Meta-analysis of pre-clinical studies on the effects of opioid receptor ligands on food intake, motivation, and choice.

The opioid receptors (OR) regulate food intake. Still, despite extensive pre-clinical research, the overall effects and individual contribution of the mu (MOR), kappa (KOR), and delta (DOR) OR subtypes to feeding behaviors and food intake remain unclear. To address this, we conducted a pre-registered systematic search and meta-analysis of rodent dose-response studies to evaluate the impact of central and peripheral administration of non-selective and selective OR ligands on intake, motivation, and choice of food. All studies had a high bias risk. Still, the meta-analysis confirmed the overall orexigenic and anorexigenic effects of OR agonists and antagonists, respectively. Our results support a larger orexigenic role for central MOR agonists among OR subtypes and that peripheral OR antagonists reduce motivation for and intake of preferred foods. In binary food choice studies, peripheral OR agonists selectively increase the intake of fat-preferred foods; in contrast, they did not increase the intake of sweet carbohydrate-preferred foods. Overall, these data support that OR regulation of intake, motivation, and choice is influenced by food macronutrient composition.

Effects on Hedonic Feeding, Energy Expenditure and Balance of the Non-opioid Peptide DYN-A2-17.

The dynorphin (DYN) peptide family includes opioid and non-opioid peptides, yet the physiological role of the non-opioid DYN peptides remains poorly understood. Recent evidence shows that administering the non-opioid peptide DYN-A2-17 into the paraventricular hypothalamic nucleus (PVN) simultaneously increased short-term intake of standard rodent chow and spontaneous physical activity (SPA). The present studies aimed to expand upon the mechanisms and role of DYN-A2-17 on food intake and energy expenditure. Injection of DYN-A2-17 in PVN increased SPA, energy expenditure and wheel running in the absence of food. Repeated DYN-A2-17 injection in PVN increased short-term chow intake, but this effect habituated over time and failed to alter cumulative food intake, body weight or adiposity. Pre-treatment with a CRF receptor antagonist into PVN blocked the effects of DYN-A2-17 on food intake while injection of DYN-A2-17 in PVN increased plasma ACTH. Finally, as DYN peptides are co-released with orexin peptides, we compared the effects of DYN-A2-17 to orexin-A and the opioid peptide DYN-A1-13 on food choice and intake in PVN when palatable snacks and chow were available. DYN-A1-13 selectively increased intake of palatable snacks. DYN-A2-17 and orexin-A decreased palatable snack intake while orexin-A also increased chow intake. These findings demonstrate that the non-opioid peptide DYN-A2-17 acutely regulates physical activity, energy expenditure and food intake without long-term effects on energy balance. These data also propose different roles of opioid, non-opioid DYN and orexin peptides on food choice and intake when palatable and non-palatable food options are available.

Role of the non-opioid dynorphin peptide des-Tyr-dynorphin (DYN-A(2-17)) in food intake and physical activity, and its interaction with orexin-A.

Food intake and physical activity are regulated by multiple neuropeptides, including orexin and dynorphin (DYN). Orexin-A (OXA) is one of two orexin peptides with robust roles in regulation of food intake and spontaneous physical activity (SPA). DYN collectively refers to several peptides, some of which act through opioid receptors (opioid DYN) and some whose biological effects are not mediated by opioid receptors (non-opioid DYN). While opioid DYN is known to increase food intake, the effects of non-opioid DYN peptides on food intake and SPA are unknown. Neurons that co-express and release OXA and DYN are located within the lateral hypothalamus. Limited evidence suggests that OXA and opioid DYN peptides can interact to modulate some aspects of behaviors classically related to orexin peptide function. The paraventricular hypothalamic nucleus (PVN) is a brain area where OXA and DYN peptides might interact to modulate food intake and SPA. We demonstrate that injection of des-Tyr-dynorphin (DYN-A(2-17), a non opioid DYN peptide) into the PVN increases food intake and SPA in adult mice. Co-injection of DYN-A(2-17) and OXA in the PVN further increases food intake compared to DYN-A(2-17) or OXA alone. This is the first report describing the effects of non-opioid DYN-A(2-17) on food intake and SPA, and suggests that DYN-A(2-17) interacts with OXA in the PVN to modulate food intake. Our data suggest a novel function for non-opioid DYN-A(2-17) on food intake, supporting the concept that some behavioral effects of the orexin neurons result from combined actions of the orexin and DYN peptides.

