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Hypertension, often referred to as ‘The silent killer’, is christened so, as it is seldom preceded by any warning signs or symptoms. With the new ACC/AHA guidelines lowering the Blood Pressure (BP) threshold values, it has resulted in a 140% relative increase in the hypertension prevalence in India, which is 3 times higher than that of in United States. Imidazoline receptor agonists control BP effectively with minimal adverse effects of sedation and mental depression that are usually associated with centrally acting antihypertensives. While having a low affinity to the α2-adrenergic receptors, these new generation centrally acting antihypertensive agents are highly selective for imidazoline receptor. Moxonidine, a second-generation centrally acting antihypertensive drug having selective agonist activity on imidazoline I1 receptors and minor activity on imidazoline α2 adrenoceptors, reduces the activity of Sympathetic Nervous System (SNS) by activating I1 imidazoline receptors in Rostral Ventrolateral Medulla (RVLM). Studies of moxonidine have shown equal effectiveness in lowering BP like other well-established antihypertensive drugs such as nifedipine, atenolol or angiotensin-converting enzyme inhibitors, with minimal adverse events. At doses of 0.2-0.6 mg, moxonidine induces satisfactory BP reduction in patients with mild-to-moderate essential hypertension. In patients with mild-to-moderate hypertension, moxonidine (0.2-0.4 mg o.d.) significantly decreased Systolic Blood Pressure/Diastolic Blood Pressure (SBP/DBP), respectively, by 19.5/11.6 mmHg. In obese, non-controlled hypertensive patients, there is a 14% and 13.5% reduction in the mean SBP and DBP, respectively, from the baseline value after moxonidine treatment and during the follow-up with an additional reduction in body weight, plasma leptin levels and Body Mass Index (BMI) (p<0.01). Thus, moxonidine could be considered as a therapeutic option in obese patients with metabolic syndrome.
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Objective To investigate the effect of I1imidazoline receptor(I1R)on the expression and function of α2Aadrener-gic receptor(α2AAR)at the cellular level.Methods After sequencing and enzymatic identification,the mouse I1R and α2AAR plas-mids were transfected into CHO cells,respectively.The radioligand receptor binding assay and flow cytometry were used to select sin-gle cell clones,and the CHO cell lines stably expressing the mouse I1R or α2AAR were established.The CHO cell line that stably ex-presses both the mouse I1R and α2AAR were also established by the same technology and strategy.Then,the radioligand receptor bind-ing assay was used to determine the affinity and expression of α2AAR. Further,the effects of I1R on the α2AAR expression and the α2AAR agonist dexmedetomidine(DEX)-induced extracellular regulated protein kinase(ERK)phosphorylation were evaluated by the Western blotting.Results After transfection of mouse I1R and α2AAR plasmids,CHO cells grew normally.In the saturation binding experiments of membrane proteins from the CHO cells that stably expressed α2AAR,the Kdand Bmaxvalues of 3H-RX821002 were(0.96 ± 0.24)nmol/L and(0.29 ± 0.03)nmol/g protein,respectively.The expression levels of I1R were significantly increased in both the CHO cells expressing I1R and the CHO cells co-expressing α2AAR and I1R(P<0.05,P<0.01),when the cells that express exogenous I1R or α2AAR alone were trasfected again with the I1R plasmids.Moreover,in the CHO cells that transfected both I1R and α2AAR sta-bly,the I1R expression upregulated the α2AAR expression(P<0.01),and further increased the ERK phosphorylation induced by DEX through activating α2AAR(P<0.01).Conclusion I1R could upregulate the α2AAR expression and the ERK phosphorylation in-duced by DEX through activating α2AAR in the CHO cells that express exogenous I1R and α2AAR.This study presents a groundwork for further exploration of the relationship between I1R and α2AAR at the molecular level in future.
