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Background: Allergic rhinitis (AR) is caused by allergic reaction to allergens such as pollen. Galanin (GAL), a neuropeptide that regulates inflammatory processes, is widely expressed in the central and peripheral nervous systems. Although neuropeptides are implicated in arthritis and chemically induced ileitis, their roles in AR remain unclear. Methods: We developed a murine model of AR and generated control, systemic sensitization, mild AR, and severe AR groups. We examined GAL and GAL receptor (GALR) mRNA and protein levels and localization patterns in each group using reverse transcription PCR, western blotting, and immunohistochemical analyses. Additionally, we evaluated the effects of M871, a GALR2 antagonist, on mice with severe AR. Results: Gal and Galr2 are expressed in nasal mucosa and brain (control) samples from control and AR mice. GAL and GALR2 were expressed at similar levels and localized to ciliated epithelial and submucosal gland cells of the nasal mucosa in all four groups. Intranasal M871 administration significantly reduced the incidence of nose rubbing behaviors and sneezing (p

A need for new therapeutic approaches are necessary for dementia conditions and memory deficits of different origins, such as Alzheimer's disease. There is complex pathophysiological mechanisms involved, affecting adult hippocampal neurogenesis, in which neuropeptides and its neurogenesis regulation seem to participate. Neuropeptide Y(NPY) Y1 receptor (Y1R) and galanin (GAL) receptor 2 (GALR2) interact in brain regions responsible for learning and memory processes, emphasizing the hippocampus. Moreover, a significant challenge for treatments involving peptide drugs is bypassing the blood-brain barrier. The current study assesses the sustained memory performance induced by GALR2 and NPYY1R agonists intranasal coadministration and their neurochemical hippocampal correlates. Memory retrieval was conducted in the object-in-place task together with in situ proximity ligation assay (PLA) to manifest the formation of GALR2/Y1R heteroreceptor complexes and their dynamics under the different treatments. We evaluated cell proliferation through a 5-Bromo-2’-deoxyuridine (BrdU) expression study within the dentate gyrus of the dorsal hippocampus. The GalR2 agonist M1145 was demonstrated to act with the Y1R agonist to improve memory retrieval at 24 hours in the object-in-place task. Our data show that the intranasal administration is a feasible technique for directly delivering Galanin or Neuropeptide Y compounds into CNS. Moreover, we observed the ability of the co-agonist treatment to enhance the cell proliferation in the DG of the dorsal hippocampus through 5- Bromo-2’-deoxyuridine (BrdU) expression analysis at 24 hours. The understanding of the cellular mechanisms was achieved by analyzing the GALR2/Y1R heteroreceptor complexes upon agonist coactivation of their two types of receptor protomers in Doublecortin-expressing neuroblasts. Our results may provide the basis for developing heterobivalent agonist pharmacophores, targeting GALR2-Y1R heterocomplexes. It involves especially the neuronal precursor cells of the dentate gyrus in the dorsal hippocampus for the novel treatment of neurodegenerative pathologies as in the Alzheimer’s disease.

It has been reported that galanin has an analgesic effect via activating galanin receptors (GALRs). This study focused on the involvement of GALR2 in the galanin-induced analgesic effect and its signaling mechanism in the nucleus accumbens (NAc) of inflammatory rats. Animal models were established through injecting carrageenan into the plantar of rats’ left hind paw. The results showed that GALR2 antagonist M871 weakened partially the galanin-induced increases in hind paw withdrawal latency (HWL) to thermal stimulation and hind paw withdrawal threshold (HWT) to mechanical stimulation in NAc of inflammatory rats. Moreover, the GALR2 agonist M1145 prolonged the HWL and HWT, while M871 blocked the M1145-induced increases in HWL and HWT. Western blotting showed that the phosphorylation of calcium/calmodulin-dependent protein kinase II (p-CaMKII) and protein kinase C (p-PKC) in NAc were upregulated after carrageenan injection, while p-PKC and p-CaMKII were downregulated after intra-NAc administration of M871. Furthermore, the CaMKII inhibitor KN93 and PKC inhibitor GO6983 attenuated M1145-induced increases in HWL and HWT in NAc of rats with inflammatory pain. These results prove that GALR2 is involved in the galanin-induced analgesic effect by activating CaMKII and PKC in NAc of inflammatory pain rats, implying that GALR2 agonists probably are potent therapeutic options for inflammatory pain.