Behavioral characterization of a model of differential susceptibility to obesity induced by standard and personalized cafeteria diet feeding.

Despite the increase in obesity prevalence over the last decades, humans show large inter-individual variability for susceptibility to diet-induced obesity. Understanding the biological basis of this susceptibility could identify new therapeutic alternatives against obesity. We characterized behavioral changes associated with propensity to obesity induced by cafeteria (CAF) diet consumption in mice. We show that Balb/c mice fed a CAF diet display a large inter-individual variability in susceptibility to diet-induced obesity, such that based on changes in adiposity we can classify mice as obesity prone (OP) or obesity resistant (OR). Both OP and OR were hyperphagic relative to control-fed mice but caloric intake was similar between OP and OR mice. In contrast, OR had a larger increase in locomotor activity following CAF diet compared to OP mice. Obesity resistant and prone mice showed similar intake of sweet snacks, but OR ate more savory snacks than OP mice. Two bottle sucrose preference tests showed that OP decreased their sucrose preference compared to OR mice after CAF diet feeding. Finally, to test the robustness of the OR phenotype in response to further increases in caloric intake, we fed OR mice with a personalized CAF (CAF-P) diet based on individual snack preferences. When fed a CAF-P diet, OR increased their calorie intake compared to OP mice fed the standard CAF diet, but did not reach adiposity levels observed in OP mice. Together, our data show the contribution of hedonic intake, individual snack preference and physical activity to individual susceptibility to obesity in Balb/c mice fed a standard and personalized cafeteria-style diet.

Role of orexin receptors in obesity: from cellular to behavioral evidence.

The orexin peptides and their two receptors are involved in multiple physiological processes, including energy homeostasis, arousal, stress and reward. Higher signaling of the orexin peptides at the orexin receptors (OXR) protects against obesity, but it is less clear how their activation in different brain regions contributes to this behavioral output. This review summarizes the evidence available for a role of central OXR in energy homeostasis and their contribution to obesity. A detailed analysis of anatomical, cellular and behavioral evidence shows that modulation of energy homeostasis by the OXR is largely dependent upon anatomical and cellular context. It also shows that obesity resistance provided by activation of the OXR is distributed across multiple brain sites with site-specific actions. We suggest that understanding the role of the OXR in the development of obesity requires considering both specific mechanisms within brain regions and interactions of orexinergic input between multiple sites.

Inwardly rectifying potassium channel Kir4.1 is responsible for the native inward potassium conductance of satellite glial cells in sensory ganglia.

Satellite glial cells (SGCs) surround primary afferent neurons in sensory ganglia, and increasing evidence has implicated the K(+) channels of SGCs in affecting or regulating sensory ganglion excitability. The inwardly rectifying K(+) (Kir) channel Kir4.1 is highly expressed in several types of glial cells in the central nervous system (CNS) where it has been implicated in extracellular K(+) concentration buffering. Upon neuronal activity, the extracellular K(+) concentration increases, and if not corrected, causes neuronal depolarization and uncontrolled changes in neuronal excitability. Recently, it has been demonstrated that knockdown of Kir4.1 expression in trigeminal ganglia leads to neuronal hyperexcitability in this ganglia and heightened nociception. Thus, we investigated the contribution of Kir4.1 to the membrane K(+) conductance of SGCs in neonatal and adult mouse trigeminal and dorsal root ganglia. Whole cell patch clamp recordings were performed in conjunction with immunocytochemistry and quantitative transcript analysis in various mouse lines. We found that in wild-type mice, the inward K(+) conductance of SGCs is blocked almost completely with extracellular barium, cesium and desipramine, consistent with a conductance mediated by Kir channels. We then utilized mouse lines in which genetic ablation led to partial or complete loss of Kir4.1 expression to assess the role of this channel subunit in SGCs. The inward K(+) currents of SGCs in Kir4.1+/- mice were decreased by about half while these currents were almost completely absent in Kir4.1-/- mice. These findings in combination with previous reports support the notion that Kir4.1 is the principal Kir channel type in SGCs. Therefore Kir4.1 emerges as a key regulator of SGC function and possibly neuronal excitability in sensory ganglia.

