Galanin peptide family regulation of glucose metabolism.

Recent preclinical and clinical studies have indicated that the galanin peptide family may regulate glucose metabolism and alleviate insulin resistance, which diminishes the probability of type 2 diabetes mellitus. The galanin was discovered in 1983 as a gut-derived peptide hormone. Subsequently, galanin peptide family was found to exert a series of metabolic effects, including the regulation of gut motility, body weight and glucose metabolism. The galanin peptide family in modulating glucose metabolism received recently increasing recognition because pharmacological activiation of galanin signaling might be of therapeutic value to improve insuin resistance and type 2 diabetes mellitus. To date, however, few papers have summarized the role of the galanin peptide family in modulating glucose metabolism and insulin resistance. In this review we summarize the metabolic effect of galanin peptide family and highlight its glucoregulatory action and discuss the pharmacological value of galanin pathway activiation for the treatment of glucose intolerance and type 2 diabetes mellitus.

Go2 G protein mediates galanin inhibitory effects on insulin release from pancreatic ß cells.

The neuropeptide galanin regulates numerous physiological activities in the body, including feeding and metabolism, learning and memory, nociception and spinal reflexes, and anxiety and related behaviors. Modulation of blood glucose levels by suppressing insulin release was the first reported activity for galanin. This inhibition was mediated by one or more pertussis toxin-sensitive G proteins of the G(i/o) subfamily. However, the molecular identities of the specific G protein(s) and intracellular effectors have not been fully revealed. Recently, we demonstrated that mice lacking G(o)2, but not other members of the G(i/o) protein family, secrete more insulin than controls upon glucose challenge, indicating that G(o)2 is a major transducer for the inhibitory regulation of insulin secretion. In this study, we investigated galanin signaling mechanisms in ß cells using cell biological and electrophysiological approaches. We found that islets lacking G(o)2, but not other G(i/o) proteins, lose the inhibitory effect of galanin on insulin release. Potentiation of ATP-sensitive potassium (K(ATP)) and inhibition of calcium currents by galanin were disrupted by anti-G(o)2α antibodies. Galanin actions on K(ATP) and calcium currents were completely lost in G(o)2(-/-) ß cells. Furthermore, the hyperglycemic effect of galanin is also blunted in G(o)2(-/-) mice. Our results demonstrate that G(o)2 mediates the inhibition of insulin release by galanin by regulating both K(ATP) and Ca(2+) channels in mice. Our findings provide insight into galanin's action in glucose homeostasis. The results may also be relevant to the understanding of galanin signaling in other biological systems, especially the central nervous system.

Inhibitory control of the cough reflex by galanin receptors in the caudal nucleus tractus solitarii of the rabbit.

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.

Dopamine-galanin receptor heteromers modulate cholinergic neurotransmission in the rat ventral hippocampus.

Previous studies have shown that dopamine and galanin modulate cholinergic transmission in the hippocampus, but little is known about the mechanisms involved and their possible interactions. By using resonance energy transfer techniques in transfected mammalian cells, we demonstrated the existence of heteromers between the dopamine D(1)-like receptors (D(1) and D(5)) and galanin Gal(1), but not Gal(2) receptors. Within the D(1)-Gal(1) and D(5)-Gal(1) receptor heteromers, dopamine receptor activation potentiated and dopamine receptor blockade counteracted MAPK activation induced by stimulation of Gal(1) receptors, whereas Gal(1) receptor activation or blockade did not modify D(1)-like receptor-mediated MAPK activation. Ability of a D(1)-like receptor antagonist to block galanin-induced MAPK activation (cross-antagonism) was used as a "biochemical fingerprint" of D(1)-like-Gal(1) receptor heteromers, allowing their identification in the rat ventral hippocampus. The functional role of D(1)-like-Gal receptor heteromers was demonstrated in synaptosomes from rat ventral hippocampus, where galanin facilitated acetylcholine release, but only with costimulation of D(1)-like receptors. Electrophysiological experiments in rat ventral hippocampal slices showed that these receptor interactions modulate hippocampal synaptic transmission. Thus, a D(1)-like receptor agonist that was ineffective when administered alone turned an inhibitory effect of galanin into an excitatory effect, an interaction that required cholinergic neurotransmission. Altogether, our results strongly suggest that D(1)-like-Gal(1) receptor heteromers act as processors that integrate signals of two different neurotransmitters, dopamine and galanin, to modulate hippocampal cholinergic neurotransmission.

