The caudal nucleus tractus solitarii (NTS) is the main central station of cough-related afferents and a strategic site for the modulation of the cough reflex. The similarities between the ...characteristics of central processing of nociceptive and cough-related inputs led us to hypothesize that galanin, a neuropeptide implicated in the control of pain, could also be involved in the regulation of the cough reflex at the level of the NTS, where galanin receptors have been found. We investigated the effects of galanin and galnon, a nonpeptide agonist at galanin receptors, on cough responses to mechanical and chemical (citric acid) stimulation of the tracheobronchial tree. Drugs were microinjected (30-50 nl) into the caudal NTS of pentobarbital sodium-anesthetized, spontaneously breathing rabbits. Galnon antitussive effects on cough responses to the mechanical stimulation of the airway mucosa via a custom-built device were also investigated. Bilateral microinjections of 1 mM galanin markedly decreased cough number, peak abdominal activity, and increased cough-related total cycle duration. Bilateral microinjections of 1 mM galnon induced mild depressant effects on cough, whereas bilateral microinjections of 10 mM galnon caused marked antitussive effects consistent with those produced by galanin. Galnon effects were confirmed by using the cough-inducing device. The results indicate that galanin receptors play a role in the inhibitory control of the cough reflex at the level of the caudal NTS and provide hints for the development of novel antitussive strategies.
The neuropeptide galanin and its receptors are expressed in brain regions implicated in drug dependence. Indeed, several lines of evidence support a role for galanin in modulating the effects of ...drugs of abuse, including morphine, cocaine, amphetamine, and alcohol. Despite these findings, the role of galanin and its receptors in the effects of nicotine is largely underexplored. Here, using mouse models of nicotine reward and withdrawal, we show that there is a significant correlation between mecamylamine-precipitated nicotine withdrawal somatic signs and basal galanin or galanin receptor 1 (GALR1) expression in mesolimbocortical dopamine regions across the BXD battery of recombinant inbred mouse lines. The non-peptide galanin receptor agonist, galnon, also blocks nicotine rewarding effects and reverses mecamylamine-precipitated nicotine withdrawal signs in ICR mice. Additionally, we conducted a meta-analysis using smoking information from six European-American and African-American data sets. In support of our animal data, results from the association study show that variants in the GALR1 gene are associated with a protective effect in nicotine dependence (ND). Taken together, our data suggest that galanin has a protective role against progression to ND, and these effects may be mediated through GALR1.
Relapse represents one of the most significant problems in the long‐term treatment of drug addiction. Cocaine blocks plasma membrane monoamine transporters and increases dopamine (DA) overflow in the ...brain, and DA is critical for the motivational and primary reinforcing effects of the drug as well as cocaine‐primed reinstatement of cocaine seeking in rats, a model of relapse. Thus, modulators of the DA system may be effective for the treatment of cocaine dependence. The endogenous neuropeptide galanin inhibits DA transmission, and both galanin and the synthetic galanin receptor agonist, galnon, interfere with some rewarding properties of cocaine. The purpose of this study was to further assess the effects of galnon on cocaine‐induced behaviors and neurochemistry in rats. We found that galnon attenuated cocaine‐induced motor activity, reinstatement and DA overflow in the frontal cortex at a dose that did not reduce baseline motor activity, stable self‐administration of cocaine, baseline extracellular DA levels or cocaine‐induced DA overflow in the nucleus accumbens (NAc). Similar to cocaine, galnon had no effect on stable food self‐administration but reduced food‐primed reinstatement. These results indicate that galnon can diminish cocaine‐induced hyperactivity and relapse‐like behavior, possibly in part by modulating DA transmission in the frontal cortex.
We found that the synthetic galanin receptor agonist, galnon, attenuated cocaine‐induced motor activity, reinstatement, and dopamine (DA) overflow in the frontal cortex at a dose that did not reduce baseline motor activity, stable self‐administration of cocaine, baseline extracellular DA levels, or cocaine‐induced DA overflow in the nucleus accumbens (NAc). These results indicate that galnon can diminish cocaine‐induced hyperactivity and relapse‐like behavior, possibly in part by modulating DA transmission in the frontal cortex.