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Thirteen compounds were isolated from the 95% aqueous EtOH extract of the rhizomes of Sophora tonkinensis by a combination of various chromatographic techniques including column chromatography over silica gel, Sphadex LH-20, MCI, ODS, and semi-preparative HPLC.Their structures were elucidated as 1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)ethanone(1), cyclo(Pro-Pro)(2), nicotinic acid(3), p-hydroxybenzonic acid(4), p-methoxybenzonic acid(5), 4-hydroxymethyl-2,6-dimethoxyphenol-1-O-β-D-glucopyranoside(6), coniferin(7), syringin(8),(-)-secoisolariciresinol-4-O-β-D-glucopyranoside(9),(-)-syringaresinol-4-O-β-D-glucopyranoside(10),(-)-syringaresinol-4,4'-di-O-β-D-glucopyranoside(11),(-)-pinoresinol-4,4'-di-O-β-D-glucopyranoside(12), and(6S,9R)-roseoside(13) by their physicochemical properties and spectroscopic data.Compound 1 was a new naturalproduct, and compounds 2,5,6,9,10,12 and 13 were obtained from the Sophora genus for the first time.Compound 1 possessed moderate cytotoxic activity against A549 human tumor cell [IC₅₀（23.05 ± 0.46）μmol•L⁻¹].
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Objective To investigate the effect of agmatine or agmatine combined with yohimbine on morphine-induced psychological dependence in mice. Methods 1. Testing the effect of agmatine or agmatin combined with yohimbine on basal locomotor activity in 60 minutes. C57BL/6J male mice were divided into four groups: control group, agmatine (1,10,20,40 and 80 mg/kg) groups, yohimbine (0.3,1,2 and 8 mg/kg) groups and yohimbine (2 mg/kg) + agmatine (80 mg/kg) group. 2. Testing theeffects of drug pretreatment on morphine-induced hyperlocomotion in 60 minutes. Mice were divided into five groups: control group, morphine (10 mg/kg) group, agmatine (1,20 and 80 mg/kg) + morphine (10 mg/kg) group,yohimbine (2 mg/kg) + morphine (10 mg/kg) group and yohimbine (2 mg/kg) + agmatine (80 mg/kg) + morphine (10 mg/kg) group. 3. Observing the effects of agmatine or agmatine combined with yohimbine on morphine induced behavioral sensitization. The mice were administrated with morphine (10 mg/kg) on the 1st , 4th and 7th day and the locomotor activity of mice was recorded for 60 minutes. Mice were divided into four groups: control group, morphine (10 mg/kg) group, agmatine (1,20 and 80 mg/kg) + morphine (10 mg/kg) groups and yohimbine (2 mg/kg) + agmatine (80 mg/kg) + morphine (10 mg/kg) group. Results Our present study showed that agmatine (1-80 mg/kg) or yohimbine (0.3-2 mg/kg), a selective antagonist of a2-adrenoceptor, had no significant effect on basal locomotor and acute morphine-induced hyperlocomotion compared with those of control group. However, the distance in the group of agmatine combined with yohimbine followed by morphine for 60 min was (22 581.6&11 694.0) cm, which was significantly lower than the acute morphine group(37 577.9±9 657.4) cm(#<0.05). In the mophine-induced behavioral sensitization model, agmatine (1,20 and 80 mg/kg) alone had no effect on morphine-induced development of behavioral sensitization in mice. But, the combination of the two drugs significantly attenuated morphine-induced behavioral sensitization. The locomotor activities in the combination treatment groups were (21 112.7±5 586.7) cm, (37 672.7±10 518.8) cm and 47 681.0±15 845.3 cm, which were lower than those of morphine group (31 156.4&8 010.5) cm(#<0.01), (51 724.9&11 364.51) cm (P<0.05) and (63 572.2&12 151.2) cm (P<0.05) on the 1st , 4th and 7th day of experiment, respectively. Conclusion Our current results demonstrated that agmatine combined with yohimbine could decrease morphine-induced psychological dependence in mice. It may provide a new strategy for psychological dependence of morphine.
