Nociceptin/Orphanin FQ (N/OFQ) is a 17-amino acid peptide that binds to the nociceptin receptor (NOP). N/OFQ and NOP receptors are expressed in numerous brain areas. The generation of specific agonists, antagonists and receptor-deficient mice or rats has enabled progress in elucidating the biological functions of N/OFQ. These tools have been employed to identify the biological significance of the N/OFQ system and how it interacts with other endogenous systems to regulate several body functions. The present review focuses on the role of N/OFQ in the regulation of body temperature and its relationship with energy balance. Critical evaluation of the literature data suggests that N/OFQ, acting through the NOP receptor, may cause hypothermia by influencing the complex thermoregulatory system that operates as a federation of independent thermoeffector loops to control body temperature at the hypothalamic level. Furthermore, N/OFQ counteracts hyperthermia elicited by cannabinoids or µ-opioid agonists. N/OFQ-induced hypothermia is prevented by ω-conotoxin GVIA, an N-type calcium channel blocker. Hypothermia induced by N/OFQ is considered within the framework of the complex action that this neuropeptide exerts on energy balance. Energy stores are regulated through the complex neural controls exerted on both food intake and energy expenditure. In laboratory rodents, N/OFQ stimulates consummatory behavior and decreases energy expenditure. Taken together, these studies support the idea that N/OFQ contributes to the regulation of energy balance by acting as an “anabolic” neuropeptide as it elicits effects similar to those produced in the hypothalamus by other neuropeptides such as orexins and neuropeptide Y.

It has been shown that electrical stimulation of the mesencephalic tectum (MT) provokes defensive responses in both humans and rodents. During an emotional aversive state, some convergent studies have also demonstrated the existence of a complex interaction between endogenous opioid peptide- and γ-aminobutyric acid (GABA)-containing connections during fear-induced responses. It has been proposed that opioid neurons exert an influence on GABAergic interneurons, which, in turn, exert inhibitory tonic control on the mesencephalic excitatory pathways. Thus, opioid peptides can disinhibit neurons that are tonically inhibited by GABA, therefore, modulating the expression of defensive behavioural reactions. In the present work, we used both electric stimulation and microinjections of the GABAA receptor antagonist bicuculline in the inferior colliculus (IC) of Wistar rats in combination with microinjections of µ- and κ-opioid receptor selective agonists into the dorsal columns of periaqueductal grey matter (dPAG) to evaluate the effects on panic-like behaviours elicited by IC electrical and chemical stimulation. The present results showed that neurochemical lesions of the dPAG caused a significant impairment in the organisation of defensive responses by IC neurons, reducing the duration [t(14)=3.0; p<0.01] of defensive immobility and the duration [t(14)=2.8; p<0.05] and frequency [t(14)=2.5; p<0.05] of escape. Paradoxically, treating the dPAG with the µ-opioid receptor agonist met-enkephalin caused a significant reduction of panic-like behaviours induced by both electrical and chemical stimulation of the IC, increasing the escape behaviour threshold [F(2,23)=13.5; p<0.001] and decreasing the frequency [F(3,36)=11.7; p<0.001] and duration [F(3,36)=11.6; p<0.001] of escape and the duration of defensive immobility [F(3,36)=16.1; p<0.05]. In contrast, treating the dPAG with the κ-opioid receptor agonist salvinorin-A increased the frequency [F(3,36)=12.4; p<0.01] and duration [F(3,34)=16.1; p<0.01] of defensive immobility induced by GABAA receptor blockade in the IC. The present results suggest the existence of a complex neuronal network in the MT in which endogenous opioid peptides and GABAergic pathways interact in the control of fear-related behavioural responses.

