Antinociceptive effects induced by injection of the galanin receptor 1 agonist M617 into central nucleus of amygdala in rats

The present study was performed to explore the antinociceptive effects of M617, a selective galanin receptor 1 agonist, in the central nucleus of amygdala (CeA) of rats. Intra-CeA injection of 0.1 nmol, 0.5 nmol and 1 nmol of M617 induced dose-dependent increases in hindpaw withdrawal latencies (HWLs) to noxious thermal and mechanical stimulations in rats. Furthermore, rats received intra-CeA administration of M617 and galanin. The HWL to noxious thermal and mechanical stimulations increased markedly, and there were no significant differences in HWLs of rats received intra-CeA administration of M617 and galanin. The results demonstrated that intra-CeA injection of M617 induced significant antinociceptive effects in CeA of rats, indicating that galanin receptor 1 may be involved in M617-induced antinociception in the CeA of rats.     

Alcohol and nutrient intake: mechanisms of reinforcement and dependence

Alcohol is not only a drug of abuse but is also a food. This combination has a significant impact on the development and consequences of alcohol abuse and dependence. Understanding the neurobiological and behavioral processes that mediate them is perhaps best approached from the perspective of ingestive behavior. Research from the Hoebel laboratory has provided innovation and leadership in understanding that feeding neuropeptides plays a significant role in alcohol intake. The research reviewed here shows that galanin and other feeding peptides increase intake and also motivate abuse and the development of dependence. In addition, the consequences of long term alcohol abuse and dependence alter nutritional systems and drinking behavior. A major challenge is understanding the role of alcohol's dual properties and feeding neuropeptide in the motivation to drink.     

Antinociceptive effects of intracerebroventricular injection of the galanin receptor 1 agonist M 617 in rats

Previous studies in our laboratory demonstrated that galanin and its receptors play important roles in nociceptive modulation in the central nervous system. The present study was performed to explore the antinociceptive effects of the galanin receptor 1 agonist M 617 in the central nervous system of rats. Intracerebroventricular injection of 0.1nmol, 0.5nmol, 1nmol or 2nmol of M 617 induced dose-dependent increases in hindpaw withdrawal latencies (HWLs) to noxious thermal and mechanical stimulations in rats. Furthermore, both intracerebroventricular injection of M 617 and galanin induced significant increases in HWLs in rats. Interestingly, there were no significant differences between the antinociceptive effects induced by M 617 and galanin, indicating that galanin receptor 1 plays main roles in galanin-induced antinociceptive effects in the brain of rats.     

Exercise-induced galanin release facilitated GLUT4 translocation in adipocytes of type 2 diabetic rats

Although galanin has been shown to increase insulin sensitivity in skeletal muscle of rats, there is no literature available about the effect of galanin on Glucose Transporter 4 (GLUT4) translocation from intracellular membrane pools to plasma membranes in adipocytes of type 2 diabetic rats. In the present study M35, a galanin antagonist was used to elucidate whether exercise-induced galanin release increased GLUT4 translocation in adipocytes of streptozotocin-induced diabetic rats. The present findings showed that plasma galanin levels after swimming training in all four trained groups were higher compared with each sedentary control. M35 treatment had an inhibitory effect on glucose infusion rates in the euglycemic-hyperinsulinemic clamp test and GLUT4 mRNA expression levels in adipocytes. Moreover, M35 treatment reduced GLUT4 concentration in both plasma membranes and total cell membranes. The ratios of GLUT4 contents in plasma membranes to total cell membranes in four drug groups were lower compared with each control. These data demonstrate a beneficial role of endogenous galanin to transfer GLUT4 from internal stores to plasma membranes in adipocytes of type 2 diabetic rats. Galanin plays a significant role in regulation of glucose metabolic homeostasis and is an important hormone relative to diabetes.     

