Stimulus-secretion coupling of arginine-induced insulin release. Insulinotropic action of agmatine

Agmatine causes a concentration-related (0.1-1.0 mM) stimulation of insulin secretion by rat pancreatic islets exposed to D-glucose (5.6-11.1 mM) but, like L-arginine, fails to affect insulin release either in the absence of glucose or at a high concentration (16.7 mM) of the hexose. Agmatine, which accumulates in islet cells, also stimulates 45Ca net uptake by the islets. The secretory response to agmatine represents a delayed process. It is enhanced by theophylline and suppressed by antimycin A or the absence of extracellular Ca2+. The insulinotropic action of agmatine is compatible with the view that endogenously formed polyamines may play a role in the secretory response of islet cells to L-arginine.     

Effects of agmatine on the survival rate in rats bled to hemorrhage

Agmatine (CAS 2482-00-0), an amine formed by decarboxylation of L-arginine, interacts with several targets like alpha2-adrenergic, imidazoline and N-methyl-D-aspartic acid (NMDA) receptors and besides it is involved in the nitric oxide mediated effects. It has also been proposed that it possesses vasodilator effects and increases glomerular filtration rate in rats. The aim of this study was to supply evidence for the effects of agmatine in a rat model of hemorrhagic shock and explain the possible mechanisms of action. The iliac arteries and veins of Sprague-Dawley rats were catheterized under urethane anesthesia and around 2 ml/100 g blood was withdrawn within 20 min until the mean arterial blood pressure was stabilized around 25 mmHg. The rats were either pretreated with physiological saline, yohimbine (an alpha2-adrenergic receptor antagonist) or L-arginine (a nitric oxide donor) intravenously before administration of agmatine (300 microg/kg). Agmatine restored blood pressure in rats pretreated with physiological saline where all rats survived. Pretreatment with L-arginine abolished the increase in blood pressure produced by agmatine and the 1 h survival rate decreased to 67% (p < 0.01). Yohimbine pretreatment also suppressed agmatine induced restoration of blood pressure; however, the survival rate was found to be 17% for 3 min. No statistically significant effect was observed in the heart rate responses. These results may suggest that agmatine may increase survival through alpha2-adrenergic receptors and restores blood pressure through nitric oxide and adrenergic mechanisms in rats bled to hemorrhage.     

Agmatine: Biological role and therapeutic potentials in morphine analgesia and dependence

Agmatine is an amine that is formed by decarboxylation of L-arginine by the enzyme arginine decarboxylase (ADC) and hydrolyzed by the enzyme agmatinase to putrescine. Agmatine binds to several target receptors in the brain and has been proposed as a novel neuromodulator. In animal studies, agmatine potentiated morphine analgesia and reduced dependence/withdrawal. While the exact mechanism is not clear, the interactions with N-methyl-D-aspartate (NMDA) receptors, alpha2-adrenergic receptors, and intracellular cyclic adenosine monophosphate (cAMP) signaling have been proposed as possible targets. Like other monoamine transmitter molecules, agmatine is rapidly metabolized in the periphery and has poor penetration into the brain, which limits the use of agmatine itself as a therapeutic agent. However, the development of agmatinase inhibitors will offer a useful method to increase endogenous agmatine in the brain as a possible therapeutic approach to potentiate morphine analgesia and reduce dependence/withdrawal. This review provides a succinct discussion of the biological role/therapeutic potential of agmatine during morphine exposure/pain modulation, with an extensive amount of literature cited for further details.     

Agmatine, a metabolite of L-arginine, reverses scopolamine-induced learning and memory impairment in rats

Agmatine (l-amino-4-guanidino-butane), a metabolite of L-arginine through the action of arginine decarboxylase, is a novel neurotransmitter. In the present study, effects of agmatine on cognitive functions have been evaluated by using one trial step-down passive avoidance and three panel runway task. Agmatine (20, 40, 80 mg/kg i.p.) was administered either in the presence or absence of a cholinergic antagonist, scopolamine (1 mg/kg i.p.). Scopolamine significantly impaired learning and memory in both passive avoidance and three panel runway test. Agmatine did not affect emotional learning, working and reference memory but significantly improved scopolamine-induced impairment of learning and memory in a dose dependent manner. Our results indicate that agmatine, as an endogenous substance, may have an important role in modulation of learning and memory functions.     

Agmatine produces antinociception in tonic pain in mice.