Learning and memory systems are intimately involved in drug addiction. Previous studies suggest that galanin, a neuropeptide that binds G-protein coupled receptors, plays essential roles in the ...encoding of memory. In the present study, we tested the function of galnon, a galanin receptor 1 and 2 agonist, in reward-associated memory, using conditioned place preference (CPP), a widely used paradigm in drug-associated memory. Either before or following CPP-inducing morphine administration, galnon was injected at four different time points to test the effects of galanin activation on different reward-associated memory processes: 15 min before CPP training (acquisition), immediately after CPP training (consolidation), 15 min before the post-conditioning test (retrieval), and multiple injection after post-tests (reconsolidation and extinction). Galnon enhanced consolidation and extinction processes of morphine-induced CPP memory, but the compound had no effect on acquisition, retrieval, or reconsolidation processes. Our findings demonstrate that a galanin receptor 1 and 2 agonist, galnon, may be used as a viable compound to treat drug addiction by facilitating memory extinction process.
Abstract Galanin’s influence on monoaminergic neurotransmission, together with its discrete CNS distribution in corticolimbic brain areas, points to a potential role for this neuropeptide in ...mediating anxiety- and depression-like responses. To evaluate this hypothesis, the non-selective galanin receptor agonist, galnon, was tested in multiple preclinical models of anxiolytic- and antidepressive-like activity. Acute administration of galnon (0.03–1 mg/kg, i.p.) dose-dependently increased punished crossings in the four plate test, with magnitude similar to the effects of the endogenous ligand, galanin (0.1–1.0 μg, i.c.v.). Moreover, the effects of galnon and galanin were blocked by central administration of the non-selective galanin receptor antagonist, M35 (10 μg, i.c.v.). Interestingly, the benzodiazepine receptor antagonist, flumazenil (1 mg/kg, i.p.), reversed galnon’s effect in the four plate test, implicating GABAergic neurotransmission as a potential mechanism underlying this anxiolytic-like response. In the elevated zero maze, galnon (0.3–3.0 mg/kg, i.p.) and galanin (0.03–0.3 μg, i.c.v.) increased the time spent in the open arms, while in the stress-induced hyperthermia model, galnon (0.3–30 mg/kg, i.p.) attenuated stress-induced changes in body temperature. Consistent with these anxiolytic-like effects, in vivo microdialysis showed that acute galnon (3 mg/kg, i.p.) treatment preferentially elevated levels of GABA in the rat amygdala, a brain area linked to fear and anxiety behaviors. In contrast to the effects in anxiety models, neither galnon (1–5.6 mg/kg, i.p.) nor galanin (0.3–3.0 μg, i.c.v.) demonstrated antidepressant-like effects in the mouse tail suspension test. Galnon (1–10 mg/kg, i.p.) also failed to reduce immobility time in the rat forced swim test. In vitro , galnon and galanin showed affinity for human galanin receptors expressed in Bowes melanoma cells ( Ki = 5.5 μM and 0.2 nM, respectively). Galanin displayed high affinity and functional potency for membranes expressing rat GALR1 receptors ( Ki = 0.85 nM; EC50 = 0.6 nM), while galnon (10 μM) failed to displace radiolabeled galanin or inhibit cAMP production in the same GALR1 cell line. Galnon (10 μM) showed affinity for NPY1, NK2, M5, and somatostatin receptors but no affinity for galanin receptors expressed in rat hippocampal membranes. Taken together, the present series of studies demonstrate novel effects of galnon in various preclinical models of anxiety and highlight the galaninergic system as a novel therapeutic target for the treatment of anxiety-related disorders. Moreover, these data indicate rodent GALR1 receptors do not mediate galnon’s in vivo activity.
Galanin is a neuropeptide with a wide variety of biological functions. Few nonpeptide ligands, capable of activating galanin receptors, are available today. Based on known pharmacophores of galanin ...and the tripeptidomimetic galnon, a combinatorial library was formulated, synthesized, and screened against the galanin receptor. An active compound, galmic, was identified and tested in vitro and in vivo for its affinity and efficacy at galanin receptors. The present work describes the total synthesis of galmic, the synthesis of its oxazole precursors, the coupling of the building blocks into a linear trimer, and the macrolactamization reaction.