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Objective To investigate the effect of agmatine or agmatine combined with yohimbine on morphine-induced psychological dependence in mice. Methods 1. Testing the effect of agmatine or agmatin combined with yohimbine on basal locomotor activity in 60 minutes. C57BL/6J male mice were divided into four groups:control group, agmatine (1,10,20,40 and 80 mg/kg) groups, yohimbine(0.3,1,2 and 8 mg/kg) groups and yohimbine(2 mg/kg)+ agmatine(80 mg/kg) group. 2. Testing the effects of drug pretreatment on morphine-induced hyperlocomotion in 60 minutes. Mice were divided into five groups: control group, morphine(10 mg/kg) group, agmatine(1,20 and 80 mg/kg)+ morphine(10 mg/kg) group,yohimbine(2 mg/kg)+ morphine(10 mg/kg) group and yohimbine(2 mg/kg)+ agmatine(80 mg/kg)+ morphine(10 mg/kg) group. 3. Observing the effects of agmatine or agmatine combined with yohimbine on morphine induced behavioral sensitization. The mice were administrated with morphine(10 mg/kg) on the 1st , 4th and 7th day and the locomotor activity of mice was recorded for 60 minutes. Mice were divided into four groups: control group, morphine(10 mg/kg) group, agmatine(1,20 and 80 mg/kg) + morphine(10 mg/kg) groups and yohimbine (2 mg/kg)+ agmatine(80 mg/kg)+ morphine(10 mg/kg) group. Results Our present study showed that agmatine(1-80 mg/kg) or yohimbine (0.3-2 mg/kg), a selective antagonist of α2-adrenoceptor, had no significant effect on basal locomotor and acute morphine-induced hyperlocomotion compared with those of control group. However, the distance in the group of agmatine combined with yohimbine followed by morphine for 60 min was(22 581.6±11 694.0) cm,which was significantly lower than the acute morphine group(37 577.9±9 657.4)cm(P<0.05). In the mophine-induced behavioral sensitization model, agmatine(1,20 and 80 mg/kg) alone had no effect on morphine-induced development of behavioral sensitization in mice. But, the combination of the two drugs significantly attenuated morphine-induced behavioral sensitization. The locomotor activities in the combination treatment groups were (21 112.7±5 586.7)cm,(37 672.7±10 518.8)cm and(47 681.0±15 845.3)cm, which were lower than those of morphine group (31 156.4±8 010.5) cm(P<0.01),(51 724.9±11 364.51)cm(P<0.05) and(63 572.2±12 151.2) cm(P<0.05) on the 1st , 4th and 7th day of experiment, respectively. Conclusion Our current results demonstrated that agmatine combined with yohimbine could decrease morphine-induced psychological dependence in mice. It may provide a new strategy for psychological dependence of morphine.
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Objective To explore the immunomodulatory mechanism of 2-(-2-benzofuranyl )-2-imidazoline(2-BFI) in rat model of experimental autoimmune encephalomyelitis (EAE).Methods Fifty fe-male Sprague-Dawley(SD) rats were randomly divided into five groups by random digit table , including con-trol group(n=10), EAE model group(n=10), low dose 2-BFI group(1.5 mg/kg, n=10), median dose 2-BFI group (3 mg/kg, n=10) and high dose 2-BFI group (6 mg/kg, n=10).The SD rat model of EAE was induced by immunizing with a guinea pigs′spinal cord homogenate ( GPSCH ) .The severity of EAE was scored according to the signs and symptoms .Pathological changes were observed through Hematoxylin-eosin staining, and then the degrees of inflammatory infiltration were evaluated .The number of activated neuroglia that expressed GFAP and iba 1 in lumbar cords was counted by immunohistochemistry .The expressions of IL-1β, IFN-γ, IL-4 and IL-10 in cervical cords were measured by ELISA .Results Compared with EAE group, rats in the low, median and high dose 2-BFI treatment group had lower incidence of EAE , prolonged latency and decreased CNS inflammation , but only the median dose group showed significant alleviation in clinical symptoms and decrease in CNS inflammatory cell infiltration (P<0.05).Immunohistochemical re-sults showed that the numbers of activated microglia were significantly inhibited ,but the numbers of activated astroglia were increased in the rats treated with median dose of 2-BFI in comparison with the EAE group ( P<0.05).Results of ELISA demonstrated that expressions of IL-1βand IFN-γin 3 mg/kg 2-BFI treated group were significantly decreased compared with that in the EAE group (P<0.05), but expressions of IL-4 and IL-10 were remarkably increased(P<0.05).Conclusion 2-BFI at median dose of 3 mg/kg has a benefi-cial neuroprotective effect on rats with EAE , and its mechanism might be related to immunodulation .