加兰肽等对人嗜铬细胞瘤细胞儿茶酚胺分泌功能的影响

目的 探讨糖皮质激素、加兰肽(GAL)等对于嗜铬细胞瘤细胞分泌儿茶酚胺功能的影响及其作用机制.方法 培养人原代嗜铬细胞瘤细胞28例,功能组16例,功能隐匿组12例.用不同浓度地塞米松、GAL、转化生长因子(TGF)、U0126、GF109203X作用后检测细胞培养基中儿茶酚胺水平,并用噻唑蓝(MTT)比色法观察嗜铬细胞瘤细胞的生长曲线变化.结果 地塞米松可导致原代培养的人嗜铬细胞瘤细胞儿茶酚胺分泌显著增加,而且其增加是与剂量相关的,培养第3天时0.1 μmol/L浓度的地塞米松使去甲肾上腺素由(20.10 ±7.25)ng/105增加至(42.07±9.41)ng/105,肾上腺素由(22.12±5.78)ng/105增加至(42.12±9.78)ng/105,而对增殖没有影响.GAL可使儿茶酚胺分泌增加,0.01 μmol/L浓度的GAL使去甲肾上腺素增加至(33.24±7.17)ng/105,肾上腺素增加至(33.09±8.05)ng/105,较地塞米松作用弱,同时增强细胞增殖,这种作用可以被U0126或GF109203X阻断.TGF增强细胞增殖但抑制儿茶酚胺分泌.结论 地塞米松、GAL可以刺激人嗜铬细胞瘤细胞合成、分泌儿茶酚胺,受体GALR2可能是GAL上述生理作用机制的主要介导途径.GAL及受体GALR2缺乏可能是部分嗜铬细胞瘤功能隐匿的主要原因.

Abstract：

Objective To investigate the effect and action mechanism of galanin and glucocorticoid on the the secretion of catecholamine in human pheochromocytoma cells. Methods By using the primary culture methods of human pheochromocytoma cell in part Ⅱ,different level of Dexamethasone,galanin,transforming growth factor (TGF) ,U0126,GF109203X affect the culture cell,then detect the catecholamine of the medium. To detect the growth curve of culture cell with methyl thiazol tetrazolium ( MTT) method.Results Dexamethasone can increase the secretion of catecholamine in primary cultural human pheochromocytoma cell,and the increasing is dose related, with 0. 1 μmol/L Dexamethasone,norepinephrine (20. 10 ±7.25) ng/105 increased to (42.07 ±9.41) ng/105 ,epinephrin (22. 12 ±5.78) ng/105 increased to (42. 12 ±9. 78) ng/105. make no difference of the proliferation. galanin can increase the secretion of catecholamine in primary cultural human pheochromocytoma cell too. with 0. 01 μmol/L galanin, norepinephrine increased to (33. 24 ± 7. 17) ng/105, epinephrin increased to (33. 09 ± 8. 05) ng/105. but the effect is weak than Dexamethasone. it can enhance the proliferation. this effect can be blocked by U0126 or GF109203X. TGF can enhance the proliferation but depress the secretion of catecholamine. Conclusion Human pheochromocytoma cell can secrete catecholamine and this function is correlated with Dexamethasone and galanin. Dexamethasone and galanin can stimulate synthesize and secretion of catecholamine in primary cultural human pheochromocytoma cell. GALR2 could be the chief pathway of mediate the physiological functions of galanin. the deficiency of Galanin and GALR2 may be the primary cause of the hiding function pheochromocytoma.     

Galanin receptor-expressing dorsal horn neurons: role in nociception

Galanin, along with enkephalins and neuropeptide Y, has been hypothesized to negatively modulate nociception in the superficial dorsal horn of the spinal cord. In the present study, we sought to determine the role of presumably excitatory dorsal horn galanin receptor-expressing neurons in nociception by selectively destroying GalR1-expressing superficial dorsal horn interneurons using lumbar intrathecal injections of the targeted cytotoxin, galanin–saporin (Gal–sap). Lumbar intrathecal injection of Gal–sap (500 ng) reduced immunoperoxidase staining for GalR1 in the superficial dorsal horn without affecting primary afferent neurons in lumbar dorsal root ganglia. Lumbar intrathecal Gal–sap also: 1 – reduced nocifensive reflex responding on the thermal plate at 0.3 °C, 44 °C, and 47 °C; 2 – increased hot side occupancy in a thermal preference task (15 °C vs 45 °C); and, 3 – decreased escape from 44 °C and 47 °C, but not 20 °C. Thus, similar to lesions of mu opiate receptor-expressing dorsal horn interneurons, selective destruction of GalR1-expressing superficial dorsal horn neurons produces heat hypo-algesia, likely due to loss of GalR1-expressing excitatory interneurons leading to reduced activation of nociceptive projection neurons in response to aversive heat. These results are different than those seen with intrathecal neuropeptide Y–saporin and suggest the potential value of selectively targeting GalR1-expressing dorsal horn neurons to control pain.     