Galnon was first reported as a low molecular weight non-peptide agonist at galanin receptors Saar et al. (2002)
Proc. Natl. Acad. Sci. USA
99, 7136–7141. Following its systemic administration, this ...synthetic ligand affected a range of important physiological processes including appetite, seizures and pain. Physiological activity of galnon could not be explained solely by the activation of the three known galanin receptors, GalR1, GalR2 and GalR3. Consequently, it was possible that galnon generates its manifold effects by interacting with other signaling pathway components, in addition to via GalR1-3. In this report, we establish that galnon: (i) can penetrate across the plasma membrane of cells, (ii) can activate intracellular G-proteins directly independent of receptor activation thereby triggering downstream signaling, (iii) demonstrates selectivity for different G-proteins, and (iiii) is a ligand to other G-protein coupled receptors (GPCRs) in addition to via GalR1-3. We conclude that galnon has multiple sites of interaction within the GPCR signaling cascade which mediate its physiological effects.
Galnon is a low-molecular weight galanin receptor ligand, with affinity towards the three galanin receptors in the micromolar range. Galnon is of interest as a drug candidate due to its stability and ...ability to pass the blood–brain barrier. Like galanin, galnon has also been shown to affect various physiological functions; however, occasionally galanin and galnon act in opposing ways. Since its introduction in 2002, galnon has been characterized to inhibit seizures, decrease feeding behaviour, diminish physical signs of opiate withdrawal and to alleviate heat-hyperalgesic response to partial sciatic nerve injury. In this review, we will summarize what is known about galnon to date.
The impairment of cognitive performance by galanin administration in rodents indicates a possible modulating effect of this neuropeptide on long-term potentiation (LTP) induction in the hippocampal ...formation. Galnon is a non-peptide, systemically active galanin receptor agonist which has been tested in feeding, seizure and forced swim task in in vivo rodent experimental models. Similarly to galanin (1–29) (i.c.v.), galnon (i.p.) has exhibited anticonvulsant effects in rats. We have investigated the effect of galnon on the synaptic transmission and plasticity in hippocampal dentate gyrus (DG) of C57Bl/6 mice and compared the galnon effects to the effect of galanin (1–29) and galmic, a non-peptide galanin receptor agonist. Similarly to galanin (1–29) and galmic, superfusion of galnon did not alter the input–output responses in DG. Administration of galnon (1
μM) significantly attenuated the LTP induction by 85.5
±
1% by 51
min after high frequency trains stimulation. This result was very similar to the effect of galanin (1–29) and galmic, which caused an 80
±
1.5% and 94
±
2% reduction in the level of field potentiation, respectively. The PPF responses, however, were not altered due to galnon superfusion which is in contrast to the effect of galanin (1–29) or galmic. In summary, these data indicate that the systemically active, non-peptide galanin receptor agonist, galnon can exert similar effects to galanin (1–29) in attenuation of DG LTP in mice.
Regulation of feeding by galnon Abramov, Urho; Florén, Anders; Echevarria, David J. ...
Neuropeptides (Edinburgh),
02/2004, Letnik:
38, Številka:
1
Journal Article
Recenzirano
Galanin is a neuropeptide that has been implicated in multiple bioactivities, inter alia eating disorders. In this study, we have examined the effects of galnon, a novel low molecular weight galanin ...receptor ligand. Previous studies have shown that galnon acts as a systemically active, blood–brain barrier crossing agonist on galanin signaling both in vitro and in vivo, inhibiting pentylenetetrazole-induced seizures. Here, intracerebroventricular (10–20 μg) and intraperitoneal (1.5–5 mg/kg) administration of galnon induced a strong, dose-dependent reduction of food intake in rats and mice. This reduction in feeding occurred without reducing general activity and was shown to be attenuated by an intracerebroventricular administration of M35, a peptide galanin antagonist. These data demonstrate that galnon is a promising tool for studies of the involvement of galanin in feeding disorders and other behavioral processes.
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