Agmatine is an endogenous polyamine metabolite formed by decarboxylation of L-arginine. In this study, the effect of agmatine on tonic pain was compared to its effect on phasic pain by using the formalin and tail-flick (TF) tests in mice. When administered intraperitoneally (ip), agmatine (37.5-300 mg/kg) exhibited a decrease in nociceptive behaviours in the first and second phase of the formalin test, which is a tonic pain model. The alpha(2) adrenoceptor antagonist yohimbine blocked the effect of agmatine in Phase 2 but did not change its effect in Phase 1. In the TF test, there was no significant change in the behaviour of agmatine-administered (75-300 mg/kg) animals. As a result, agmatine appears to have an analgesic effect on tonic rather than phasic pain, and alpha(2) receptors seem partly to have a role in the antinociceptive effect of agmatine on tonic pain.     

Agmatine potentiates the analgesic effect of morphine by an alpha(2)-adrenoceptor-mediated mechanism in mice.

The effects of agmatine, which is an endogenous polyamine metabolite formed by decarboxylation of L-arginine, and a combination of agmatine and morphine on tail-flick test have been investigated in mice. Adult male Swiss-Webster mice were used in the study. Agmatine (10, 20 and 40 mg/kg), clonidine (0.15 mg/kg), yohimbine (0.625 and 1.25 mg/kg), or saline were injected into mice intraperitoneally. Morphine (1 and 2 mg/kg) was given subcutaneously. Agmatine alone did not produce any significant change on radiant tail-flick latencies, but it potentiated significantly and dose-dependently morphine-induced (1 mg/kg) analgesia. The potentiating effect of agmatine (40 mg/kg) on morphine-induced analgesia was blocked completely by yohimbine (0.625 mg/kg), a selective alpha(2)-adrenoceptor antagonist, pretreatment. Clonidine (0.15 mg/kg), an alpha(2-)adrenergic receptor agonist, caused a significant increase of the tail-flick latencies of the mice. Yohimbine (0.625 mg/kg) also blocked clonidine-induced analgesia. In addition, yohimbine (0.625 mg/kg) was ineffective on the tail-flick test and did not produce any significant change on the morphine-induced analgesia. Our results indicate that cotreatment of agmatine with morphine produces antinociceptive enhancement via an alpha(2-)adrenergic receptor-mediated mechanism and agmatine-morphine combination may be an effective therapeutic strategy for medical treatment of pain.     

Effect of intrathecal agmatine on inflammation-induced thermal hyperalgesia in rats

Agmatine, an endogenous ligand, interacts both with the alpha2-adrenoceptors and with the imidazoline binding sites. The effect of intrathecally administered agmatine on carrageenan-induced thermal hyperalgesia was investigated by means of a paw-withdrawal test in rats. The effect of agmatine on morphine-induced anti-hyperalgesia was also studied. Intrathecal agmatine in doses larger than 250 microg caused a decrease in the pain threshold, with vocalization and agitation lasting for several hours in all animals. Agmatine alone at 1-100 microg did not give rise to any change in the thermal withdrawal threshold in the contralateral non-inflamed paw. Agmatine pretreatment was found to dose-dependently attenuate the thermal hyperalgesia induced by intraplantar carrageenan. The effect of 100 microg agmatine was completely lost by 60 min, whereas the effect of 50 microg was of similar magnitude but exhibited a longer duration. Agmatine posttreatment had a slighter effect. Agmatine pretreatment (100 microg) together with 1 microg morphine (subeffective dose) has significantly higher anti-hyperalgesic effect then the individual compounds by themselves. These are the first data demonstrating the behavioral and anti-hyperalgesic effects of intrathecal agmatine. The results reveal important interactions between intrathecal agmatine and opioids in thermal hyperalgesia.     

Is agmatine a novel neurotransmitter in brain?

Recent evidence suggests that agmatine, which is an intermediate in polyamine biosynthesis, might be an important neurotransmitter in mammals. Agmatine is synthesized in the brain, stored in synaptic vesicles in regionally selective neurons, accumulated by uptake, released by depolarization, and inactivated by agmatinase. Agmatine binds to alpha2-adrenoceptors and imidazoline binding sites, and blocks NMDA receptor channels and other ligand-gated cationic channels. Furthermore, agmatine inhibits nitric oxide synthase, and induces the release of some peptide hormones. As a result of its ability to inhibit both hyperalgesia and tolerance to, and withdrawal from, morphine, and its neuroprotective activity, agmatine has potential as a treatment of chronic pain, addictive states and brain injury.     