Muitas plantas são utilizadas pela população para o tratamento e a cura de doenças. Entre elas encontram-se a Persea major Kopp, Piper mollicomum Kunth. e Serjania erecta Radlk. as quais são utilizadas para diversas enfermidades, inclusive para tratar distúrbios do trato gastrointestinal. O objetivo deste trabalho foi estudar os efeitos dos extratos dessas três plantas sobre a motilidade gastrointestinal. Camundongos Swiss foram tratados com os extratos pela via oral 1 hora antes da administração de uma solução semisólida de carboximetilcelulose 1,5% e vermelho de fenol 0,05% e, após 15 minutos, o esvaziamento gástrico e o trânsito intestinal avaliados. O extrato hidroalcoólico da P. major (100 a 1000 mg Kg-1, p.o.) e o extrato hidroalcoólico da P. mollicomum (100 e 300 mg Kg-1, p.o.) aumentaram o trânsito intestinal. No entanto, somente o extrato da P. major (100 e 300 mg Kg-1) também aumentou o esvaziamento gástrico. O extrato etanólico da S. erecta (100 a 1000 mg Kg-1, p.o.) não alterou a motilidade gastrointestinal. Estes resultados sugerem que a Persea major e a Piper mollicomum mereçam estudos mais aprofundados em busca de princípios ativos ou matéria vegetal efetiva para o tratamento de distúrbios do trato gastrointestinal como a constipação.

The potential anxiolytic and antipanic properties of cannabidiol have been shown; however, its mechanism of action seems to recruit other receptors than those involved in the endocannabinoid-mediated system. It was recently shown that the model of panic-like behaviors elicited by the encounters between mice and snakes is a good tool to investigate innate fear-related responses, and cannabidiol causes a panicolytic-like effect in this model. The aim of the present study was to investigate the 5-hydroxytryptamine (5-HT) co-participation in the panicolytic-like effects of cannabidiol on the innate fear-related behaviors evoked by a prey versus predator interaction-based paradigm. Male Swiss mice were treated with intraperitoneal (i.p.) administrations of cannabidiol (3 mg/kg, i.p.) and its vehicle and the effects of the peripheral pre-treatment with increasing doses of the 5-HT1A receptor antagonist WAY-100635 (0.1, 0.3 and 0.9 mg/kg, i.p.) on instinctive fear-induced responses evoked by the presence of a wild snake were evaluated. The present results showed that the panicolytic-like effects of cannabidiol were blocked by the pre-treatment with WAY-100635 at different doses. These findings demonstrate that cannabidiol modulates the defensive behaviors evoked by the presence of threatening stimuli, and the effects of cannabidiol are at least partially dependent on the recruitment of 5-HT1A receptors.

Nociceptin/orphanin FQ (N/OFQ), the endogenous ligand of the N/OFQ peptide (NOP) receptor, is a neuropeptide regulating gastrointestinal functions. The present study investigated the influence of acute cold-restraint stress and of short- and long-lasting peripheral infusion of N/OFQ on the level of synaptophysin, an exocytotic protein involved in neural plasticity. Exposure to cold-restraint stress for 3 h or subcutaneous infusion of N/OFQ, 1 μg/kg/h for 4 h, induced a significant increase of the area of synaptophysin-immunoreactive nerve fibers in the fundic mucosa, while prolonged subcutaneous infusion of N/OFQ, 1 μg/kg/h for 52 h and for 14 days, did not modify the synaptophysin-immunostained fibers. In the colonic mucosa stress exposure and subcutaneous infusion of N/OFQ, at any time point considered, had no significant effect on the area of synaptophysin-immunoreactive nerve fibers. Synaptophysin immunoreactive nerve fibers were decreased in knockout rats for the NOP receptor gene both in the fundic and colonic mucosa. Synaptophysin-immunoreactivity was demonstrated in cells located in the basal portion of the fundic mucosa. Our study is the first to show that the N/OFQ/NOP receptor system influences the expression of synaptophysin and hence the process of exocytosis both in nerve terminals and in cells.

