Clonidine, an antihypertensive drug, binds to alpha 2-adrenergic and imidazoline receptors. The endogenous ligand for imidazoline receptors may be a clonidine-displacing substance, a small molecule isolated from bovine brain. This clonidine-displacing substance was purified and determined by mass spectroscopy to be agmatine (decarboxylated arginine), heretofore not detected in brain. Agmatine binds to alpha 2-adrenergic and imidazoline receptors and stimulates release of catecholamines from adrenal chromaffin cells. Its biosynthetic enzyme, arginine decarboxylase, is present in brain. Agmatine, locally synthesized, is an endogenous agonist at imidazoline receptors, a noncatecholamine ligand at alpha 2-adrenergic receptors and may act as a neurotransmitter.

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Agmatine, decarboxylated arginine, is a metabolic product of mammalian cells. Considering the close structural similarity between L-arginine and agmatine, we investigated the interaction of agmatine and nitric oxide synthases (NOSs), which use L-arginine to generate nitric oxide (NO) and citrulline. Brain, macrophages and endothelial cells were respectively used as sources for NOS isoforms I, II and III. Enzyme activity was measured by the production of nitrites or L-citrulline. Agmatine was a competitive NOS inhibitor but not an NO precursor. Ki values were approx. 660 microM (NOS I), 220 microM (NOS II) and 7.5 mM (NOS III). Structurally related polyamines did not inhibit NOS activity. Agmatine, therefore, may be an endogenous regulator of NO production in mammals.

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 (allodynia͞hyperalgesia) 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.A gmatine (AG) is formed by the enzymatic decarboxylation of L-arginine (1). It has been discovered recently in mammals (2, 3), where it is expressed in the central nervous system. In brain, AG meets most of the criteria of a neurotransmitter͞ neuromodulator (4): it is synthesized, stored, and released from specific networks of neurons (5, 6), is inactivated by energydependent reuptake mechanisms (7), is degraded enzymatically (8), and binds with high affinity to ␣ 2 -adrenergic and imidazoline (I 1 ) receptors (2, 9). In addition, AG antagonizes N-methyl-Daspartate receptors (NMDAR) (10) and inhibits all isoforms of nitric oxide synthase (NOS) (11,12). NMDAR antagonists and NOS inhibitors prevent adaptive changes in neuronal function, including opioid tolerance (13,14), persistent pain (15-17), and spinal cord injury (SCI) (18-21). Therefore, AG, which antagonizes͞inhibits both NMDAR and NOS, should moderate chronic pain accompanying inflammation, neuropathy or SCI. We report here that AG, when exogenously administered, selectively relieves allodynic, hyperalgesic, and autotomy-like states accompanying spinal nerve injury, peripheral inflammation, and excitotoxic SCI, respectively. Moreover, as in brain (5, 6), we have detected AG in spinal cord, indicating that AG may be an endogenous modulator of pain pathways. Fig. 1D; 400-500 g, Harlan Teklad (Fig. 5C); 200-250 g, Charles River Breeding Laboratories (Figs. 3 and 4)]. All experiments were approved by the Institutional Animal Care and Use Committees. Each group had at least five animals; each animal was used only once.Chemicals. The following chemicals were used: MK801 (Merck); LY235959 (Lilly Research Laboratories, Indianapolis); carrageenan (CARRA), ketamine, dextromethorphan, ifenprodil, aminoguanidine, N -nitro-L-arginine methyl ester (L-NAME), AG, NMDA, substance P (SP), memantine, and ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)͞meta...

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