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Opioid addiction, also termed opioid dependence, is a chronic, relapsing disorder in brain, which induces a series of severe problems in the aspects of society, economy and public health. Because the neurobiological mechanisms of opioid dependence haven't been clarified, it lacks effective medical interventions. Researches on opioid dependence are focusing on clarifying its neurobiological mechanisms and discovering effective anti-relapse drugs. Agmatine is a candidate for neurotransmitter or neuromodulator, and considered as an endogenous ligand for imidazoline receptors. Based on our previous work, its pharmacological characteristics and possible mechanisms of agmatine inhibiting opioid dependence were reviewed.
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Objective: Clonidine, by activating peripheral α-adrenoceptors, produces transient pressor response after i. v. injection in anesthetized animals. Moxonidine, with at least 40-fold higher affinity to I1-imidazoline receptors than to α2-adrenoceptors, produces also a transient pressor response. This work was designed to investigate whether I1-imidazoline receptors are involved in this pressor effect of moxonidine. Methods: Female spontaneously hypertensive rats (SHRs, aged 14-16 weeks) were anesthetized with urethane. To observe the transient pressor responses, moxonidine 0. 1, 0. 3, 1. 0 mg/kg (intravenous, i. v.), 2.0 μg (intracerebroventricular, i. c. v.) and 1.0, 10.0 mg/kg (intragastric, i. g.) were administrated in different groups of rats. To evaluate the roles of α1-adrenoceptors, α2-adrenoceptors and I1-imidazoline receptors in the transient pressor responses to moxonidine, prazosin (10.0 μg/kg), yohimbine (2.0 mg/kg), phentolamine (0.2 mg/kg), idazoxan (1.0 mg/kg) or yohimbine + idazoxan (2.0 mg/kg + 1.0 mg/kg) were intravenously given to the animals before moxonidine 0.3 mg/kg i. v.). Results: It was found that i. v. moxonidine produced a greater pressor response than clonidine when producing a similar reduction of blood pressure. This effect of moxonidine was not influenced by prazosin, but was partly inhibited by yohimbine, phentolamine or idazoxan, and completely blocked by the combination of yohimbine and idzaxon. Neither i. c. v. injection nor i. g. administration of moxonidine induced transient pressor responses. Conclusion: The transient pressor response of i. v. moxonidine is mediated by both peripheral I1-imidazoline receptors and α2-adrenoceptors.
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BACKGROUND: Previous studies suggest that systemic administration of agmatine, endogenous ligand for imidazoline receptors has anti-hypernociceptive effects in experimental animal. However the peripheral effects of agmatine on inflammatory pain have not yet been elucidated. Here we examined the effects of intra-articular injection of agmatine in the induction and maintenance phase of arthritic pain. In addition, we sought to determine the potential contribution of imidazoline and alpha(2)-adrenergic receptors to the antinociceptive effects using clonidine which is mixed alpha(2)-adrenoceptor and imidazoline receptor agonist. METHODS: To induce arthritis in rats, 2% lambda-carrageenan (50microliter, in saline) was injected into the joint of the right hind limb under enflurane anesthesia. Either agmatine (10, 50, 100microgram/40microliter) or clonidine (10, 50, 100microgram/40microliter) was injected into the knee joint cavity immediately before or 4 hr after carrageenan injection. Weight load tests were performed to measure pain-related behavior in freely walking rats. RESULTS: The intraarticular injection of agmatine into the knee joint had no effects in the both phase of induction and maintenance of arthritic pain at any dose tested. However, injection of clonidine reversed arthritic pain, when injected 4 h after carrageenan injection. CONCLUSIONS: In rats, agmatine has no peripheral effect on inflammatory pain and imidazoline receptors in the periphery may not contribute to the anti-inflammatory pain.
