Neuropeptides最新文献

Background

The oxidizable glycolytic end-product L-lactate is a gauge of nerve cell metabolic fuel stability that metabolic-sensory hindbrain A2 noradrenergic neurons impart to the brain glucose-regulatory network. Current research investigated the premise that hindbrain lactate deficiency exerts sex-specific control of energy sensor and transmitter marker protein responses to hypoglycemia in ventromedial hypothalamic nucleus (VMN) glucose-regulatory nitrergic and γ-aminobutyric acid (GABA) neurons.

Methods

Nitric oxide synthase (nNOS)- or glutamate decarboxylase_65/67 (GAD)-immunoreactive neurons were laser-catapult-microdissected from male and female rat VMN after subcutaneous insulin injection and caudal fourth ventricular L-lactate or vehicle infusion for Western blot protein analysis.

Results

Hindbrain lactate repletion reversed hypoglycemia-associated augmentation (males) or inhibition (females) of nitrergic neuron nNOS expression, and prevented up-regulation of phosphorylated AMPK 5’-AMP-activated protein kinase (pAMPK) expression in those neurons. Hypoglycemic suppression of GABAergic neuron GAD protein was averted by exogenous lactate over the rostro-caudal length of the male VMN and in the middle region of the female VMN. Lactate normalized GABA neuron pAMPK profiles in hypoglycemic male (caudal VMN) and female (all VMN segments) rats. Hypoglycemic patterns of norepinephrine (NE) signaling were lactate-dependent throughout the male VMN, but confined to the rostral and middle female VMN.

Conclusions

Results document, in each sex, regional VMN glucose-regulatory transmitter responses to hypoglycemia that are controlled by hindbrain lactate status. Hindbrain metabolic-sensory regulation of hypoglycemia-correlated nitric oxide or GABA release may entail AMPK-dependent mechanisms in specific VMN rostro-caudal segments in each sex. Additional effort is required to examine the role of hindbrain lactoprivic-sensitive VMN neurotransmitters in lactate-mediated attenuation of hypoglycemic hyperglucagonemia and hypercorticosteronemia in male and female rats.

The correlation between sleep and epilepsy has been argued over the past decades among scientists. Although the similarities and contrasts between sleep and epilepsy had been considered, their intertwined nature was not revealed until the nineteenth century. Sleep is recognized as a recurring state of mind and body through alternating brain electrical activities. It is documented that sleep disorders are associated with epilepsy. The origin, suppression, and spread of seizures are affected by sleep. As such, in patients with epilepsy, sleep disorders are a frequent comorbidity. Meanwhile, orexin, a wake-promoting neuropeptide, provides a bidirectional effect on both sleep and epilepsy. Orexin and its cognate receptors, orexin receptor type 1 (OX1R) and type 2 (OX2R), orchestrate their effects by activating various downstream signaling pathways. Although orexin was considered a therapeutic target in insomnia shortly after its discovery, its potential usefulness for psychiatric disorders and epileptic seizures has been suggested in the pre-clinical studies. This review aimed to discuss whether the relationship between sleep, epilepsy, and orexin is clearly reciprocal.

In recent years, the association between neuroinflammation and opioid dependence has attracted considerable attention. Curcumin, a component of the Curcuma longa, has been shown to act as a suppressor of glial cells and inflammatory cytokines. The main goal of this study was to explore the attenuating effects of curcumin on morphine dependence with a focus on neuroinflammation and μ-opioid receptors in the rat prefrontal cortex. To induce morphine dependence in male Wistar rats, morphine was administered i.p. once daily for 18 days in an escalating dose of 10, 20, and 40 mg/kg. Curcumin (2.5, 5, and 10 mg/kg, i.p.) was given from the days 10th to 18th. Immunofluorescence staining and ELISA methods were used to evaluate glial cells activity and inflammatory cytokines levels, respectively. Western blotting was used to evaluate the expression of μ-opioid receptors. The administration of curcumin (2.5, 5, and 10 mg/kg) for 9 days significantly attenuated the symptoms of morphine withdrawal syndrome. The prefrontal cortex concentration of TNF-α and IL-6 was also reduced by curcumin (2.5, 5, and 10 mg/kg) significantly. Furthermore, curcumin decreased the number of Iba1 and GFAP positive cells in morphine-dependent rats. Moreover, the expression of μ-opioid receptors was significantly reduced by curcumin (10 mg/kg). The results of this study demonstrate that curcumin attenuates morphine dependence in rats through an inhibitory effect on neuroinflammation and a decrease in the expression of μ-opioid receptors in the prefrontal cortex.

Neuropathic pain is a chronic and debilitating condition characterised by episodes of hyperalgesia and allodynia. It occurs following nerve damage from disease, inflammation or injury and currently impacts up to 17% of the UK population. Existing therapies lack efficacy and have deleterious side effects that can be severely limiting.