Various studies have reported that galanin can promote axonal regeneration of dorsal root ganglion neurons in vitro and inhibit neuropathic pain. However, little is known about its effects on diabetic peripheral neuropathy, and in vivo experimental data are lacking. We hypothesized that repeated applications of exogenous galanin over an extended time frame may also repair nerve damage in diabetic peripheral neuropathy, and relieve pain in vivo. We found that neuropathic pain occurred in streptozotocin-induced diabetic rats and was more severe after sciatic nerve pinch injury at 14 and 28 days than in diabetic sham-operated rats. Treatment with exogenous galanin alleviated the neuropathic pain and promoted sciatic nerve regeneration more effectively in diabetic rats than in non-diabetic rats after sciatic nerve pinch injury. This was accompanied by changes in the levels of endogenous galanin, and its receptors galanin receptor 1 and galanin receptor 2 in the dorsal root ganglia and the spinal dorsal horn when compared with nerve pinch normal rats. Our results show that application of exogenous galanin daily for 28 days can promote the regeneration of injured sciatic nerves, and alleviate neuropathic pain in diabetic rats.

Anxiety is evoked by a threatening situation and display adaptive or defensive behaviors, found similarly in animals and humans. Neuropeptide Y (NPY) Y1 receptor (NPYY1R) and Galanin (GAL) receptor 2 (GALR2) interact in several regions of the limbic system, including the amygdala. In a previous study, GALR2 enhanced NPYY1R mediated anxiolytic actions on spatiotemporal parameters in the open field and elevated plus maze, involving the formation of GALR2/NPYY1R heteroreceptor complexes in the amygdala. Moreover, the inclusion of complementary ethological parameters provides a more comprehensive profile on the anxiolytic effects of a treatment. The purpose of the current study is to evaluate the anxiolytic effects and circuit activity modifications caused by coactivation of GALR2 and NPYY1R. Ethological measurements were performed in the open field, the elevated plus-maze and the light-dark box, together with immediate early gene expression analysis within the amygdala-hypothalamus-periaqueductal gray (PAG) axis, as well as in situ proximity ligation assay (PLA) to demonstrate the formation of GALR2/NPYY1R heteroreceptor complexes. GALR2 and NPYY1R coactivation resulted in anxiolytic behaviors such as increased rearing and head-dipping, reduced stretch attend postures and freezing compared to single agonist or aCSF injection. Neuronal activity indicated by cFos expression was decreased in the dorsolateral paracapsular intercalated (ITCp-dl) subregion of the amygdala, ventromedial hypothalamic (VMH) nucleus and ventrolateral part of the periaqueductal gray (vlPAG), while increased in the perifornical nucleus of the hypothalamus (PFX) following coactivation of GALR2 and NPYY1R. Moreover, an increased density of GALR2/NPYY1R heteroreceptor complexes was explicitly observed in ITCp-dl, following GALR2 and NPYY1R coactivation. Besides, knockdown of GALR2 was found to reduce the density of complexes in ITCp-dl. Taken together, these results open up the possibility that the increased anxiolytic activity demonstrated upon coactivation of NPYY1R and GALR2 receptor was related to actions on the ITCp-dl. GALR2-NPYY1R heteroreceptor complexes may inhibit neuronal activity, by also modifying the neuronal networks of the hypothalamus and the PAG. These results indicate that GALR2/NPYY1R interactions in medial paracapsular intercalated amygdala can provide a novel integrative mechanism in anxiolytic behavior and the basis for the development of heterobivalent agonist drugs targeting GALR2/NPYY1R heteromers, especially in the ITCp-dl of the amygdala for the treatment of anxiety.