Receptor–receptor interactions within receptor mosaics. Impact on neuropsychopharmacology

Future therapies for diseases associated with altered dopaminergic signaling, including Parkinson's disease, schizophrenia and drug addiction or drug dependence may substantially build on the existence of intramembrane receptor–receptor interactions within dopamine receptor containing receptor mosaics (RM; dimeric or high-order receptor oligomers) where it is believed that the dopamine D₂ receptor may operate as the ‘hub receptor’ within these complexes. The constitutive adenosine A_2A/dopamine D₂ RM, located in the dorsal striato-pallidal GABA neurons, are of particular interest in view of the demonstrated antagonistic A_2A/D₂ interaction within these heteromers; an interaction that led to the suggestion and later demonstration that A_2A antagonists could be used as novel anti-Parkinsonian drugs. Based on the likely existence of A_2A/D₂/mGluR5 RM located both extrasynaptically on striato-pallidal GABA neurons and on cortico-striatal glutamate terminals, multiple receptor–receptor interactions within this RM involving synergism between A_2A/mGluR5 to counteract D₂ signaling, has led to the proposal of using combined mGluR5 and A_2A antagonists as a future anti-Parkinsonian treatment. Based on the same RM in the ventral striato-pallidal GABA pathways, novel strategies for the treatment of schizophrenia, building on the idea that A_2A agonists and/or mGluR5 agonists will help reduce the increased dopaminergic signaling associated with this disease, have been suggested. Such treatment may ensure the proper glutamatergic drive from the mediodorsal thalamic nucleus to the prefrontal cortex, one which is believed to be reduced in schizophrenia due to a dominance of D₂-like signaling in the ventral striatum. Recently, A_2A receptors also have been shown to counteract the locomotor and sensitizing actions of cocaine and increases in A_2A receptors have also been observed in the nucleus accumbens after extended cocaine self-administration, probably representing a compensatory up-regulation to counteract the cocaine-induced increases in dopamine D₂ and D₃ signaling. Therefore, A_2A agonists, through antagonizing D₂ and D₃ signaling within A_2A/D₂ and A_2A/D₃ RM heteromers in the nucleus accumbens, may be found useful as a treatment for cocaine dependence. Furthermore, antagonistic cannabinoid CB₁/D₂ interactions requiring A_2A receptors have also been discovered and possibly operate in CB₁/D₂/A_2A RM located principally on striatal glutamate terminals but also on some ventral striato-pallidal GABA neurons, thereby opening up a new mechanism for the integration of endocannabinoid, DA and adenosine mediated signals. Thus, A_2A, mGluR5 and/or CB₁ receptors can form integrative units with D₂ receptors within RM displaying different compositions, topography and localization. Also galaninR/5-HT_1A RM probably participates in the transmission of the ascending 5-hydroxytryptamine neurons, where galanin receptors antagonize 5-HT_1A recognition and signaling. Subtype specific galanin receptor antagonists may therefore represent novel antidepressant drugs. These results suggest the importance of a complete understanding of the function of these RM with regard to disease. Ultimately receptor–receptor interactions within RM that modify dopaminergic and serotonergic signaling may give new strategies for treatment of a wide range of diseases associated with altered dopaminergic and serotonergic signaling.     

Stimulation of anterior pituitary galanin and prolactin gene expression in suckling rats

Recent evidence suggests that galanin, may regulate prolactin (PRL) secretion during lactation. In this article, we describe the regulation of anterior pituitary galanin and PRL gene expression during pregnancy and after parturition in the rat. Expression of galanin and PRL in the anterior pituitary were significantly higher at d 20 of pregnancy compared to diestrus. One day after parturition, galanin mRNA levels increased a further 4.5-fold. This post partum increase in gene expression was not observed for PRL. The increase in galanin gene expression was maintained above the diestrous level for at least 10 d after parturition. PRL mRNA expression, on the other hand, was largely unchanged after parturition. Although the increase in galanin gene expression 1 d after parturition was independent of suckling, subsequently, galanin, gene expression was significantly higher in nursing mothers. Anterior pituitary galanin gene expression was 12-fold higher in nursing mothers compared with those that were not, 3 d after parturition. Similarly, PRL gene expression was significantly lower in mothers who were not suckling their pups 3 d after parturition. Initiation of suckling alone was insufficient to stimulate galanin and PRL expression. Despite suckling for 2 d, removal of the suckling stimulus subsequently resulted in a rapid decrease in galanin gene expression. Hence, the stimulatory effect of suckling on galanin expression requires a sustained suckling stimulus. In conclusion, the data support the hypothesis that anterior pituitary galanin plays an important role during lactation, likely acting to amplify lactotroph stimulation through paracrine and autocrine mechanisms.