Characterization of the nociceptin receptor (ORL-1) agonist, Ro64-6198, in tests of anxiety across multiple species.

RATIONALE: Previous studies have demonstrated behaviors indicative of anxiolysis in rats pretreated with the nociceptin receptor (opioid receptor like-1, ORL-1) agonist, Ro64-6198. OBJECTIVES: The aim of this study was to examine the effects of Ro64-6198 in anxiety models across three species: rat, guinea pig, and mouse. In addition, the receptor specificity of Ro64-6198 was studied, using the ORL-1 receptor antagonist, J-113397, and ORL-1 receptor knockout (KO) mice. Finally, neurological studies examined potential side effects of Ro64-6198 in the rat and mouse. RESULTS: Ro64-6198 (3-10 mg/kg) increased punished responding in a rat conditioned lick suppression test similarly to chlordiazepoxide (6 mg/kg). This effect of Ro64-6198 was attenuated by J-113397 (10 mg/kg), but not the mu opioid antagonist, naltrexone (3 mg/kg). In addition, Ro64-6198 (1-3 mg/kg) reduced isolation-induced vocalizations in rat and guinea pig pups. Ro64-6198 (3 mg/kg) increased the proportion of punished responding in a mouse Geller-Seifter test in wild-type (WT) but not ORL-1 KO mice, whereas diazepam (1-5.6 mg/kg) was effective in both genotypes. In rats, Ro64-6198 reduced locomotor activity (LMA) and body temperature and impaired rotarod, beam walking, and fixed-ratio (FR) performance at doses of 10-30 mg/kg, i.e., three to ten times higher than an anxiolytic dose. In WT mice, Ro64-6198 (3-10 mg/kg) reduced LMA and rotarod performance, body temperature, and FR responding, but these same measures were unaffected in ORL-1 KO mice. Haloperidol (0.3-3 mg/kg) reduced these measures to a similar extent in both genotypes. These studies confirm the potent, ORL-1 receptor-mediated, anxiolytic-like effects of Ro64-6198, extending the findings across three species. Ro64-6198 has target-based side effects, although the magnitude of these effects varies across species.

Transgenic overexpression of neuromedin U promotes leanness and hypophagia in mice.

Recent work has shown that neuromedin U (NmU), a peptide initially identified as a smooth muscle contractor, may play a role in regulating food intake and energy homeostasis. To further evaluate this putative function, we measured food intake, body weight, energy expenditure and glucose homeostasis in transgenic mice that ubiquitously overexpress murine proNmU. NmU transgenic mice were lighter and had less somatic and liver fat, were hypophagic, and had improved insulin sensitivity as judged by an intraperitoneal insulin tolerance test. Transgenic mice had higher levels of hypothalamic NPY, POMC and MCH mRNA. There was no difference in O2 consumption between genotypes; however, NmU transgenic mice displayed a modest increase in respiratory quotient during food deprivation and refeeding. There were no behavioral disturbances in the NmU transgenic mice that could account for the results (e.g. changes in locomotor activity). When placed on a high-fat diet, transgenic mice remained lighter than wild-type mice and ate less, but gained weight at a rate similar to wild-type mice. Despite the increased weight gain with high-fat feeding, glucose tolerance was significantly improved in the transgenic mice. These findings support the hypothesized role of NmU as an endogenous anorexigenic peptide.

Flexible sigmoidoscopy as a screening procedure for neoplasia of the colon.

Two hundred asymptomatic United States veterans older than 40 years of age were evaluated with a flexible sigmoidoscope plus Hemoccult stool tests. Mean distance and time for the former were 56.4 centimeters and 7.4 minutes, respectively. There were no complications. Polyps greater than or equal to 0.5 centimeter in diameter were found in 11.9 per cent of those older than 50 years. No polyps of this size were found in patients younger than 50 year of age. Results of Hemoccult tests were negative in 83.3 per cent of those with polyps. A flexible sigmoidoscope is a safe, rapid and effective means of identifying that portion of the asymptomatic adult population having colonic polyps. For this purpose, it is vastly more sensitive than Hemoccult stool testing. Because of the relationship between colonic polyps and carcinoma, this technique may prove invaluable in the identification of those patients with an increased potential for the development of carcinoma of the colon.

Fiberoptic pansigmoidoscopy. An evaluation and comparison with rigid sigmoidoscopy.

A flexible 60-cm fiberoptic sigmoidoscope was evaluated in 139 patients. In 120 patients flexible sigmoidoscopy was compared with routine rigid sigmoidoscopy with respect to patient tolerance, distance of inspection, procedure time, and diagnostic yield. All patients were prepared with a single cleansing enema, and given no analgesia. Despite the fact that the flexible instrument was inserted nearly 3 times as far into the colon (55 cm versus 20 cm), more patients preferred the flexible examination. Significant pathological lesions were discovered by the flexible examination in 39% of patients, whereas rigid sigmoidoscopy discovered lesions in only 13%. Fluoroscopy performed during flexible sigmoidoscopy in 19 additional patients revealed that the instrument tip had reached the descending colon or beyond in 84% of patients. There were no complications. The flexible fiberoptic pansigmoidoscope offers promise as a practical diagnostic tool for a rapid and complete examination in patients with suspected colorectal diseases.