesocerebrum, and there were positive fibers in the neuropile of postcerebrum and mesocerebrum; likewise, immunopositive fibers were found in the neuropile of pedal, pleural and parietal ganglia. The presence of NADPH-diaphorase in the interneurons of procerebrum suggests the participation of this enzyme in the production of nitric oxide for the processing of the olfactory information, as has been suggested in mammalian olfactory tissue.

Histochemical distribution of NADPH-diaphorase in the cerebral ganglion of the crayfish Cambarellus montezumae.

The presence and localization of NADPH-diaphorase in the cerebral ganglion of the crayfish Cambarellus montezumae was shown. The reactivity of this enzyme was found in the deuterocerebrum, mainly in the commissure, in fibers of olfactory and accessory lobes, and in the laterodorsal group of cells. The presence of this enzyme in these cerebral regions suggests that nitric oxide is involved in primary sensory afferents in the crayfish.

Naloxone effects on the visual evoked potentials recorded from the main and accessory visual pathways of the cat.

1. The effects produced by repetitive i.v. administration of naloxone (1, 2 or 4 mg/kg) on the visual evoked potentials (VEPs) recorded along the main and accessory visual pathways were investigated in a modified "encéphale isolé" cat preparation. 2. Naloxone provoked a progressive amplitude enhancement and latency reduction of some components, depending on the structure analyzed, the dose used and the number of administrations applied. Electroretinogram (ERG) and N1-P1 VEP components of optic chiasm (OCh), lateral geniculate body (LGB) and visual cortex (VC) did not present significant changes. 3. Late-latency components (more than 200 msec) appeared in the VEPs of LGB and VC, mainly when 4 mg/kg were used. 4. Our results suggest that endogenous opioids have a modulatory role in the processing of sensory information at different levels of the visual system.

Massed amygdaloid kindling in encéphale isolé cats: its facilitation by naloxone.

The effect of repetitive administration of naloxone on the development of massed amygdaloid kindling in 'encéphale isolé' cats was studied. Electrical amygdaloid kindling was carried out with a 15 min inter-stimulus interval (ISI) in a control situation with intravenous (i.v.) naloxone administration (2, 4, and 8 mg/kg), 5 min prior to amygdaloid stimulation. It was found that it was possible to complete the amygdaloid kindling process in the encéphale isolé preparation reaching generalized electrographic tonic-clonic self-sustained seizures. The enhancement of the duration, frequency, and propagation of the after-discharge (AD) was accentuated by naloxone which also induced a progressive amplitude increment of the first potential evoked by the onset of the tetanus. The number of trials needed to achieve seizure generalization was reduced in dose-dependent manner by naloxone. The ability of naloxone to accelerate the development of amygdaloid kindling may be related to an inhibitory role of opioid peptides in this process.

Capsaicin or feeding with red peppers during gestation changes the thermonociceptive response of rat offspring.

Capsaicin is responsible for the pungent sensation produced by red peppers on the body's mucous membranes. This substance is found naturally in the gender Capsicum, widely used in the diet of different cultures in America, Asia, and Africa. In this paper we used the hot plate model (53 +/- 0.5 degrees C) to study the effect of acute thermonociceptive stimulus on escape response latency in the offspring of rats that were treated during gestation, either with an aqueous red pepper solution (Capsicum frutescens, approximately 2.75 mg of capsaicin in 1 ml/day, by gavage during the second week), or with capsaicin (0.5 mg/day SC, during the second week). These groups were compared with their respective controls. We found that the difference between the manipulated control group and the one given the aqueous red pepper solution was 41.33%, and between the vehicle control and the one treated with capsaicin was 30.59%. These increments on the escape response latency were statistically significant. Our results show that both treatments, the aqueous red pepper extract and low doses of capsaicin on pregnant rats. produce an increment on escape response latency due to a thermonociceptive stimulus.

Self-mutilation in the Lesch-Nyhan syndrome: a corporal consciousness problem?--a new hypothesis.

The Lesch-Nyhan syndrome (LNS) has been extensively studied from the genetic and biochemical point of view. The main characteristic of the syndrome is the self-mutilation feature, which has been poorly studied and understood. We propose a new hypothesis about the self-mutilation physiopathology, which is related to the supersensitivity of the dopaminergic D1 receptors in the neuromatrix found in the cingulum cortex region. The LNS shows an increase of uric acid levels as a result of the deficiency of hypoxanthine phosphoribosyltransferase enzyme. This increase could induce damage to dopaminergic neurons. As a consequence, a decrease in dopamine synthesis during gestation and the early postnatal period could occur, producing a functional dopaminergic denervation of the D1 receptors, located on the prefrontal cortex, specifically in the cingulum bundle projections. This phenomenon could induce a codification disturbance in the 'genetic body' of the neuromatrix, that could be expressed functionally as anosognosia, giving rise to self-mutilation. We suggest that this self-mutilation is a pain consciousness problem.

Long-term management of GERD. Why using endoscopy just now?