Subject(s)
Animals , Rats , Agmatine , Anesthesia , Arthritis , Carrageenan , Clonidine , Enflurane , Extremities , Imidazoline Receptors , Inflammation , Injections, Intra-Articular , Joints , Knee , Knee Joint , WalkingABSTRACT
Objective:Clonidine,by activating peripheral α-sbrenoceptors, produces transient pressor response after i.v.injection in anesthetized animals.Moxonidine, with at least 40-fold higher affinity to I1-imidazoline receptors than to α2-adrenoceptors,produces also a transient pressor response. This work was designed to investigate whether I1-imidazoline receptors are involved in this pressor effect of moxonidine. Methods:Female spontaneously hypertensive rats(SHRs,aged 14-16 weeks)were anesthetized with urethane.To observe the transient pressor responses,moxonidine 0.1,0.3,1.0mg/kg(intravenous,i.v),2.0μg(intracerebroventricular,i.c.v.)and 1.0,10.0mg/kg(intragastric,i.g.)were administrated in different groups of rats.To evaluate the roles of α1-adrenoceptors,α2-adrenoceptors and I1-imidazoline receptors in the transient pressor responses to moxonidine, prazosin(10.0μg/kg),yohimbine(2.0mg/kg),phentolamine(0.2mg/kg),idazoxan(1.0mg/kg)or yohimbine+idazoxan(2.0mg/kg+1.0mg/kg)were intravenously given to the animals before moxonidine 0.3mg/kg (i.v.).Results:It was found that i.v.moxonidine produced a greater pressor response than clonidine when producing a similar reduction of blood pressure.This effect of moxonidine was not influenced by prazosin, but was partly inhibited by yohimbine, phentolamine or idazoxan,and completely blocked by the combination of yohimbine and idzaxon.Neither i.c.v.injection nor i.g. administration of moxonidine induced transient pressor responses.Conclusion:The transient pressor response of i.v. moxonidine is mediated by both peripheral I1-imidazoline receptors and α2-adrenoceptors.
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Objective:Clonidine,by activating peripheral α-sbrenoceptors, produces transient pressor response after i.v.injection in anesthetized animals.Moxonidine, with at least 40-fold higher affinity to I1-imidazoline receptors than to α2-adrenoceptors,produces also a transient pressor response. This work was designed to investigate whether I1-imidazoline receptors are involved in this pressor effect of moxonidine. Methods:Female spontaneously hypertensive rats(SHRs,aged 14-16 weeks)were anesthetized with urethane.To observe the transient pressor responses,moxonidine 0.1,0.3,1.0mg/kg(intravenous,i.v),2.0μg(intracerebroventricular,i.c.v.)and 1.0,10.0mg/kg(intragastric,i.g.)were administrated in different groups of rats.To evaluate the roles of α1-adrenoceptors,α2-adrenoceptors and I1-imidazoline receptors in the transient pressor responses to moxonidine, prazosin(10.0μg/kg),yohimbine(2.0mg/kg),phentolamine(0.2mg/kg),idazoxan(1.0mg/kg)or yohimbine+idazoxan(2.0mg/kg+1.0mg/kg)were intravenously given to the animals before moxonidine 0.3mg/kg (i.v.).Results:It was found that i.v.moxonidine produced a greater pressor response than clonidine when producing a similar reduction of blood pressure.This effect of moxonidine was not influenced by prazosin, but was partly inhibited by yohimbine, phentolamine or idazoxan,and completely blocked by the combination of yohimbine and idzaxon.Neither i.c.v.injection nor i.g. administration of moxonidine induced transient pressor responses.Conclusion:The transient pressor response of i.v. moxonidine is mediated by both peripheral I1-imidazoline receptors and α2-adrenoceptors.