Molecular basis for the antiproliferative effect of agmatine in tumor cells of colonic, hepatic, and neuronal origin

The aim of the present study was to challenge potential mechanisms of action underlying the inhibition of tumor cell proliferation by agmatine. Agmatine inhibited proliferation of the human hepatoma cells HepG2, the human adenocarcinoma cells HT29, the rat hepatoma cells McRH7777, and the rat pheochromocytoma cells PC-12. Inhibition of proliferation of HepG2 cells was associated with an abolition of expression of ornithine decarboxylase (ODC) protein and a doubling of mRNA content encoding ODC. In HepG2 cells, silencing of ODC-antizyme-1, but not of antizyme inhibitor, by RNA interference resulted in an increase of agmatine's antiproliferative effect. Thus, the distinct decrease in intracellular polyamine content by agmatine was due to a reduced translation of the synthesizing protein ODC but was not essentially mediated by induction of ODC-antizyme or blockade of antizyme inhibitor. In interaction experiments 1 mM L-arginine, 1 mM D-arginine, 1 mM citrulline, 100 microM N(omega)-nitro-L-arginine methyl ester, 1 and 10 microM sodium nitroprusside, and 1 microM N1-guanyl-1,7-diaminoheptane failed to alter agmatine's antiproliferative effect. Hence, the antiproliferative effect of agmatine in HT29 and HepG2 cells is due to an interaction with neither the NO synthases, the hypusination of eIF5A, nor an agmatine-induced reduction in availability of intracellular L-arginine. L-Arginine and citrulline, but not d-arginine, inhibited tumor cell proliferation by themselves. Their inhibitory effect was abolished after silencing of arginine decarboxylase (ADC) expression by RNA interference indicating the conversion to agmatine by ADC. Finally, in the four cell lines under study, agmatine-induced inhibition of cell proliferation was paralleled by an increase in intracellular caspase-3 activity, indicating a promotion of apoptosis.     

Determination of α(2)-adrenoceptor and imidazoline receptor involvement in augmentation of morphine and oxycodone analgesia by agmatine and BMS182874

Studies have demonstrated that clonidine (α(2)-adrenoceptor and imidazoline receptor agonist) and BMS182874 (endothelin ET(A) receptor antagonist) potentiate morphine and oxycodone analgesia. Agmatine, an endogenous clonidine-like substance, enhances morphine analgesia. However, its effect on oxycodone analgesia and its interaction with endothelin ET(A) receptor antagonists are not known. The present study was performed to determine the effect of agmatine on morphine and oxycodone analgesia and the involvement of α(2)-adrenoceptors, imidazoline receptors, opioid receptors, and endothelin receptors. Antinociception at various time intervals was determined by the tail-flick latency method in mice. Agmatine produced dose-dependent increase in tail-flick latency, while BMS182874 did not produce any change over the 360-min observation period. Agmatine significantly potentiated morphine as well as oxycodone analgesia which was not altered by BMS182874. BMS182874 pretreatment did not increase the analgesic effect produced by agmatine alone. Agmatine-induced potentiation of morphine and oxycodone analgesia was blocked by idazoxan (imidazoline receptor/α(2)-adrenoceptor antagonist) and yohimbine (α(2)-adrenoceptor antagonist). BMS182874-induced potentiation of morphine or oxycodone analgesia was not affected by yohimbine. However, idazoxan blocked BMS182874-induced potentiation of oxycodone but not morphine analgesia. This is the first report demonstrating that agmatine potentiates not only morphine but also oxycodone analgesia in mice. Potentiation of morphine and oxycodone analgesia by agmatine appears to involve α(2)-adrenoceptors, imidazoline receptors, and opioid receptors. In addition, imidazoline receptors may be involved in BMS182874-induced potentiation of oxycodone but not morphine analgesia. It is concluded that agmatine may be used as an adjuvant in opiate analgesia.     

Agmatine, an endogenous modulator of noradrenergic neurotransmission in the rat tail artery.