Early results with the use of endoscopic techniques in the treatment of gastro-oesophageal reflux disease (GERD) have been recently reported. Methods used are an injection of biocompatible substances within the lower oesophageal sphincter (LES), LES ablation using radio-frequency, and suture of folds in the area distal to the Z-line. The latter--endoscopic gastroplasty--is most difficult, but this technique has been most widely accepted by gastroenterologists to this date. Effectiveness of these endoscopic management systems in the long-term control of GERD has never been compared to a control group. This fact, together with the proven efficacy of anti-secretory drugs and the refinement of laparoscopic surgery during the past few years, has led physicians to be more demanding regarding early results. This review will discuss each method available, and issues answered by reported studies to this day are approached.

[Self-expanding esophageal metal stents in the palliative treatment of esophageal cancer]. / Prótesis metálicas esofágicas autoexpandibles en el tratamiento paliativo del cáncer de esófago.

We report our experience of two years (February 1993-February 1995) in the endoscopic treatment with self-expanding prosthesis (Ultraflex) of 21 patients with inoperable malignant oesophageal stenosis. 23 prosthesis were implanted enabling swallowing in less than 24 h. There were no major complications. In two occasions the prosthesis was obstructed by tumoral growth needing replacement. The prosthesis was occluded by solid food in four cases, which were resolved endoscopically.

Usefulness of capsule endoscopy in patients with suspected small bowel disease.

AIM: To study the usefulness and safety of capsule endoscopy as a diagnostic tool in various small bowel disorders. DESIGN: A retrospective analysis of a series of cases. MATERIAL AND METHODS: Between August 2001 and August 2002, 92 capsule endoscopy procedures were performed in 88 patients (53M/39F, age: 43.87 +/- 16.78). Indications included: chronic diarrhea (n=33); unknown abdominal pain (n=29); occult gastrointestinal bleeding or iron-deficiency anemia (n=13); abdominal discomfort in NSAID takers (n=7); staging of gastrointestinal tumors (n=4), and asymptomatic controls (n=2). Previously performed gastroscopy, colonoscopy, and small-bowel follow-through were not conclusive in all patients. RESULTS: Most frequently relevant findings included: jejuno-ileal aphtas and ulcerations (29 patients), vascular malformations (13 patients), and intestinal neoplasm (6 patients). The groups with a higher rate of findings related to this indication were occult gastrointestinal bleeding (76.92%) and chronic diarrhea (67.85%), with the lowest rate in the abdominal pain group (34.48%). Therapeutic strategy was directly changed in 36 of 88 patients (40.90%) because of capsule-endoscopic findings. The only observed complication was the failed excretion of one of the capsules because of an unknown ulcerated intestinal stricture. CONCLUSIONS: Capsule endoscopy is a safe procedure which can study the entire small bowel, meaning a valuable tool for the management of patients with suggestive signs and symptoms of intestinal disorders.

Short- and medium-term clinical efficacy of three endoscopic therapies for achalasia: a single-blinded prospective study.

OBJECTIVE: to compare the efficacy of three endoscopic therapies for achalasia and to identify predictors of response. DESIGN: prospective, single-blinded study at short and medium term. MATERIAL AND METHODS: 22 patients (9M/13 F; mean age: 47.45 +/- 21.01 years) with confirmed clinical and manometric achalasia were randomised in three groups: intrasphincteric injections of botulinum toxin (group 1: 10 patients ), injections of 1% polidocanol (group 2:6 patients), and a combined therapy with both of them (group 3: 6 patients). Clinical response was evaluated by a score (0-5) of tested symptoms (dysphagia, regurgitation and chest pain) at 1 and 24 weeks post-treatment. RESULTS: at 24 weeks post-treatment group 2 had the best complete response (CR) rate (33.33%), whereas CR in both the botulinum toxin and combined therapy groups was 10 and 0%, respectively. Groups 1 and 2 got an overall improvement in clinical score at 1 (p= 0.02) and 24 weeks (p= 0.04). Five patients (50%) in group 1, two patients (33.33%) in group 2, and three patients (50%) in group 3 needed other therapies (dilation or surgery) because of treatment failure. Separately, neither age nor sex, time from diagnosis or type of therapy could distinguish responders from non-responders in these three groups. However, absence of response within the first week, and an initial clinical score above 7 were predictive factors of poor response at six months. CONCLUSIONS: short- and medium-term clinical response to these endoscopic therapies was limited. The absence of response at seven days and a severe initial clinical score were predictive factors of poor medium-term response.

[Treatment and outcome of infantile cholesteatoma surgery]. / Tratamiento y resultados en la cirugia del colesteatoma infantil.

Infantile Cholesteatoma has been lately the aim of a large number of papers dealing with its natural history and optimal treatment. The outcome of 26 cases of ear surgery, done between 1990 and 1991, are reviewed. The etiology of Cholesteatoma was congenital in 2 cases, iatrogenic in an other one and unknown for the remainder (88%). Fifteen (15) closed surgical procedures and 11 open were carry out, achieving global removal of lesions in 76 percent of cases. Ninety-one (91%) of open tympanoplasties and 66 percent of closed procedures. Six cases evolved to recidivation (and later reoperatively reconverted in open cases) owing either to the erosion of the ossicular chain or encroachment of the recessus. Reconstructions of the ossicular chain was undertaken in 61.5 percent of cases and the hearing preserved in all instances and improved in 35 percent of reconstructions.