Galanin peptide family as a modulating target for contribution to metabolic syndrome.

Metabolic syndrome (MetS) is defined as abdominal central obesity, atherogenic dyslipidemia, insulin resistance, glucose intolerance and hypertension. The rapid increasing prevalence of MetS and the consequent diseases, such as type 2 diabetes mellitus and cardiovascular disorder, are becoming a global epidemic health problem. Despite considerable research into the etiology of this complex disease, the precise mechanism underlying MetS and the association of this complex disease with the development of type 2 diabetes mellitus and increased cardiovascular disease remains elusive. Therefore, researchers continue to actively search for new MetS treatments. Recent animal studies have indicated that the galanin peptide family of peptides may increase food intake, glucose intolerance, fat preference and the risk for obesity and dyslipidemia while decreasing insulin resistance and blood pressure, which diminishes the probability of type 2 diabetes mellitus and hypertension. To date, however, few papers have summarized the role of the galanin peptide family in modulating MetS. Through a summary of available papers and our recent studies, this study reviews the updated evidences of the effect that the galanin peptide family has on the clustering of MetS components, including obesity, dyslipidemia, insulin resistance and hypertension. This line of research will further deepen our understanding of the relationship between the galanin peptide family and the mechanisms underlying MetS, which will help develop new therapeutic strategies for this complex disease.

A Caenorhabditis elegans allatostatin/galanin-like receptor NPR-9 inhibits local search behavior in response to feeding cues.

Movement in Caenorhabditis elegans is the result of sensory cues creating stimulatory and inhibitory output from sensory neurons. Four interneurons (AIA, AIB, AIY, and AIZ) are the primary recipients of this information that is further processed en route to motor neurons and muscle contraction. C. elegans has >1,000 G protein-coupled receptors (GPCRs), and their contribution to sensory-based movement is largely undefined. We show that an allatostatin/galanin-like GPCR (NPR-9) is found exclusively in the paired AIB interneuron. AIB interneurons are associated with local search/pivoting behavior. npr-9 mutants display an increased local search/pivoting that impairs their ability to roam and travel long distances on food. With impaired roaming behavior on food npr-9 mutants accumulate more intestinal fat as compared with wild type. Overexpression of NPR-9 resulted in a gain-of-function phenotype that exhibits enhanced forward movement with lost pivoting behavior off food. As such the animal travels a great distance off food, creating arcs to return to food. These findings indicate that NPR-9 has inhibitory effects on the AIB interneuron to regulate foraging behavior, which, in turn, may affect metabolic rate and lipid storage.

Is Galanin a Promising Therapeutic Resource for Neural and Nonneural Diseases?

BACKGROUND: Galanin (GAL) constitutes a family of neuropeptides composed of four peptides: (i) galanin (GAL), (ii) galanin-message associated peptide (GAMP), (iii) galanin-like peptide (GALP), and (iv) alarin. GAL contains 29/30 amino acids, and its biological action occurs through the interactions with its various receptors (GALR1, GALR2, and GALR3). The neuropeptide GAL regulates several physiological and pathophysiological functions in the central nervous system, the peripheral nervous system, and the peripheral organs. GAL is secreted mainly by oligodendrocytes, astrocytes, and the gastrointestinal tract, and its effect depends on the interaction with its different receptors. These receptors are expressed mainly in the central, peripheral nervous systems and the intestines. OBJECTIVE: The present review evaluates the role of GAL family in inflammatory diseases. An overview is given of the signaling and pharmacological effects due to the interaction between GAL and GALR in different cell types. The potential use of GAL as a therapeutic resource is critically discussed. CONCLUSION: GAL is suggested to have an anti-inflammatory function in some situations and a proinflammatory function in others. The literature on GAL is controversial and currently not conclusive. This could be due to the complexity of the metabolic network signaling induced by the interactions between GAL and GALR. In the next future, GAL might be a promising therapeutic resource for several diseases, but its practical use for disease control is presently not advisable.

The galanin peptide family: receptor pharmacology, pleiotropic biological actions, and implications in health and disease.