1. We investigated the vascular effects of agmatine (decarboxylated arginine), an endogenous ligand for alpha 2-adrenoceptors and non-adrenoceptor imidazoline (I-) receptors, present in endothelium, smooth muscle and plasma, using the rat tail artery as a model. 2. While by itself agmatine (10 nM-1 mM) was without effect on isolated arterial rings, at the highest concentration used (1 mM) it slightly increased EC50 values for contractions elicited respectively by the alpha 1- and alpha 2- adrenoceptor agonists methoxamine and clonidine. 3. Agmatine (0.03-1 mM) produced a concentration-dependent transient inhibition of the contractions induced by transmural nerve stimulation (TNS; 200 mA, 0.2 ms, 1 Hz, 10 s). This effect was abolished by the alpha 2-adrenoceptor antagonists, rawolscine and idazoxan. 4. In the presence of rawolscine or idazoxan, agmatine produced a concentration-dependent delayed facilitation of TNS-induced contractions, which was prevented by cocaine. 5. Neither inhibitory nor potentiating actions were produced by agmatine on contractions induced by noradrenaline (NA) administration. 6. Agmatine did not directly affect [3H]-NA uptake in bovine cultured chromaffin cells. 7. Agmatine can regulate vascular function by two opposing actions at sympathetic nerve terminals, with different latencies: a transient inhibition of NA release mediated by prejunctional alpha 2-adrenoceptors and a cocaine-sensitive delayed facilitation the mechanism of which is undetermined at present. 8. The results reveal the existence of a novel endogenous amine modulating NA release in the perivascular sympathetic terminals.     

胍丁胺对小鼠和大鼠镇痛及增强吗啡镇痛

AIM: To study the effect of agmatine on pain and morphine analgesia. METHODS: The effect of agmatine on pain was observed in mouse heat radiant tail-flick test, mouse acetic acid writhing test, and rat 4% saline test. Its enhancing effect on analgesia of morphine and clonidine was assessed in rat and mouse heat radiant tail-flick tests. RESULTS: Agmatine did not significantly prolong tail-flick latency of mice, but reduced the number of acetic acid-induced writhing of mice and inhibited writhing responses to saline completely. It potentiated the analgesic effects of morphine and clonidine in dose-dependent manner and decreased the analgesic ED50 of morphine and clonidine by more than 75% in mouse heat radiant tail-flick test. These effects of agmatine were antagonized by idazoxan. CONCLUSION: Agmatine has weak analgesic effects and potentiates morphine and clonidine analgesia by activation of imidazoline receptors.     

胍丁胺阻断培养大鼠海马神经元电压门控性钙通道

目的:通过观察胍丁胺对大鼠海马神经元电压门控性离子通道的影响来探讨其作用机制。方法:使用膜片箝全细胞记录技术,采用压力注射给药的方法,在培养的新生大鼠海马神经元上观察胍丁胺对其电压门控性钠、钾、钙离子通道的作用。结果:胍丁胺(500 μmol/L)对钠、钾通道(快速失敏钾通道I_A和延迟整流钾通道I_K)没有显著的作用。胍丁胺能抑制钙电流,其抑制作用随浓度增加而加强。在胍丁胺浓度为0.1,0.5,1.5,10.0,50.0和100 μmol/L时,其对电压门控性钙电流的抑制率分别为(21±4)％,(35±6)％ ,(49±6)％,(67±4)％,(69±6)％,(86±8)％和(87±9)％,IC_(50)为1.2±0.4 μmol/L。双因素方差分析显示,细胞膜不同箝制电压水平和不同浓度胍丁胺对钙电流的抑制效应之间存在着明显的交互作用。结论:胍丁胺以浓度依赖性和电压依赖性方式,可逆性地抑制海马神经元电压门控性钙通道,对钙通道的阻断作用可能是胍丁胺产生生理和药理学作用的机制之一。     

Vascular effects of long-term propranolol administration after chronic nitric oxide blockade

The ability of agmatine, formed from L-arginine by the enzyme arginine decarboxylase (ADC), to modulate vasomotor function in rat aorta was investigated in the present study. Agmatine-mediated modulation of vasomotor tone was studied in organ chambers, protein expression quantified by Western blot analysis and cyclic guanosine 5'-monophosphate (cGMP) levels measured by radioimmunoassay. Agmatine (10(-10) to 10(-3) M) produced concentration-dependent relaxations (82+/-5%) in phenylephrine-contracted endothelium intact rat aorta. Relaxations to agmatine were diminished on denudation of endothelium and nitric oxide synthase (NOS) inhibition by L-Nomega-nitro arginine or soluble guanylate cyclase inhibition by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (P<0.001) abolished agmatine-mediated relaxations, while relaxations were insensitive to inducible NOS inhibition by 1400W. Agmatine-treated aorta demonstrated increased protein expression of phosphorylated S473-Akt and phosphorylated S1177-endothelial nitric oxide synthase (eNOS), and elevated the levels of cyclic GMP (P<0.01). Agmatine-mediated potentiation of relaxations and elevation of cGMP levels was sensitive to phosphatidylinositol 3'-kinase inhibitor, wortmannin. Relaxations to agmatine were also affected by pre-treatment with tetraethylammonium (P<0.01) or apamin (P<0.05), and were not affected by charybdotoxin. Relaxations to agmatine were partially affected by pre-treatment of aortic rings with barium chloride (P<0.05), and glybenclamide (P<0.05). Results obtained suggest that agmatine activates protein kinase B/Akt to phosphorylate eNOS and elevate cyclic GMP levels to produce vasodilatation of aorta. Agmatine-mediated relaxations in rat aorta seems to be mediated mainly by endothelial NO-mediated activation of small conductance Ca2+-activated K+ channels, and partly by ATP-sensitive and inward rectifying K+ channels.     