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Objective:Clonidine,by activating peripheral α-sbrenoceptors, produces transient pressor response after i.v.injection in anesthetized animals.Moxonidine, with at least 40-fold higher affinity to I1-imidazoline receptors than to α2-adrenoceptors,produces also a transient pressor response. This work was designed to investigate whether I1-imidazoline receptors are involved in this pressor effect of moxonidine. Methods:Female spontaneously hypertensive rats(SHRs,aged 14-16 weeks)were anesthetized with urethane.To observe the transient pressor responses,moxonidine 0.1,0.3,1.0mg/kg(intravenous,i.v),2.0μg(intracerebroventricular,i.c.v.)and 1.0,10.0mg/kg(intragastric,i.g.)were administrated in different groups of rats.To evaluate the roles of α1-adrenoceptors,α2-adrenoceptors and I1-imidazoline receptors in the transient pressor responses to moxonidine, prazosin(10.0μg/kg),yohimbine(2.0mg/kg),phentolamine(0.2mg/kg),idazoxan(1.0mg/kg)or yohimbine+idazoxan(2.0mg/kg+1.0mg/kg)were intravenously given to the animals before moxonidine 0.3mg/kg (i.v.).Results:It was found that i.v.moxonidine produced a greater pressor response than clonidine when producing a similar reduction of blood pressure.This effect of moxonidine was not influenced by prazosin, but was partly inhibited by yohimbine, phentolamine or idazoxan,and completely blocked by the combination of yohimbine and idzaxon.Neither i.c.v.injection nor i.g. administration of moxonidine induced transient pressor responses.Conclusion:The transient pressor response of i.v. moxonidine is mediated by both peripheral I1-imidazoline receptors and α2-adrenoceptors.
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OBJECTIVE: The aim of the this study was to compare the effects of clonidine (a alpha2-adrenoceptor and imidazoline receptor agonist), yohimbine (a selective alpha2-adrenoceptor antagonist) and idazoxan (a alpha2-adrenoceptor and imidazoline receptor antagonist) on extracellular monoamines and their metabolites by using the awakening animal microdialysis and high-performance liquid chromatography with electrochemical detection (HPLC-ECD) in brain regions, which are suggested to have regulatory role in depression. METHODS: We used intracerebral microdialysis in awakening rats by inserting probe through the dorsal hippocampus and occipital cortex especially in primary visual cortex, We studied respective effects of 2.0 mg/kg of clonidine, 5.0 mg/kg of yohimbine, and 5.0 mg/kg of idazoxan on the release of MHPG (a major metabolite of norepinephrine), norepinephrine (NE), DOPAC (a major metabolite of dopamine), and 5-HIAA (a main metabolite of serotonin) by intraperitoneal administration. RESULTS: Clonidine decreased the release of MHPG, NE, DOPAC, and 5-HIAA in both dorsal hippocampus and occipital cortex regions, and there were no significant differences in releasing pattern of all monoamines and their metabolites. Both yohimbine and idazoxan enhanced the release of MHPG, NE, DOPAC, and 5-HIAA in both brain regions, but there were significant differences in releasing pattern of NE and 5-HIAA. Idazoxan induced the delayed and higher efflux of NE and 5-HIAA in the primary visual cortex than yohimbine, but not in the hippocampus. CONCLUSION: This study shows that the selective alpha2-adrenoceptor antagonists increase basal monoamine output and enhance the metabolism of them in the hippocampus and primary visual cortex, and the imidazoline receptor has modulatory role in the regulation of monoamine release in primary visual cortex than hippocampus. It also suggests that high turnover rate of serotonin and norepinephrine in primary visual cortex may contribute to the pathophysiological role in depression.