Several studies have suggested the involvement of the hippocampus in the elaboration of epilepsy. There is evidence that suggests the hippocampus plays an important role in the affective and motivational components of nociceptive perception. However, the exact nature of this involvement remains unclear. Therefore, the aim of this study was to determine the role of muscarinic and nicotinic cholinergic receptors in the dorsal hippocampus (dH) in the organization of postictal analgesia. In a neuroanatomical study, afferent connections were found from the somatosensory cortex, the medial septal area, the lateral septal area, the diagonal band of Broca, and the dentate gyrus to the dH; all these areas have been suggested to modulate convulsive activity. Outputs to the dH were also identified from the linear raphe nucleus, the median raphe nucleus (MdRN), the dorsal raphe nucleus, and the locus coeruleus. All these structures comprise the endogenous pain modulatory system and may be involved either in postictal pronociception or antinociception that is commonly reported by epileptic patients. dH-pretreatment with cobalt chloride (1.0 mmol/L CoCl2/0.2 μL) to transiently inhibit local synapses decreased postictal analgesia 10 min after the end of seizures. Pretreatment of the dH with either atropine or mecamylamine (1.0 μg/0.2 μL) attenuated the postictal antinociception 30 min after seizures, while the higher dose (5.0 μg/0.2 μL) decreased postictal analgesia immediately after the end of seizures. These findings suggest that the dH exerts a critical role in the organization of postictal analgesia and that muscarinic and nicotinic cholinergic receptor-mediated mechanisms in the dH are involved in the elaboration of antinociceptive processes induced by generalized tonic-clonic seizures.

Type II arabinogalactan (AG) is a polysaccharide found in Maytenus ilicifolia (Celastraceae), a plant reputed as gastroprotective. Oral and intraperitoneal administration of the AG protected rats from gastric ulcers induced by ethanol. No alteration of mechanisms related to acid gastric secretion and gastrointestinal motility were observed. In vitro, the AG showed a potent scavenging activity against the radical of DPPH (2,2-diphenyl-1-picrylhydrazyl) with an IC50 value of 9.3 microM. However, the mechanism of the gastroprotective action remains to be identified.

Several pharmacological targets have been proposed as modulators of panic-like reactions. However, interest should be given to other potential therapeutic neurochemical agents. Recent attention has been given to the potential anxiolytic properties of cannabidiol, because of its complex actions on the endocannabinoid system together with its effects on other neurotransmitter systems. The aim of this study was to investigate the effects of cannabidiol on innate fear-related behaviors evoked by a prey vs predator paradigm. Male Swiss mice were submitted to habituation in an arena containing a burrow and subsequently pre-treated with intraperitoneal administrations of vehicle or cannabidiol. A constrictor snake was placed inside the arena, and defensive and non-defensive behaviors were recorded. Cannabidiol caused a clear anti-aversive effect, decreasing explosive escape and defensive immobility behaviors outside and inside the burrow. These results show that cannabidiol modulates defensive behaviors evoked by the presence of threatening stimuli, even in a potentially safe environment following a fear response, suggesting a panicolytic effect.

H+, K+-ATPase enzyme is a therapeutic target for the treatment of gastric disturbances. Several medicinal plants and isolated compounds inhibit the acid gastric secretion through interaction with the proton pump. In order to add new properties to some natural constituents, five compounds, a benzylated derivative of vincoside, a diterpene (abietic acid) and three alkaloids (cephaeline, vinblastine and vindoline), were tested for their activities on gastric H+,K+-ATPase isolated from rabbit stomach. All the compounds inhibited H+, K+-ATPase activity with varied potency. The IC50 value for benzylvincoside was 121 (50-293) μM, and for abietic acid 177 (148-211) μM. The alkaloids cephaeline, vinblastine and vindoline inhibited the H+,K+-ATPase activity with IC50 values of 194, 761 and 846 μM, respectively. The results suggest that benzylvincoside, abietic acid and cephaeline can be important sources for the development of anti-secretor agents.

Salvinorin A is a novel hallucinogen isolated from the widely available leaves of Salvia divinorum. Based on its mechanism of action, salvinorin A has shown potential as a stimulant abuse therapeutic. However, there are no methods for the detection of salvinorin A or its metabolites in biological fluids. In order to begin developing salvinorin A as a potential therapeutic, an understanding of its metabolism is needed. Here, a straightforward synthesis of a deuterium labeled analog of salvinorin A and its utility as an internal standard for the detection of salvinorin A and its metabolites in biological fluids by LC–MS is described.