Mechanisms involved in the antinociception caused by agmatine in mice

The present study examined the antinociceptive effects of agmatine in chemical behavioural models of pain. Agmatine (1-30 mg/kg), given by i.p. route, 30 min earlier, produced dose-dependent inhibition of acetic acid-induced visceral pain, with mean ID50 value of 5.6 mg/kg. Given orally, 60 min earlier, agmatine (10-300 mg/kg) also produced dose-related inhibition of the visceral pain caused by acetic acid, with mean ID50 value of 147.3 mg/kg. Agmatine (3-100 mg/kg, i.p.) also caused significant and dose-dependent inhibition of capsaicin- and glutamate-induced pain, with mean ID50 values of 43.7 and 19.5 mg/kg, respectively. Moreover, agmatine (1-100 mg/kg, i.p.) caused marked inhibition of both phases of formalin-induced pain, with mean ID50 values for the neurogenic and the inflammatory phases of 13.7 and 5.6 mg/kg, respectively. The antinociception caused by agmatine in the acetic acid test was significantly attenuated by i.p. treatment of mice with L-arginine (precursor of nitric oxide, 600 mg/kg), naloxone (opioid receptor antagonist, 1 mg/kg), p-chlorophenylalanine methyl ester (PCPA, an inhibitor of serotonin synthesis, 100 mg/kg once a day for 4 consecutive days), ketanserin (a 5-HT2A receptor antagonist, 0.3 mg/kg), ondansetron (a 5-HT3 receptor antagonist, 0.5 mg/kg), yohimbine (an alpha2-adrenoceptor antagonist, 0.15 mg/kg) or by efaroxan (an I1 imidazoline/alpha2-adrenoceptor antagonist, 1 mg/kg). In contrast, agmatine antinociception was not affected by i.p. treatment of animals with pindolol (a 5-HT1A/1B receptor antagonist, 1 mg/kg) or idazoxan (an I2 imidazoline/alpha2-adrenoceptor antagonist, 3 mg/kg). Likewise, the antinociception caused by agmatine was not affected by neonatal pre-treatment with capsaicin. Together, these results indicate that agmatine produces dose-related antinociception in several models of chemical pain through mechanisms that involve an interaction with opioid, serotonergic (i.e., through 5-HT2A and 5-HT3 receptors) and nitrergic systems, as well as via an interaction with alpha2-adrenoceptors and imidazoline I1 receptors.     

OCT2 and MATE1 provide bidirectional agmatine transport

Agmatine is a biogenic amine (l-arginine metabolite) of potential relevance to several central nervous system (CNS) conditions. The identities of transporters underlying agmatine and polyamine disposition in mammalian systems are not well-defined. The SLC-family organic cation transporters (OCT) OCT1 and OCT2 and multidrug and toxin extrusion transporter-1 (MATE1) are transport systems that may be of importance for the cellular disposition of agmatine and putrescine. We investigated the transport of [(3)H]agmatine and [(3)H]putrescine in human embryonic kidney (HEK293) cells stably transfected with hOCT1, hOCT2, and hMATE1. Agmatine transport by hOCT1 and hOCT2 was concentration-dependent, whereas only hOCT2 demonstrated pH-dependent transport. hOCT2 exhibited a greater affinity for agmatine (K(m) = 1.84 ± 0.38 mM) than did hOCT1 (K(m) = 18.73 ± 4.86 mM). Putrescine accumulation was pH- and concentration-dependent in hOCT2-HEK cells (K(m) = 11.29 ± 4.26 mM) but not hOCT1-HEK cells. Agmatine accumulation, in contrast to putrescine, was significantly enhanced by hMATE1 overexpression, and was saturable (K(m) = 240 ± 31 μM; V(max) = 192 ± 10 pmol/min/mg of protein). Intracellular agmatine was also trans-stimulated (effluxed) from hMATE1-HEK cells in the presence of an inward proton-gradient. The hMATE1-mediated transport of agmatine was inhibited by polyamines, the prototypical substrates MPP+ and paraquat, as well as guanidine and arcaine, but not l-arginine. These results suggest that agmatine disposition may be influenced by hOCT2 and hMATE1, two transporters critical in the renal elimination of xenobiotic compounds.     