Galanin receptor 2 (GalR2) is a G-protein coupled receptor (GPCR) implicated in the control and processing of painful stimuli. Within the nervous system it is expressed in key tissues involved in these actions such as dorsal root ganglia (DRG) and the dorsal horn of the spinal cord. Stimulation of GalR2 is widely reported to have a role in the attenuation of inflammatory and neuropathic pain. Several studies have indicated GalR2 as a possible drug target, highlighting the potential of specific GalR2 agonists to both provide efficacy and to address the side-effect profiles of current pain therapies in clinical use.

A strong biological target for drug discovery will be well validated with regards to its role in the relevant disease pathology. Ideally there will be good translational models, sensitive probes, selective and appropriate molecular tools, translational biomarkers, a clearly defined patient population and strong opportunities for commercialisation. Before GalR2 can be considered as a drug target suitable for investment, key questions need to be asked regarding its expression profile, receptor signalling and ligand interactions. This article aims to critically review the available literature and determine the current strength of hypothesis of GalR2 as a target for the treatment of neuropathic pain.

Depression is the second leading cause of disability in the world population, for which currently available pharmacological therapies either have poor efficacy or have some adverse effects. Accumulating evidence from clinical and preclinical studies demonstrates that the amygdala is critically implicated in depressive disorders, though the underlying pathogenesis mechanism needs further investigation. In this literature review, we overviewed depression and the key role of Gamma-aminobutyric acid (GABA) and Glutamate neurotransmission in depression. Notably, we discussed a new cholecystokinin-dependent plastic changes mechanism under stress and a possible antidepressant response of cholecystokinin B receptor (CCKBR) antagonist. Moreover, we discussed the fundamental role of the amygdala in depression, to discuss and understand the pathophysiology of depression and the inclusive role of the amygdala in this devastating disorder.

The regulatory peptide 26RFa (QRFP) is involved in the control of glucose homeostasis at the periphery by acting as an incretin, and in the brain by mediating the central antihyperglycemic effect of insulin, indicating the occurrence of a close relationship between 26RFa and insulin in the regulation of glucose metabolism. Here, we investigated the physiological interactions between 26RFa and insulin in two complementary models i.e. a model of obese/hyperglycemic mice deficient for 26RFa and a model of diabetic mice deficient for insulin. For this, transgenic 26RFa-deficient mice were made obese and chronically hyperglycemic by a 3-month high fat diet (HFD) and second group of mice was made diabetic by destruction of the β cells of the pancreatic islets using a single injection of streptozotocin. Our data reveal that 26RFa deficiency does not impact significantly the “glycemic” phenotype of the HFD mice. The pancreatic islets, liver, white adipose tissue masses are not altered by the lack of 26RFa production but the brown adipose tissue (BAT) weight is significantly increased in these animals. In diabetic insulin-deficient mice, the injection of 26RFa does not exhibit any beneficial effect on the impaired glucose homeostasis characterizing this model. Finally, we show that streptozotocin diabetic mice display lowered plasma 26RFa levels as compared to untreated mice, whereas the expression of the peptide in the duodenum is not affected.

Taken together, the present results indicate that dysregulation of glucose homeostasis in obese/hyperglycemic mice is not aggravated by the absence of 26RFa that may be compensated by the increase of BAT mass. In diabetic insulin-deficient mice, the antihypergycemic effect of 26RFa is totally blunted probably as a result of the impaired insulin production characterizing this model, avoiding therefore the action of the peptide.

Prolactin-releasing peptide (PrRP) is an anorexigenic neuropeptide that attenuates food intake and increases energy expenditure. We designed three series of new lipidized PrRP31 analogs of different lengths of fatty acids attached at amino acids 1 or 11 directly or via linkers, part of them acetylated at the N-terminus and/or modified with dichlorophenylalanine (PheCl₂) at the C-terminus. We tested their affinity for and activation of signaling pathways relevant to receptors GPR10, NPFF-R2, and NPFF-R1, effect on food intake in fasted or freely fed mice and rats, and stability in rat plasma. We aimed to select a strong dual GPR10/NPFF-R2 agonist whose affinity for NPFF-1 was not enhanced. The selected potent analog was then tested for body weight-lowering potency after chronic administration in mice with diet-induced obesity. PrRP31 analogs lipidized by monocarboxylic fatty acids showed strong dual affinity for both GPR10 and NPFF-R2 and activated MAPK/ERK1/2, Akt and CREB in cells overexpressing GPR10 and NPFF-R2. The selected analog stabilized at N- and C-termini and palmitoylated through the TTDS linker to Lys¹¹ is a powerful dual agonist GPR10/NPFF-R2 at not enhanced affinity for NPFF-R1. It showed strong anti-obesity properties in mice with diet-induced obesity and became a potential compound for further studies.

