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...

Intraspinal injections of the AMPA-metabotropic receptor agonist quisqualic acid (QUIS) were made in an effort to simulate injury induced elevations of excitatory amino acids (EAAs), a well documented neurochemical change following spinal cord injury (SCI). The progressive pathological sequela associated with QUIS injections closely resembles the cascade of events described following ischemic and traumatic SCI and the pathogenesis of cavities in the clinical condition of post-traumatic syringomyelia. Using different injection parameters, i.e. depth and volume, to deliver QUIS into the cord the results have shown that the technique of intraspinal injection can be used to produce graded patterns of neuronal loss in specific regions of the spinal gray matter. Furthermore, neuronal loss in the dorsal horn, sparing the superficial laminae, results in the onset of spontaneous (excessive grooming behavior) and evoked (mechanical allodynia and thermal hyperalgesia) behaviors commonly associated with experimental models of chronic neuropathic pain. Thus, the present results provide a morphological correlate of spontaneous and evoked pain related behaviors following excitotoxic SCI. The behavioral characteristics combined with the similarities between QUIS induced injury and the clinical pathology of SCI support the use of the excitotoxic model in studies related to the central mechanism(s) of altered sensation, including pain, following spinal injury.

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Objective: This work exposed rats to low levels of the organophosphate insecticide chlorpyrifos and monitored for toxic effects, including weight gain.Methods: Rats received either a subcutaneous injection of chlorpyrifos, 5 mg/kg/day, or an equal volume of vehicle daily for 4 months. Subjects were observed for 30 minutes after injection for signs of acute toxicity. Body weights were recorded at baseline, 2 months, 3 months, and 4 months. At the end of the experiment, the weights of hearts, medial lobe of the livers, peri-nephric fat pads, and gastrocnemius muscles were recorded. Effects of chlorpyrifos on adipocyte differentiation in culture were studied. Results were compared using RMANOVA.Results: No signs of acute cholinergic toxicity were observed after injections in any subject. Rats in the 5 mg/kg group were significantly heavier than those in the control group by 2 months (335.7 Ϯ 16.7 g vs. 318.6 Ϯ 15.8 g; p ϭ 0.034). This difference increased at 3 months (350.1 Ϯ 16.4 g vs. 322.3 Ϯ 21.3 g p ϭ 0.006) and 4 months (374.4 Ϯ 22.2 g vs. 340.2 Ϯ 25.2 g p ϭ 0.006). At 4 months, the weights of the perinephric fat pads were significantly increased in the chlorpyrifos group relative to controls (2.867 ϩ 0.516 vs. 1.130 ϩ 0.171, p ϭ 0.0039). The two groups showed no weight differences between hearts, livers, and gastrocnemius muscles. Chlorpyrifos did not affect adipocyte differentiation in tissue culture.Conclusions: Chronic exposure to chlorpyrifos at 5 mg/kg/day caused an increase in rat body weight when compared to controls. This increase was in adipose tissue. Chlorpyrifos did not induce differentiation of adipocytes in culture.

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