Low-grade gliomas in children: tumor volume response to radiation.

OBJECT: The authors conducted a retrospective review to examine and document the frequency, degree, and timing of the radiologically confirmed response to radiotherapy of low-grade gliomas in children. METHODS: Between 1963 and 1995, 80 patients 17 years of age or younger were referred to the London Regional Cancer Centre in London, Ontario after diagnosis of a low-grade glioma. All patients underwent surgical resection or biopsy procedures and 47 underwent radiotherapy (40 postoperatively and seven at the time of tumor progression). Nineteen patients with residual measurable lesions who received radiation therapy were selected for volumetric analysis of tumor response to this treatment. The extent and timing of response to radiation were determined by the process of comparing postoperative, preirradiation computerized tomography (CT) scans with postirradiation, follow-up CT scans. For one patient the comparison was made by using serial magnetic resonance images. Residual tumor was found on postoperative CT scans in all cases. The mean preradiotherapy tumor volume was 17.1 cm3, and the postradiotherapy volume was reduced to a mean of 11.5 cm3. A reduction in tumor volume was demonstrated in eight patients by the time of their first postirradiation follow-up CT scan and in two patients a slower reduction in volume over time was shown, bringing the total number of "responders" to 10. In five of these 10 patients the tumor had shown a maximum response by the time of the first postirradiation CT scan; the median time to response was 3.3 months. A 25% or greater reduction in tumor volume was seen in eight (42%) of the 19 patients. A 50% or greater reduction was noted in five (26%) of the patients. A complete response was demonstrated at 7, 12, and 15 months, and 5 years, respectively, in four patients (21%). One responder's tumor eventually increased in size after radiotherapy and he died of his disease. The magnitude of the radiographically demonstrated response to radiation did not correlate significantly with clinical outcome (that is, survival or symptom improvement). CONCLUSIONS: On the basis of this CT scan analysis of the response of low-grade gliomas in children to radiotherapy, the authors suggest that these lesions respond to radiation, as demonstrated by tumor shrinkage on serial imaging. Major or complete responses occur occasionally. However, low-grade gliomas in children mimic other benign brain tumors such as pituitary adenomas and meningiomas in that, although growth is frequently arrested after radiotherapy, residual tumor can persist for many years, illustrating that tumor shrinkage may not be a good measure of treatment efficacy. Nevertheless, radiation therapy can result in improvement of clinical symptomatology in association with or independent of visible tumor reduction. As radiation treatment techniques become increasingly conformal and because studies indicate that lower doses of radiation may be equally effective, improvement of symptoms may be an important consideration when weighing treatment options, particularly in patients with residual or unresectable disease.

Low-grade gliomas in children: tumor volume response to radiation.

