Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Effect of intrathecal agmatine on inflammation-induced thermal hyperalgesia in rats. 1019 55

Antagonists of glutamate receptors of the N-methyl-d-aspartate subclass (NMDAR) or inhibitors of nitric oxide synthase (NOS) prevent nervous system plasticity. Inflammatory and neuropathic pain rely on plasticity, presenting a clinical opportunity for the use of NMDAR antagonists and NOS inhibitors in chronic pain. Agmatine (AG), an endogenous neuromodulator present in brain and spinal cord, has both NMDAR antagonist and NOS inhibitor activities. We report here that AG, exogenously administered to rodents, decreased hyperalgesia accompanying inflammation, normalized the mechanical hypersensitivity (allodynia/hyperalgesia) produced by chemical or mechanical nerve injury, and reduced autotomy-like behavior and lesion size after excitotoxic spinal cord injury. AG produced these effects in the absence of antinociceptive effects in acute pain tests. Endogenous AG also was detected in rodent lumbosacral spinal cord in concentrations similar to those previously detected in brain. The evidence suggests a unique antiplasticity and neuroprotective role for AG in processes underlying persistent pain and neuronal injury.
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PMID:Agmatine reverses pain induced by inflammation, neuropathy, and spinal cord injury. 1098 43

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.
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PMID:Agmatine potentiates the analgesic effect of morphine by an alpha(2)-adrenoceptor-mediated mechanism in mice. 1137 23

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.
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PMID:Agmatine produces antinociception in tonic pain in mice. 1142 73

Recent evidence suggests that agmatine, an endogenous polyamine metabolite, might be an important neurotransmitter in central nervous system and has potential as a treatment of pain. The aim of our study was to evaluate the effect of agmatine on allodynia in two experimental neuropathic pain models, the spinal nerve ligation (SNL) model and the streptozocin (STZ)-induced diabetic neuropathy in rats, and to determine if the N-methyl-D-aspartate (NMDA) receptor antagonists and the nitric oxide synthase (NOS) inhibitors influence this effect of agmatine. Nerve injury was produced by tight ligation of the left L5 and L6 spinal nerves, and diabetic neuropathy is induced with the injection of a single dose of STZ; these procedures resulted in tactile allodynia in the hindpaw. Tactile allodynia was detected by application of von Frey filaments to the plantar surface of the foot. Agmatine reduced mechanical allodynia with its higher doses. Dizocilpine maleate (MK-801), a NMDA receptor antagonist, and the NOS inhibitors, N(G)-nitro-L-arginine methyl ester and 7-nitroindazole, did not influence the antiallodynic effect of agmatine. These results suggest that agmatine has an antiallodynic effect in both spinal nerve ligation and diabetic models and may be a promising drug in the treatment of neuropathic pain.
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PMID:Systemic agmatine attenuates tactile allodynia in two experimental neuropathic pain models in rats. 1261 7

Effect of agmatine (10-400 mg/kg) on neuropathic pain in a rat model produced by loose ligatures around the common sciatic nerve was studied. The involvement of possible alterations in nitric oxide (NO) levels [measured as its stable metabolites nitrate + nitrite] and in noradrenergic activity [measured as norepinephrine and 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) levels] in this effect was also investigated biochemically in the brainstem and cerebellum. Agmatine increased the neuropathic pain threshold at 300 and 400 mg/kg. There was almost a twofold increase in nitrate + nitrite levels in the brainstem and cerebellum of the rats with neuropathic pain and agmatine decreased the high nitrate + nitrite levels only in the brainstem at 300 mg/kg and both in the brainstem and cerebellum at 400 mg/kg. Ligation of sciatic nerve resulted in almost twofold increase in norepinephrine and MHPG levels only in the brainstem of the rats. Agmatine decreased MHPG levels at 300 and 400 mg/kg, however it decreased norepinephrine levels only at the higher dose. These findings indicate that agmatine decreases neuropathic pain, an effect which may involve the reduction of NO levels and noradrenergic activity in the brain.
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PMID:Agmatine attenuates neuropathic pain in rats: possible mediation of nitric oxide and noradrenergic activity in the brainstem and cerebellum. 1275 36

