ABSTRACT
Neurotensin (NT) is a neuropeptide that induces a wide range of biological activities including hypothermia and analgesia. Such effects are mediated by the NT receptors Ntsr1, Ntsr2 and Ntsr3, although the involvement of each receptor in specific NT functions remains unknown. To address nociceptive function in vivo, we generated both Ntsr1-deficient and Ntsr2-deficient mice. In addition, histochemical analyses of both Ntsr1 and Ntsr2 mRNAs were performed in the mouse brain regions involved in NT-related nociception. The expression of Ntsr2 mRNA was greater than that of Ntsr1 in the periaqueductal gray (PAG) and the rostral ventral medulla (RVM). The mutant and control mice were subjected to the examination of thermal nociception, and in the hot plate test, a significant alteration in jump latency was observed in Ntsr2-deficient mice compared to Ntsr1-deficient or wild-type control mice. Latencies of tail flick and hind paw licking of the mutant mice were not affected compared to control mice. These results suggest that Ntsr2 has an important role in thermal nociception compared to Ntsr1, and that these mutant mice may represent a useful tool for the development of analgesic drugs.
Subject(s)
Pain/metabolism , Receptors, Neurotensin/metabolism , Animals , Behavior, Animal , Cloning, Molecular/methods , Gene Expression Regulation , Hot Temperature/adverse effects , In Situ Hybridization/methods , Medulla Oblongata/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Neurotensin/metabolism , Pain/physiopathology , Pain Measurement , Pain Threshold/physiology , Periaqueductal Gray/metabolism , RNA, Messenger/biosynthesis , Reaction Time , Receptors, Neurotensin/deficiency , Receptors, Neurotensin/genetics , Receptors, Neurotensin/physiology , Reverse Transcriptase Polymerase Chain Reaction/methodsABSTRACT
Several studies reported that peripheral administration of bombesin (BN) and gastrin-releasing peptide (GRP) improved some forms of memory performance. In the present study, we examined the role of endogenous BN-like peptide(s) for the acquisition of inhibitory avoidance learning in mice using BN-like peptide receptor antagonists. An administration of [Leu(13)-(psi-CH(2)NH)-Leu(14)]BN (antagonizes GRP-R>neuromedin B receptor (NMB-R)) impaired the performance of inhibitory avoidance learning in all doses (16, 32, 64 nmol/kg). While the effect was somewhat lesser than [Leu(13)-(psi-CH(2)NH)-Leu(14)]BN, BIM23127 (antagonizes NMB-R>GRP-R) also impaired performance in a moderate dose (32 nmol/kg). These results showed that endogenous BN-like peptides have some role(s) for the modulation of learning and memory, and suggest that NMB/NMB-R pathway may also be involved in the memory acquisition and modulation as well as GRP/GRP-R pathway.
Subject(s)
Avoidance Learning/physiology , Receptors, Bombesin/antagonists & inhibitors , Receptors, Bombesin/physiology , Animals , Avoidance Learning/drug effects , Darkness , Female , Lighting , Mice , Mice, Inbred C57BL , Neural Conduction/drug effects , Neural Conduction/physiology , Peptides, Cyclic/pharmacology , Reaction Time/drug effects , Reaction Time/physiologyABSTRACT
Neuromedin B (NMB) is a mammalian bombesin (BN)-like peptide that exerts its function via the neuromedin B receptor (NMB-R). The NMB/NMB-R system is involved in stress response, and therefore we examined behavioral properties in female mice lacking NMB-R using a restraint-induced stress paradigm. Thirty minutes of restraint in a wire mesh cage constituted a sufficient stress stimulus for mice as evidenced by elevated blood glucose concentrations in stressed wild-type and NMB-R-deficient mice. Using a one-trial passive avoidance test, stressed NMB-R-deficient mice exhibited a marked reduction in memory performance. NMB-R-deficient mice exhibited elevated spontaneous activity in a novel environment compared to non-stressed mutant mice after 30-min stress, and a similar difference was also observed between stressed/non-stressed wild-type mice. An elevated plus maze test showed that the stress stimulus had no effect on anxiety in either wild-type or NMB-R-deficient mice. Furthermore, pain response of wild-type and NMB-R-deficient mice induced by electric foot shock was not affected under either stressed or non-stressed conditions. These results indicate that impaired memory performance in stressed NMB-R-deficient mice is not a consequence of changes in spontaneous activity, anxiety, or pain response, and suggest that the NMB/NMB-R pathway may play a role in regulating the stress response via the neural system that controls learning and memory.
Subject(s)
Avoidance Learning , Receptors, Bombesin/deficiency , Stress, Physiological/psychology , Animals , Blood Glucose/analysis , Electroshock , Female , Genotype , Maze Learning , Metabolism, Inborn Errors/physiopathology , Mice , Motor Activity , Pain/physiopathology , Restraint, Physical , Stress, Physiological/physiopathologyABSTRACT
Neuromedin B (NMB) is a bombesin-like peptide that exerts its function via NMB receptor (NMB-R). The NMB/NMB-R pathway is involved in the regulation of a wide variety of behaviors, such as spontaneous activity, feeding, and anxiety-related behavior. In the current study, we assessed the effects of stress on maternal behavior in female NMB-R-deficient mice. Non-stressed NMB-R-deficient and wild-type mice showed normal maternal behavior. However, immediately after undergoing restraint-induced stress (30 min) both genotypes of mice exhibited severely decreased maternal behaviors. Furthermore, 30 min after stress induction, maternal behavior in wild-type mice recovered to near normal levels whereas that of NMB-R-deficient mice remained significantly lower. These results indicate that NMB-R-deficient mice suffer more severely from stress and suggest that dysfunction in the NMB/NMB-R pathway may constitute one of the risk factors of stress vulnerability.
Subject(s)
Maternal Behavior/physiology , Receptors, Bombesin/physiology , Animals , Behavior, Animal/physiology , Chi-Square Distribution , Female , Mice , Mice, Knockout , Receptors, Bombesin/genetics , Restraint, Physical , Risk Assessment , Statistics, NonparametricABSTRACT
Bombesin, its family of bombesin-like peptides, and many other peptides/hormones modulate biological and behavioral functions in animals. Among the wide variety of functions influenced by bombesin/bombesin-like peptides, the most prominent may be their role in feeding-related behavior. Over many years, intensive psychopharmacological studies have addressed the mechanisms by which these peptides induce feeding suppression, and the results suggest the applicability of bombesin/bombesin-like peptides for the treatment of eating disorders and/or obesity in humans. Recent studies using gene-knockout mice also shed new light on the relationship between bombesin/bombesin-like peptides and feeding behavior. In addition, genetic analyses of the possible links between bombesin/bombesin-like peptides/receptors and human obesity have also been undertaken. Here, we briefly review the literature pertaining to the relationship between bombesin/bombesin-like peptides and feeding behavior-with particular attention to human subjects-and discuss the pharmacotherapeutic potential of bombesin/bombesin-like peptides with regard to obesity.