The galanin peptide family consists of the "parental" galanin, galanin-message-associated peptide (GMAP) which derives from the same peptide precursor gene product as galanin, galanin-like peptide (GALP) encoded by a different gene, and the recently discovered peptide alarin which is encoded by a splice variant of the GALP gene. The galanin receptor family currently comprises 3 members, GalR1, GalR2, and GalR3, which are all G-protein-coupled receptors. This review will provide an overview of the comprehensive, pharmacological characterization of endogenous and synthetic galanin receptor ligands and their interactions with the galanin receptors, a summary of the various (pleiotropic) biological actions of galanin and GALP (and alarin), and briefly discuss the implications of pathological changes for health and disease and potential clinical therapeutics. Since its discovery more than 20 years ago, a large number of putative physiological functions have been ascribed to galanin, and active research still continues to validate these functions and determine their importance for physiology and pathology. Since the more recent identification of GALP, considerable research has identified functions for this peptide in the central nervous system (CNS), but the identity of its preferred, native receptor is still unknown. Little is known of the role of alarin apart from evidence of its expression and a vasoactive action in the skin. The wide range of functions of the galanin peptide family indicates an essential role for galanin signaling in "mind and body homeostasis" and a potential therapeutic efficacy in a variety of human diseases, particularly epilepsy, Alzheimer's disease, and diabetes.

GABAB receptors are required for galanin modulation of membrane properties of neurons in the arcuate nucleus of rats.

Galanin-mediated modulation of the arcuate nucleus (Arc) neurons is thought to be involved in the regulation of feeding behavior, hormone secretion, and reproduction. We previously reported that galanin perfusion significantly hyperpolarized the resting membrane potential and suppressed the spontaneous firing in the Arc neurons in slice preparation. In this study, we focused on the cellular and molecular mechanisms underlying the galanin effect. The galanin action is mediated by the galanin receptors (GAL1/2/3R). We found that activation of galanin receptors alone is not sufficient to mediate the galanin effect on resting membrane potential and spontaneous firing; co-activation of GABA(B) receptors is required for galanin to accomplish its modulation on the membrane properties of Arc neurons. In more details, the effect of galanin on the membrane properties of Arc neurons is blocked by either lowering the extracellular Ca(2+) or the inhibition of GABA(B) receptors with the selective GABA(B) antagonist, saclofen. In addition, activation of GABA(B) receptors by baclofen restored the galanin effect under low Ca (2+) conditions. These results suggest that GABA(B) receptors may serve as a molecular gate for galanin signaling, and thus can be targeted to manipulate the galanin-mediated physiological and behavioral responses.

Galaninergic intramural nerve and tissue reaction to antral ulcerations.

BACKGROUND: Well-developed galaninergic gastric intramural nerve system is known to regulate multiple stomach functions in physiological and pathological conditions. Stomach ulcer, a disorder commonly occurring in humans and animals, is accompanied by inflammatory reaction. Inflammation can cause intramural neurons to change their neurochemical profile. Galanin and its receptors are involved in inflammation of many organs, however, their direct participation in stomach reaction to ulcer is not known. Therefore, the aim of the study was to investigate adaptive changes in the chemical coding of galaninergic intramural neurons and mRNA expression encoding Gal, GalR1, GalR2, GalR3 receptors in the region of the porcine stomach directly adjacent to the ulcer location. METHODS: The experiment was performed on 24 pigs, divided into control and experimental groups. In 12 experimental animals, stomach antrum ulcers were experimentally induced by submucosal injection of acetic acid solution. Stomach wall directly adjacent to the ulcer was examined by: (1) double immunohistochemistry-to verify the changes in the number of galaninergic neurons (submucosal, myenteric) and fibers; (2) real-time PCR to verify changes in mRNA expression encoding galanin, GalR1, GalR2, GalR3 receptors. KEY RESULTS: In the experimental animals, the number of Gal-immunoreactive submucosal perikarya was increased, while the number of galaninergic myenteric neurons and fibers (in all the stomach wall layers) remained unchanged. The expression of mRNA encoding all galanin receptors was increased. CONCLUSIONS & INTERFERENCES: The results obtained unveiled the participation of galanin and galanin receptors in the stomach tissue response to antral ulcerations.