Object. The authors conducted a retrospective review to examine and document the frequency, degree, and timing of the radiologically confirmed response to radiotherapy of low-grade gliomas in children. Methods. Between 1963 and 1995, 80 patients 17 years of age or younger were referred to the London Regional Cancer Centre in London, Ontario, after diagnosis of a low-grade glioma. All patients underwent surgical resection or biopsy procedures and 47 underwent radiotherapy (40 postoperatively and seven at the time of tumor progression). Nineteen patients with residual measurable lesions who received radiation therapy were selected for volumetric analysis of tumor response to this treatment. The extent and timing of response to radiation were determined by the process of comparing postoperative, preirradiation computerized tomography (CT) scans with postirradiation, follow-up CT scans. For one patient the comparison was made by using serial magnetic resonance images. Residual tumor was found on postoperative CT scans in all cases. The mean preradiotherapy tumor volume was 17.1 cm(3), and the postradiotherapy volume was reduced to a mean of 11.5 cm(3). A reduction in tumor was demonstrated in eight patients by the time of their first postirradiation follow-up CT scan and in two patients a slower reduction in volume over time was shown, bringing the total number of "responders" to 10. In five of these 10 patients the tumor had shown a maximum response by the time of the first postirradiation CT scan; the median time to response was 3.3 months. A 25% or greater reduction in tumor volume was seen in eight (42%) of the 19 patients. A 50% or greater reduction was noted in five (26%) of the patients. A complete response was demonstrated at 7, 12, and 15 months, and 5 years, respectively, in four patients (21%). One responder's tumor eventually increased in size after radiotherapy and he died of his disease. The magnitude of the radiographically demonstrated response to radiation did not correlate significantly with clinical outcome (that is, survival or symptom improvement). Conclusions. On the basis of this CT scan analysis of the response of low-grade gliomas in children to radiotherapy, the authors suggest that these lesions respond to radiation, as demonstrated by tumor shrinkage on serial imaging. Major or complete responses occur occasionally. However, low-grade gliomas in children mimic other benign brain tumors such as pituitary adenomas and meningiomas in that, although growth is frequently arrested after radiotherapy, residual tumor can persist for many years, illustrating that tumor shrinkage may not be a good measure of treatment efficacy. Nevertheless, radiation therapy can result in improvement of clinical symptomatology in association with or independent of visible tumor reduction. As radiation treatment techniques become increasingly conformal and because studies indicate that lower doses of radiation may be equally effective, improvement of symptoms may be an important consideration when weighing treatment options, particularly in patients with residual or unresectable disease.

In vitro preclinical evaluation studies with the echinocandin antifungal MK-0991 (L-743,872).

The echinocandin MK-0991, formerly L-743,872, is a water-soluble lipopeptide that has been demonstrated in preclinical studies to have potent activity against Candida spp., Aspergillus fumigatus, and Pneumocystis carinii. An extensive in vitro biological evaluation of MK-0991 was performed to better define the potential activities of this novel compound. Susceptibility testing with MK-0991 against approximately 200 clinical isolates of Candida, Cryptococcus neoformans, and Aspergillus isolates was conducted to determine MICs and minimum fungicidal concentrations MF(s). The MFC at which 90% of isolates are inhibited for 40 C. albicans clinical isolates was 0.5 microg/ml. Susceptibility testing with panels of antifungal agent-resistant species of Candida and C. neoformans isolates indicated that the MK-0991 MFCs for these isolates are comparable to those obtained for susceptible isolates. Growth kinetic studies of MK-0991 against Candida albicans and Candida tropicalis isolates showed that the compound exhibited fungicidal activity (i.e., a 99% reduction in viability) within 3 to 7 h at concentrations ranging from 0.06 to 1 microg/ml (0.25 to 4 times the MIC). Drug combination studies with MK-0991 plus amphotericin B found that this combination was not antagonistic against C. albicans, C. neoformans, or A. fumigatus in vitro. Studies with 0 to 50% pooled human or mouse serum established that fungal susceptibility to MK-0991 was not significantly influenced by the presence of human or mouse serum. Results from resistance induction studies suggested that the susceptibility of C. albicans was not altered by repeated exposure (40 passages) to MK-0991. Erythrocyte hemolysis studies with MK-0991 with washed and unwashed human or mouse erythrocytes indicated minimal hemolytic potential with this compound. These favorable results of preclinical studies support further studies with MK-0991 with humans.