No abstract

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...

Persistent postmastectomy pain (PPMP) is a major individual and public health problem. Increasingly, psychosocial factors such as anxiety and catastrophizing are being revealed as crucial contributors to individual differences in pain processing and outcomes. Furthermore, differences in patients’ responses to standardized quantitative sensory testing (QST) may aid in the discernment of who is at risk for acute and chronic pain after surgery. However, characterization of the variables that differentiate those with PPMP from those whose acute postoperative pain resolves is currently incomplete. The purpose of this study was to investigate important surgical, treatment-related, demographic, psychophysical, and psychosocial factors associated with PPMP by comparing PPMP cases with PPMP-free controls. Pain was assessed using the breast cancer pain questionnaire to determine the presence and extent of PPMP. Psychosocial and demographic information were gathered via phone interview, and women underwent a QST session. Consistent with most prior research, surgical and disease-related variables did not differ significantly between cases and controls. Furthermore, treatment with radiation, chemotherapy, or hormone therapy was also not more common among those with PPMP. In contrast, women with PPMP did show elevated levels of distress-related psychosocial factors such as anxiety, depression, catastrophizing, and somatization. Finally, QST in nonsurgical body areas revealed increased sensitivity to mechanical stimulation among PPMP cases, while thermal pain responses were not different between the groups. These findings suggest that an individual’s psychophysical and psychosocial profile may be more strongly related to PPMP than their surgical treatment.