The galanin and galanin receptor subtypes, its regulatory role in the biological and pathological functions.

The multitalented neuropeptide galanin was first discovered 30 years ago but initially no biologic activity was found. Further research studies discovered the presence of galanin in the brain and some peripheral tissues, and galanin was identified as a modulator of neurotransmission in the central and peripheral nervous system. Over the last decade there were performed very intensive studies of the neuronal actions and also of nonneuronal actions of galanin. Other galanin family peptides have been described, namely galanin, galanin-like peptide, galanin-message associated peptide and alarin. The effect of these peptides is mediated through three galanin receptors subtypes, GalR1, GalR2 and GalR3 belonging to G protein coupled receptors, and signaling via multiple transduction pathways, including inhibition of cyclic AMP/protein kinase A (GalR1, GalR3) and stimulation of phospholipase C (GalR2). This also explains why one specific molecule of galanin can be responsible for different roles in different tissues. The present review summarizes the information currently available on the relationship between the galaninergic system and known pathological states. The research of novel galanin receptor specific agonists and antagonists is also very promising for its future role in pharmacological treatment. The galaninergic system is important target for current and future biomedical research.

Galanin receptor antagonists : a potential novel pharmacological treatment for mood disorders.

The pathophysiology of mood disorders involves several genetic and social predisposing factors, as well as a dysregulated response to chronic stress. Accumulated evidence during the last two decades has implicated disturbances in brain serotonin and/or noradrenaline (norepinephrine) neurotransmission in the aetiology of depression. In fact, current pharmacological treatment for mood disorders is based on the use of drugs that act mainly by enhancing brain serotonin and noradrenaline neurotransmission by blockade of the active reuptake mechanism for these neurotransmitters. However, current antidepressant drugs have a delayed onset of therapeutic action, and a substantial number of patients do not respond adequately to them. In addition, these drugs have a number of adverse effects that limit patient compliance. In view of this, there is an intense search to identify novel (receptor) targets for antidepressant therapy. Recent studies have indicated that several neuropeptides and their receptors are potential candidates for the development of novel antidepressant treatment. In this context, galanin is of particular interest, since it is co-localised with serotonin in the dorsal raphe nucleus and with noradrenaline in the locus coeruleus, nuclei known to play a major role in affective disorders and in the action of antidepressant drugs. The actions of galanin are mediated by three receptor subtypes (GAL1, GAL2 and GAL3), which are coupled to different intracellular effector systems. Studies in rats have shown that galanin administered intracerebroventricularly is a potent inhibitor of mesencephalic serotonergic neurotransmission, as indicated by a long-lasting reduction in the release of serotonin in the hippocampus. This inhibitory effect is related to activation of the galanin receptors located on the dorsal raphe neurons. Moreover, intracerebroventricular galanin alters the gene expression of serotonin 5-HT1A autoreceptors in the dorsal raphe and also changes their functional activity. In addition, galanin produces a functional blockade of postsynaptic 5-HT1A receptor-mediated responses. Both pharmacological and genetic studies suggest a role for galanin in depression-like behaviour in rodent models. Transgenic mice overexpressing galanin under the control of the platelet-derived growth factor-beta promoter display increased immobility in the forced swim test. Intracerebroventricular administration of galanin in the rat increases depression-like behaviour, and this is fully blocked by the nonselective peptide galanin receptor antagonist M35. Importantly, M35 alone administered intracerebroventricularly produces an antidepressant-like effect. Recently, newly developed receptor-specific nonpeptidergic galanin GAL3 receptor antagonists (SNAP-37889 and SNAP-398299), which cross the blood-brain barrier after systemic administration, have shown antidepressant-like activity in several animal models. On the other hand, stimulation of the GAL2 receptor at the raphe level by local application of the GAL2 receptor agonist galanin (2-11) has been shown to increase serotonin levels in the hippocampus and dorsal raphe. These results indicate an important (mainly inhibitory) role of galanin as a regulator of brain serotonin and 5-HT1A receptor-mediated transmission, which may be of potential importance for understanding mood disorders and for the development of antidepressant drugs. Taken together, the present evidence suggests that antidepressant efficacy may be associated with compounds acting as antagonists at the GAL3 and/or possibly GAL1 receptors, and/or agonists at the GAL2 receptor.