Agmatine attenuates methamphetamine-induced conditioned place preference in rats

The polyamine agmatine modulates a variety of behavioral effects including the abuse-related effects of opioids and has been proposed as a potential medication candidate for the treatment of opioid abuse. However, little is known of the effects of agmatine on the abuse-related effects of other drugs of abuse. This study examined the effects of agmatine on the rewarding effects of methamphetamine in rats using a conditioned place preference paradigm. Methamphetamine (0.1-1.0mg/kg) dose-dependently increased the time spent in methamphetamine-paired side (place preference). Agmatine, at doses that did not produce place preference or aversion (10-32mg/kg), significantly decreased the development of methamphetamine-induced place preference when agmatine was administered in combination with methamphetamine during place conditioning. Agmatine also significantly decreased the expression of methamphetamine-induced place preference when an acute injection of agmatine was given immediately before test session. These doses of agmatine do not alter the motor activity in rats, suggesting that the observed attenuation of methamphetamine-induced place preference was not due to general behavioral disruption. Together, these data suggests that agmatine attenuates the rewarding effects of methamphetamine and may be able to modulate the abuse liability of methamphetamine.     

胍丁胺对吗啡所致小鼠耐受和物质依赖的作用

目的 观察胍丁胺对吗啡所致耐受和依赖的作用。方法 分别在小鼠耐受和跳跃实验中观察胍丁胺抑制吗啡所致耐受和物质依赖的作用,结果：胍下胺０．１２５～２．５ｍｇ．ｋｇ＾－１剂量依赖性地阻止小鼠对吗啡耐受,用吗啡预处理小鼠使吗啡镇痛ＥＤ５０（２０．１,１４．４－２８．０ｍｇ．ｋｇ＾－１）与盐水组相比（６．３,５．１－７．８ｍｇ．ｋｇ＾－１）增加３倍以上,用胍丁胺和吗啡共同预处理小鼠则使吗啡丧失引直耐受的能     

Agmatine and a cannabinoid agonist, WIN 55212-2, interact to produce a hypothermic synergy

Agmatine blocks morphine withdrawal symptoms and enhances morphine analgesia in rats. Yet, the role of agmatine in the pharmacological effects of other abused drugs has not been investigated. The present study investigates the effect of agmatine administration on the hypothermic response to cannabinoids. Hypothermia is an effective endpoint because cannabinoid agonists produce a rapid, reproducible, and significant decrease in body temperature that is abolished by cannabinoid CB(1) receptor antagonists. WIN 55212-2, a cannabinoid agonist, was administered to rats by itself and with agmatine. WIN 55212-2 (1, 2.5, 5 and 10 mg/kg, i.m.) caused a significant hypothermia. Agmatine (10, 25 and 50 mg/kg, i.p.) was ineffective. For combined administration, agmatine (50 mg/kg, i.p.) enhanced the hypothermic effect of WIN 55212-2 (1, 2.5, 5 and 10 mg/kg, i.m.). The enhancement was strongly synergistic, indicated by a 2.7-fold increase in the relative potency of WIN 55212-2. The central administration of agmatine (25 and 50 mug/rat, i.c.v.) significantly increased the hypothermic effect of WIN 55212-2 (2.5 mg/kg, i.m.). This indicates that agmatine acts through a central mechanism to augment cannabinoid-evoked hypothermia. Idazoxan (2 mg/kg, i.p.), an imidazoline antagonist, blocked the enhancement by agmatine, thus suggesting that imidazoline receptor activation is required for agmatine to enhance cannabinoid-evoked hypothermia. The present data reveal that agmatine and a cannabinoid agonist interact to produce a hypothermic synergy in rats. These results show that agmatine acts in the brain and via imidazoline receptors to enhance cannabinoid-evoked hypothermia.