Brief exposure of mice to unavoidable predatory stimuli is associated with behavioral and neurochemical changes consistent with increased anxiety [Belzung C, El Hage W, Moindrot N, Griebel G, Behavioral and neurochemical changes following predatory stress in mice, Neuropharmacology, 41 (2001) 400–408] and produces short-term impaired learning restored by acute fluoxetine treatment, but not by diazepam [El Hage W, Peronny S, Griebel G, Belzung C, Impaired memory following predatory stress in mice is improved by fluoxetine, Prog Neuropsychopharmacol Biol Psychiatry, 28 (2004) 123–128]. The present study investigated long-lasting changes induced by a unique unavoidable cat exposure in BALB/c mice on learning abilities using learning tests (radial maze, spatial configuration of objects recognition test). Results from the group comparison showed that predatory exposure induced significant learning disabilities in the radial maze (16 to 22 days poststressor) and in the spatial configuration of objects recognition test (26 to 28 days poststressor). These findings indicate that memory impairments may persist for extended periods beyond a predatory stress. This animal model of unique exposure of mice to unavoidable predatory stimuli has proven to be a useful model for the study of reactions to traumatic stress.

Electric fields are among physical stimuli that have revolutionized therapy. Occurring endogenously or exogenously, the electric field can be used as a trigger for controlled drug release from electroresponsive drug delivery systems, can stimulate wound healing and cell proliferation, may enhance endocytosis or guide stem cell differentiation. Electric field pulses may be applied to induce cell fusion, can increase the penetration of therapeutic agents into cells, or can be applied as a standalone therapy to ablate tumors. This review describes the main therapeutic trends and overviews the main physical, chemical and biological mechanisms underlying the actions of electric fields. Overall, the electric field can be used in therapeutic approaches in several ways. The electric field can act on drug carriers, cells and tissues. Understanding the multiple effects of this powerful tool will help harnessing its full therapeutic potential in an efficient and safe way.

It is well established that d-cycloserine (DCS), a partial agonist of the NMDA receptor glycine site, enhances learning and memory processes. Although the effects of DCS have been especially elucidated in the extinction and reconsolidation of aversive behavioral paradigms or drug-related behaviors, they have not been clearly determined in appetitive tasks using natural reinforcers. The current study examined the effects of pre-retrieval intra-basolateral amygdala (BLA) infusions of DCS on the extinction and reconsolidation of an appetitive odor discrimination task. Rats were trained to discriminate between three odors, one of which was associated with a palatable food reward, and, 20 min prior to extinction learning (experiment 1) or reactivation (experiment 2), they received bilateral intra-BLA infusions of DCS or vehicle. In experiment 1, DCS infusion reduced the rate of extinction learning, weakened extinction retention in a post-extinction test and enhanced reacquisition of the ODT task. In experiment 2, DCS improved subsequent memory expression in the reconsolidation test performed one day after the reactivation session. Such results indicate the involvement of BLA NMDA receptors in odor-food reward associative memory and suggest that DCS may potentiate the persistence or strength of the original memory trace.

Ethnopharmacological relevance: Pfaffia glomerata (Spreng) Pedersen (Amaranthaceae) is a medicinal plant known in Brazil as "Paratudo" and "Brazilian ginseng" and is commonly used as tonic, antidiabetic and to treat gastric disorders.Aim of the study: This study evaluates the possible mechanism by which hydroalcoholic extract (HE) of Pfaffia glomerata exerts its antinociceptive effect.Materials and methods: The HE was evaluated in acetic acid and glutamate models of pain or by biting behavior following intrathecal (i.t.) administration of agonists of excitatory aminoacids (EAA) receptors glutamate and pro-inflammatory cytokines, IL-1 beta and TNF-alpha in mice.Results: Oral administration of HE produced dose-dependent inhibition of acetic acid-induced visceral pain and glutamate-induced pain, with ID50 of 64.6 (47.7-87.5) mg/kg and ID50 of 370.8 (253.4-542.7) mg/kg, respectively. The HE (300 mg/kg, p.o.) antinociception, in the acetic acid test, was not affected by i.p. treatment of animals with naloxone. In addition, HE (300 mg/kg, p.o.) inhibited the pain-related behaviors induced by i.t. injection of trans-ACPD and TNF-alpha, but not by NMDA, AMPA, kainate or IL-1 beta.Conclusions: Our results suggest that inhibition of glutamatergic metabotropic receptors and TNF-alpha may account for the antinociceptive action reported for the HE in models of chemical pain used in this study. (C) 2009 Published by Elsevier Ireland Ltd.