Activation of peripheral galanin receptors: differential effects on nociception.

Numerous reports suggest a significant role of peripheral galanin (GAL) in pain transmission; however, due to the lack of selective galanin receptor agonists and antagonists, the role of GAL receptors (GalR1-3) in pain transmission remains unclear. In this study, a new agonist, M617, that preferentially binds to GalR1, a GalR2 agonist (AR-M1896), and a GalR2 antagonist (M871) were tested in the periphery to elucidate the role of peripheral GalR1 and GalR2 in nociception. Ipsilateral, but not contralateral, hindpaw injection of M617 reduced capsaicin (CAP)-induced flinching by approximately 50%, suggesting that GalR1 activation produces anti-nociception. This anti-nociceptive effect was blocked by intraplantar injection of the non-selective GalR antagonist M35. In contrast ipsilateral, but not contralateral, intraplantar injection of GalR2 agonist AR-M1896 enhanced the CAP-induced nociception (1.7-fold). The GalR2 antagonist M871 blocked the pro-nociceptive effect of AR-M1896 in a dose-dependent manner. This antagonist had no effect on nociceptive behaviors induced by CAP alone. The data demonstrate that activation of peripheral GalR1 results in anti-nociception but activation of peripheral GalR2 produces pro-nociception. Thus, the use of these pharmacological tools may help to elucidate the contribution of GalR subtypes in nociceptive processing, identifying potential drug targets for the treatment of peripheral pain.

Kisspeptin and its receptor: new gatekeepers of puberty.

The recent finding that the hormone kisspeptin plays a pivotal role in the onset of puberty is one of the biggest discoveries in human reproductive biology in 30 years. Mutations in the receptor for kisspeptin cause humans and mice to fail to reach puberty and to be sterile. It is the first time since the identification of gonadotrophin-releasing hormone that a single gene is found to have such a dramatic effect on reproduction. This discovery opens new possibilities in the treatment of reproductive disorders such as delayed or advanced puberty, infertility and sex hormone-dependent cancers.

Antinociceptive role of galanin in the spinal cord of rats with inflammation, an involvement of opioid systems.

The present study investigated the role of galanin in the transmission of nociceptive information in the spinal cord of rats with inflammation. Bilateral decreases in hindpaw withdrawal latencies (HWLs) to thermal and mechanical stimulation were observed after acute inflammation induced by injection of carrageenan into the plantar region of the rat left hindpaw. Intrathecal injection of galanin induced significant increases in the HWLs to thermal and mechanical stimulation in rats with inflammation. The galanin-induced antinociceptive effect was more pronounced in rats with inflammation than that in intact rats. The antinociceptive effect of galanin was partly inhibited by intrathecal injection of naloxone. Furthermore, intrathecal administration of galantide, an antagonist of galanin receptor, could attenuate the antinociceptive effect induced by intraperitoneal injection of morphine, suggesting an involvement of opioid systems in the galanin-induced antinociception. The results indicate that galanin plays an important role in the transmission of nociceptive information in the spinal cord of rats with inflammation, and opioid systems are involved in the galanin-induced antinociception.

Galanin and galanin receptors in human cancers.

The increasing interest in peptides and peptide receptors in cancer is based on the possibility of receptor targeting, because peptide receptors are often expressed in different human tumors. The neuropeptide galanin has also been suggested to be involved in the development of neuroendocrine tumors based on the development of estrogen-induced tumors in estrogen-sensitive rats. This study summarizes our current knowledge on the expression of galanin peptide and galanin receptors in different human neuroendocrine tumors. The expression of both, peptide and corresponding receptor, seems to be a common feature of human gliomas, pheochromocytomas, pituitary and neuroblastic tumors. The co-expression of galanin and its receptors supports a role for galanin in tumor cell pathology via autocrine/paracrine mechanisms.

Galanin and its receptors: introduction to the Third International Symposium, San Diego, California, USA, 21-22 October 2004.