Stress suppresses the sense of pain, a physiological phenomenon known as stress-induced analgesia (SIA). Brain orexin peptides regulate many physiological functions, including wakefulness and nociception. The contribution of the orexinergic system within the nucleus accumbens (NAc) in the modulation of antinociception induced by forced swim stress (FSS) remains unclear. The present study addressed the role of intra-accumbal orexin receptors in the antinociceptive responses induced by FSS during the persistent inflammatory pain model in the rat. Stereotaxic surgery was performed unilaterally on 106 adult male Wistar rats weighing 250–305 g. Different doses (1, 3, 10, and 30 nmol/ 0.5 μl DMSO) of orexin-1 receptor (OX1r) antagonist (SB334867) or OX2 receptor antagonist (TCS OX2 29) were administered into the NAc five minutes before exposure to FSS for a 6-min period. The formalin test was carried out using formalin injection (50 μl; 2.5%) into the rat's hind paw plantar surface, which induces biphasic pain-related responses. The first phase begins immediately after formalin infusion and takes 3–5 min. Subsequently, the late phase begins 15–20 min after formalin injection and takes 20–40 min. The findings demonstrated that intra-accumbal microinjection of SB334867 or TCS OX2 29 attenuated the FSS-induced antinociception in both phases of the formalin test, with the TCS OX2 29 showing higher potency. Moreover, the effect of TCS OX2 29 was more significant during the early phase of the formalin test. The results suggest that OX1 and OX2 receptors in the NAc might modulate the antinociceptive responses induced by the FSS.

The chimeric peptide EN-9 was reported as a κ-opioid/neuropeptide FF receptors bifunctional agonist that modulated chronic pain with no tolerance. Many lines of evidence have shown that the effect of the κ-opioid receptor is mediated by not only its specific activation but also downstream events participation, especially interaction with the μ-opioid receptor pathway in antinociception and tolerance on most occasions. The present study investigated the acute and chronic cross-tolerance of EN-9 with μ-opioid receptor agonist EM-2, DAMGO, and morphine after intracerebroventricularly (i.c.v) injection in the mouse tail-flick test. In the acute tolerance test, EN-9 showed symmetrical acute cross-tolerance to DAMGO but no cross-tolerance to EM2. In the chronic tolerance test, EN-9 had no tolerance after eight days of repeated administration. However, EN-9 illustrated complete cross-tolerance to morphine and symmetrical cross-tolerance to EM2. In addition, inhibition of NPFF receptor could induce the tolerance development of EN-9. These findings indicated that supraspinal EN-9-induced antinociception contains additional components, which are mediated by the downstream μ-opioid receptor pathway both in acute and chronic treatment, whereas the subtypes of μ-opioid receptor or NPFF system pathway involved in antinociceptive effects induced by EN-9 are complex. Identifying the receptor mechanism could help design preferable bifunctional opioid compounds.

Background and aims

The contractile effects of tachykinins on the gastrointestinal tract are well-known, but how they modulate slow-waves, particularly in species capable of emesis, remains largely unknown. We aimed to elucidate the effects of tachykinins on myoelectric and contractile activity of isolated gastrointestinal tissues of the Suncus murinus.

Methods

The effects of substance P (SP), neurokinin (NK)A, NKB and selective NK₁ (CP122,721, CP99,994), NK₂ (SR48,968, GR159,897) and NK₃ (SB218,795, SB222,200) receptor antagonists on isolated stomach, duodenum, ileum and colon segments were studied. Mechanical contractile activity was recorded using isometric force displacement transducers. Electrical pacemaker activity was recorded using a microelectrode array.

Results

Compared with NKA, SP induced larger contractions in stomach tissue and smaller contractions in intestinal segments, where oscillation magnitudes increased in intestinal segments, but not the stomach. CP122,721 and GR159,897 inhibited electrical field stimulation-induced contractions of the stomach, ileum and colon. NKB and NK₃ had minor effects on contractile activity. The inhibitory potencies of SP and NKA on the peristaltic frequency of the colon and ileum, respectively, were correlated with those on electrical pacemaker frequency. SP, NKA and NKB inhibited pacemaker activity of the duodenum and ileum, but increased that of the stomach and colon. SP elicited a dose-dependent contradictive pacemaker frequency response in the colon.

Conclusion

This study revealed distinct effects of tachykinins on the mechanical and electrical properties of the stomach and colon vs. the proximal intestine, providing a unique aspect on neuromuscular correlation in terms of the effects of tachykinin on peristaltic and pacemaker activity in gastrointestinal-related symptoms.