Agmatine is a novel endogenous guanido amine synthesized from arginine by arginine decarboxylase. Among several biologic effects, the ability of agmatine to protect against ischemic injury and chronic neuropathic pain is particularly interesting. Because inflammation is a common contributor to these conditions, we sought to determine if agmatine acts by decreasing the production of proinflammatory molecules such as nitric oxide and if agmatine synthesis is regulated by inflammatory stimuli. We tested whether agmatine affects astroglial and macrophage (RAW 264.7 cell line) nitric oxide synthase-2 (NOS-2) expression. NOS-2 was induced in these cells by incubation with lipopolysaccharide (LPS) plus three cytokines for astrocytes and LPS alone for RAW 264.7 cells in the presence and absence of varying concentrations of agmatine. NOS-2 activity was assessed after 24 hours by nitrite accumulation in the culture media. Agmatine dose-dependently inhibited nitrite accumulation, and shorter incubation with agmatine (1 and 4 hours) also caused significant reduction. Agmatine decreased the expression of NOS-2 activity and NOS-2 protein as determined by immunoblot analysis. Incubation of astrocytes and RAW 264.7 cells with LPS/cytokines for 2 hours resulted in an increase in arginine decarboxylase (ADC) activity, whereas longer-term incubation (12-17 hours) lowered ADC activity. Agmatine levels in these cells are increased after 6-hour incubation with LPS/cytokines. These results show that agmatine inhibits the production of nitric oxide by decreasing the activity of NOS-2 in macrophages and astroglial cells by decreasing the levels of NOS-2 protein. These findings provide a molecular basis for the neuroprotective and anti-inflammatory actions of agmatine.
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PMID:Regulation of inducible nitric oxide synthase and agmatine synthesis in macrophages and astrocytes. 1502 66

Agmatine has been previously proposed to represent a novel neurotransmitter. One of the criteria required to test that hypothesis is that the exogenously administered chemical produces pharmacological effects similar to the physiological effects of the putative neurotransmitter. Since agmatine was first identified in brain, approximately sixty studies of the in vivo effects of exogenously administered agmatine have been reported. Despite the assertion that agmatine functions as a neuromodulator/neurotransmitter, the vast majority of experiments have administered agmatine through systemic (rather than central) routes of administration. Systemic delivery of agmatine for studies of centrally mediated phenomenon (e.g., pain, spinal cord injury, cardiovascular responses) relies on the presumption that agmatine (a polar compound) gains appreciable access to the CNS. The mechanism by which agmatine crosses the blood-brain barrier is not well understood. A number of studies have examined the in vivo effects of agmatine following central administration (e.g., intracerebroventricular and intrathecal). This paper summarizes and provides a comparison between the systemic versus central routes of administration for delivery of agmatine in experimental subjects.
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PMID:Neuropharmacokinetic and dynamic studies of agmatine (decarboxylated arginine). 1502 73

Agmatine is a polycationic amine synthesized from L-arginine by arginine decarboxylase in brain and several tissues. It binds to N-methyl-D-aspartate (NMDA) subtype of glutamatergic, alpha(2)-adrenergic and imidazoline (I) receptors. The present study was designed to investigate effect of agmatine on acute and mononeuropathic pain after chronic constriction injury (CCI). CCI was created by four loose ligations around the right sciatic nerve. The analgesic threshold in rats was evaluated by using thermal hyperalgesia/allodynia (THA) at 4 degrees C. The evaluations were made preoperatively, on postoperative day 15, and after drug administration. Agmatine (10, 20, 40, 80, and 100 mg/kg) was administered intraperitoneally for 5 days beginning on postoperative day 15. Agmatine significantly reduced the hyperalgesia in all doses applied. When agmatine was injected intraperitoneally (10, 20, 40, 80, and 100 mg/kg), it increased the nociceptive threshold in the tail-immersion test in a dose-dependent manner, but it had no effect in the hot-plate test. This effect of agmatine in the tail-immersion test was blocked by both yohimbine (1 mg/kg) and idazoxan (0.5 mg/kg). When agmatine was administered intracerebroventricularly (25-200 microg/10 microL), it increased the nociceptive threshold in the hot-plate but not in the tail-immersion test. We conclude that agmatine, an endogenous substance derived from arginine, can modulate both acute and chronic pain.
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PMID:Effect of agmatine on acute and mononeuropathic pain. 1502 74

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.
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PMID:Mechanisms involved in the antinociception caused by agmatine in mice. 1585 29


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