The Third Galanin Symposium presented many different and exciting results on galanin research reflecting a major progress since the previous symposium in 1998. A major impression was the many possible relationships of galaninergic mechanisms to important brain functions such as development, cognition and ageing as well as many aspects related to a wide spectrum of diseases, including Alzheimer's disease, anxiety/depression, addiction, obesity, pain and tumour growth. These studies were based on an extensive armament of methodologies including various strains of transgenic mice. Unfortunately, the pharmaceutical industry had only a minor participation. Nevertheless, exciting developments in the generation of agonists and antagonists are emerging, providing hope that we at the next symposium will be able to validitate many of the challenging hypotheses concerning galanin and disease with the help of pharmacological tools.

Galaninergic mechanisms at the spinal level: focus on histochemical phenotyping.

The 29/30 amino acid neuropeptide galanin is present in a small population of DRG neurons under normal condition but is strongly upregulated after nerve injury. There is evidence that this upregulated galanin has trophic actions, for example promoting neurite outgrowth as well as influencing pain processing. In fact, both pro- and antinociceptive effects have been reported, probably relating to activation of different receptors. It has been proposed that presynaptic GalR2 receptors are pro-nociceptive by enhancing release of excitatory transmitters in the dorsal horn, and anti-nociceptive via an action on GalR1-positive interneurons. These neurons have recently been shown to be glutamatergic. Several other peptides and molecules are also regulated by nerve injury. Here we focus on neuropeptide tyrosine (NPY), which is upregulated in parallel with galanin. We review data reporting on coexistence between galanin and NPY and between these two peptides and the two NPY receptors Y1 and Y2. The data show considerable overlap, and it will be an important task to analyse how cross-talk between these neuropeptides can influence pain processing. It is proposed that such cross-talk can occur by release of peptides from DRGs neuron somata within dorsal root ganglia. To what extent these mechanisms shown to exist in rodents also occur in human is important, if one wants to discuss novel strategies for pain treatment on the basis of these findings. So far information is limited, but it has been demonstrated that galanin is expressed in DRGs and possibly also regulated.

Involvements of galanin and its receptors in antinociception in nucleus accumbens of rats with inflammatory pain.

This study tested the hypothesis that antinociceptive effects of galanin and its receptors in nucleus accumbens (NAc) of rats with inflammatory pain provoked by subcutaneous injection of 0.1 ml of 2% carrageenin into the sole of the rat's left hindpaw. The hindpaw withdrawal latencies (HWLs) in response to thermal and mechanical stimulation significantly decreased in bilateral hindpaws at 3 and 4 hour after a subcutaneous injection of carrageenin. However intra-NAc injection of 2 and 3 nmol, but not 1 nmol of galanin markedly induced an increase in the HWLs in a dose-dependent way. Western blot also showed, that the expression of galanin receptor 1 (GalR1) and galanin receptor 2 (GalR2) were significantly upregulated in NAc at 3 hour after a subcutaneous injection of carrageenin. In addition, the rats were intra-NAc injected galanin, 5 min later following by intra-NAc injection of galanin receptor antagonist galantide, the galanin-induce antinociceptive effects were suppressed by galantide. The results demonstrated that galanin and its receptors might be involved in antinociception in the NAc of rats with inflammatory pain.

An antinociceptive role of galanin in the arcuate nucleus of hypothalamus in intact rats and rats with inflammation.

In the arcuate nucleus of hypothalamus (ARC), galaninergic fibers form synaptic contacts with proopiomelanocortin neurons, which are involved in pain modulation. The present study assessed the role of exogenous and endogenous galanin in the modulation of nociception in the ARC of rats. The hindpaw withdrawal latency (HWL) to thermal and mechanical stimulation was assessed by the hot-plate test and the Randall Selitto Test. Intra-ARC injection of galanin dose-dependently increased the HWLs in intact rats, indicating an antinociceptive role of exogenous galanin in the ARC. The antinociceptive effect of galanin was blocked by following intra-ARC injection of galantide, a putative galanin receptor antagonist, suggesting that the antinociceptive effect of galanin is mediated by galanin receptors. Moreover, intra-ARC injection of galanin increased the HWL in rats with inflammation. Intra-ARC administration of galantide alone reduced the HWLs in rats with inflammation, while there were no influences of galantide on the HWL in intact rats. Taken together, the results show that galanin has an antinociceptive role in the ARC of intact rats and rats with inflammation.