Subject(s)
Animals , Rats , 3,4-Dihydroxyphenylacetic Acid , Brain , Chromatography, Liquid , Clonidine , Depression , Hippocampus , Hydroxyindoleacetic Acid , Idazoxan , Metabolism , Methoxyhydroxyphenylglycol , Microdialysis , Norepinephrine , Serotonin , Visual Cortex , YohimbineABSTRACT
Objective To investigate the effects of clonidine on the expression of myocardial ? subunit of inhibitory G protein (Gi?) in severely scalded rats and the mechanisms. Methods A scald model of 30% total body surface area Ⅲdegree burn on the back of rats was established. The basal and Gpp (NH) p, forsklin stimulated activity of adenylate cyclase (AC), and Gi? in cardiac myocytes were determined by indirect enzyme radiochemical assay and Western blotting, respectively. Results Clonidine at the dosage of 1-3 mg?kg -1 inhibited significantly the increase in the myocardial Gi? levels. Clonidine at the dosage of 0.3-3 mg?kg -1 partially reversed the decrease in the basal activity, and clonidine at the dosage of 1-3 mg?kg -1 showed the similar effect on the decrease in the Gpp (NH) p stimulated activity. Efaroxan, an I 1 imidazoline receptor antagonist, could partially reverse the inhibitory effect of clonidine on myocardial Gi? levels. Conclusion Clonidine can inhibit the elevation of myocardial Gi? levels, and the mechanisms of the inhibition may possibly be associated with the stimulatory effect of clonidine on I 1 imidazoline receptors.
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Nischarin is a novel protein interacting with integrin ?5 subunit.A series of studies have indicated that Nischarin plays an important role in inhibiting tumor cells migration and invasion.Meanwhile it may also serve as the functional I1-imidazoline receptor.To study this protein will be in favour of understanding the biological mechanisms of inhibiting cell migration and developing novel drugs such as inhibitors for tumor invasion.The article mainly reviews the recent progress in studies on Nischarin.
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Aim To evaluate the analgesic effect of agmatine on inflammatory pain and its influence on the analgesic effect of morphine. To investigate whether the mechanism of analgesic effect of agmatine is related to activation of imidazoline receptor or to affect the release of endogenous glutamate and gamma-aminobutyric acid (GABA) from rat spinal cord slices. Methods The formalin test in rats was used as a long-lasting inflammatory pain model. Effects of agmatine on basal and K+ evoked release of endogenous glutamate and GABA from rat spinal cord slices were determined by high performance liquid chromatography (HPLC). Results Pretreatment with agmatine (ip or sc) inhibited the second phase of the nociceptive response of rats and potentiated the analgesic effect of morphine in phase 2, but not in phase 1. Idazoxan did not attenuate the analgesic effect of agmatine. Agmatine (1, 10, 100, 1000 ?mol?L -1 ) had no effect on the basal release of glutamate and GABA from spinal cord slices, nor did it affect the K+ (50 mmol?L -1 ) evoked release of glutamate and GABA contents. Conclusions Agmatine has an analgesic effect and enhances morphine analgesia in the second but not the first phase of formalin-induced nociception. Its analgesic effect does not likely involve imidazoline receptor. The mechanism of the analgesic effect of agmatine may not be associated with inhibiting glutamate release nor increasing the GABA content.
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BACKGROUND: A spinal nerve ligation (SNL) injury may produce a neuropathic pain syndrome that includes tactile allodynia. This pain state may be diminished by sympathectomy. Intradermal (I.D.) injection of norepinephrine (NE) evokes pain in patients with sympathetically maintained pain. Recently, we reported the effect of intrathecal (I.T.) brimonidine and rilmenidine on the sympathetic nervous system. Therefore, we conducted a behavioral test to investigate the effects of sympathetic stimulation by I.D. NE on mechanical allodynia in rats with a SNL injury. METHODS: Male SD rats were prepared with ligation of the left lumbar 5th and 6th spinal nerves and lumbar I.T. catheter implantation. NE 10ng I.D. was administered in normal and SNL rats to investigate the change of cutaneous sensitivity to tactile stimuli. NE 30ng I.D. was administered before and after I.T. injection of brimonidine 3ng and rilmenidine 30ng in SNL rats. Using a von Frey hair (VFH) test, we examined the effects of NE on the withdrawal threshold. Allodynic thresholds for the withdrawal response of the lesioned hindpaw to VFH stimuli were assessed. RESULTS: Intradermal NE produced a reduction of the withdrawal threshold in normal and allodynic rats. An allodynic state induced by a SNL was aggravated by NE. In allodynic rats, the baseline threshold of a lesioned left hindpaw was markedly low and such a state was maintained during the behavioral experiment. The antiallodynic effects of I.T. brimonidine and rilmenidine were produced in both pre- and post-treatment of NE. CONCLUSIONS: The results suggest that a sympathetic component is likely involved in the mechanism of mechanical allodynia produced by a SNL injury.
