fmrfamide and Disease-Models--Animal

Dedicated neuronal circuits enable animals to engage in specific behavioral responses to environmental stimuli. We found that hypoxic stress enhanced gustatory sensory perception via previously unknown circuitry in Caenorhabditis elegans. The hypoxia-inducible transcription factor HIF-1 upregulated serotonin (5-HT) expression in specific sensory neurons that are not normally required for chemosensation. 5-HT subsequently promoted hypoxia-enhanced sensory perception by signaling through the metabotropic G protein-coupled receptor SER-7 in an unusual peripheral neuron, the M4 motor neuron. M4 relayed this information back into the CNS via the FMRFamide-related neuropeptide FLP-21 and its cognate receptor, NPR-1. Thus, physiological detection of hypoxia results in the activation of an additional, previously unrecognized circuit for processing sensory information that is not required for sensory processing under normoxic conditions.

Topics: Animals; Animals, Genetically Modified; Behavior, Animal; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Chemotactic Factors; Disease Models, Animal; Feeding Behavior; FMRFamide; Gene Expression Regulation; GTP-Binding Protein alpha Subunits, Gs; Hypoxia; Membrane Transport Modulators; Movement; Mutation; Nerve Net; Neurons; Pharynx; Receptors, Neuropeptide Y; Serotonin; Transcription Factors; Tryptophan Hydroxylase; Up-Regulation

Our previous study showed that YGGFMKKKFMRFamide (YFa), a chimeric peptide of Met-enkephalin, and Phe-Met-Arg-Phe-NH2 induced naloxone-reversible antinociception and attenuated the development of tolerance to morphine analgesia. In continuation, the present study investigated which specific opioid receptors-mu, delta or kappa-mediate the observed YFa antinociception pharmacologically using specific antagonists and whether chronic administration of YFa at 26.01 micromol/kg per day induces tolerance and its effect on the expression of mu and kappa opioid receptors from day 4 to day 6, with endomorphine-1 (EM-1) and saline taken as positive and negative controls, respectively. Quantitative differential expression analysis was carried out by real-time reverse-transcriptase polymerase chain reaction, and the corresponding changes in protein levels were assessed by Western blot. A pharmacological investigation revealed that nor-binaltorphimine, a specific kappa opioid receptor-1 (KOR1) antagonist, completely antagonized the antinociception induced by 39.01 micromol/kg of YFa. Importantly, its chronic intraperitoneal administration did not result in significant tolerance over 6 days, whereas EM-1 induced significant tolerance after day 4. Differential expression analysis revealed that EM-1 caused up-regulation of mu opioid receptor-1 on day 4, followed by down-regulation on later days. Interestingly, YFa treatment caused a decrease on day 4, followed by an increase in the expression of KOR1 from day 5 onward. In conclusion, YFa induces kappa-specific antinociception, with no development of tolerance during 6 days of chronic treatment, which further articulates new directions for improved designing of peptide-based analgesics that may be devoid of adverse effects like tolerance.

Topics: Analgesics, Opioid; Analysis of Variance; Animals; Behavior, Animal; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Enkephalin, Methionine; FMRFamide; Gene Expression Regulation; Male; Naltrexone; Narcotic Antagonists; Oligopeptides; Pain Measurement; Rats; Rats, Wistar; Reaction Time; Receptors, Opioid, kappa; Receptors, Opioid, mu; Time Factors

Topics: Amino Acid Sequence; Animals; Blood Pressure; Death; Disease Models, Animal; Female; FMRFamide; Heart Rate; Molecular Sequence Data; Naloxone; Neuropeptides; Rats; Resuscitation; Shock, Hemorrhagic

Central administration of FMRFamide in rats dose dependently increased the duration of time spent in the open arm of an elevated plus maze and enhanced the number of drink contacts in the thirsty rat conflict test. Similarly in the social interaction test, animals pretreated with FMRFamide spent sufficient time in active social interaction as compared to controls. Neuropeptide FMRFamide antagonized the anxiogenic effect of yohimbine and enhanced the antianxiety effect of diazepam in rats. The results indicate anxiolytic action of FMRFamide and the mechanism of such an action may involve serotonergic transmission.

Topics: Amino Acid Sequence; Animals; Anti-Anxiety Agents; Conflict, Psychological; Disease Models, Animal; Drinking; FMRFamide; Injections, Intraventricular; Male; Maze Learning; Molecular Sequence Data; Neuropeptides; Neurotransmitter Agents; Rats; Social Behavior