Subject(s)
Animals , Humans , Male , Rats , Catheters , Hair , Hyperalgesia , Ligation , Models, Animal , Neuralgia , Norepinephrine , Spinal Nerves , Sympathectomy , Sympathetic Nervous System , Brimonidine TartrateABSTRACT
BACKGROUND: Clonidine, an alpha2 adrenoceptor agonist, has been known to have an antiallodynic effect in many animal and human studies. Clonidine, however, acts on imidazoline receptors as well as alpha2 adrenoceptors. Recently, the effect of clonidine on the symapthetic nervous system was reported to be mediated via the activation of the imidazoline receptor system but not the alpha2 adrenergic receptor system. Therefore, we conducted a behavioral test to investigate the effects of alpha2 adrenoceptors and imidazoline receptors on mechanical allodynia in rats with spinal nerve ligation (SNL) injury. METHODS: Male Sprague Dawley rats were prepared with tight ligation of the left lumbar 5th and 6th spinal nerves and chronic lumbar intrathecal catheter implantation for drug administration. Using a von Frey hair (VFH) test, we examined the effects of intrathecal (IT) brimonidine (0.03 - 3 microgram), clonidine (3 - 10 microgram), and rilmenidine (1 - 30 microgram) in SNL rats. Measurements of the baseline value VFH test was conducted at each dose to compare with the preoperative state. In addition, an antagonistic study with rauwolscine or yohimbine was performed to investigate the reversal of antiallodynic effects of each agonist. Allodynic thresholds for the withdrawal response of the left lesioned hindpaw to VFH stimuli were assessed and converted to %MPE. RESULTS: The antiallodynic effects of brimonidine, clonidine, and rilmenidine were produced in a dose dependent manner. The antiallodynic effects of IT brimonidine but not rilmenidine were significantly antagonized by alpha2 antgonists rauwolscine and yohimbine (P < 0.05). CONCLUSIONS: The results suggest that mechanical allodynia produced by a SNL injury is reduced by an imidazoline receptor agonist as well as alpha2 adrenergic receptor agonists and sympathetic activation is more likely mediated by spinal imidazoline receptors.
Subject(s)
Animals , Humans , Male , Rats , Adrenergic Agonists , Catheters , Clonidine , Hair , Hyperalgesia , Imidazoline Receptors , Ligation , Nervous System , Rats, Sprague-Dawley , Receptors, Adrenergic , Spinal Nerves , Yohimbine , Brimonidine TartrateABSTRACT
Objective:To explore the roles of the caudal ventrolateral medulla(CVLM) in the central anti-hypertensive mechanism. Methods : In 20 urethane-anesthetized SD rats, the effects of I1-imidazoline receptor and ?2-adrenceptor antagonists (microinjection into the CVLM) on the cardiovascular responses induced by intravenous clonidine were observed. Results: Prior bilateral microinjection of mixed antagonist idazoxan (I1-imidazoline receptor and a2-adrenceptor) into the CVLM not only decreased the mean arterial pressure [(-17. 3 ? 6. 9) mmHg, 1 mmHg = 0. 133 kPa, P
ABSTRACT
Agmatine was first identified and characterized as a candidate for CDS (clonidine displacing substance) in the bovine brain in 1994. The following researches demonstrated that agmatine was a widely distributed endogenous substance and performed a lot of biological functions in the central nervous system. The evidences revealed its targets were diverse and its mechanisms were complicated. Now it is well accepted that agmatine is a new neurotransmitter and/or neuromodulator and it might be an endogenous ligand of imidazoline receptor.