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.

Context Persistent pain is common following surgical treatment of breast cancer, but fairly little is known about the changes in sensory processing that accompany such pain syndromes. Objectives This study employed quantitative sensory testing (QST) to compare psychophysical responses to standardized noxious stimulation in two groups of women who had previously undergone breast cancer surgery: women with (n=37) and women without (n=34) persistent post-operative pain. Methods Participants underwent a single testing session in which responses to a variety of noxious stimuli were assessed. Results Findings suggested that women with chronic pain after breast cancer surgery display enhanced temporal summation of mechanical pain, deficits in endogenous pain inhibition, and more intense painful after-sensations compared with those without long-term pain. Some of these group differences were mediated by higher levels of pain catastrophizing in the group of women with persistent pain. Conclusion These findings suggest that persistent post-operative pain is associated with alterations in central nervous system pain-modulatory processes. Future treatment studies might benefit from targeting these pain-modulatory systems, and additional studies using functional neuroimaging methods might provide further valuable information about the pathophysiology of long-term post-surgical pain in women treated for breast cancer.

Supplemental Digital Content is Available in the Text. Chronic pain severity and interference worsened under conditions of social distancing, with certain sociodemographic factors and high pain catastrophizing associated with greater impact.

Persistent pain after breast cancer surgery (PPBCS) is increasingly recognized as a potential problem facing a sizeable subset of the millions of women who undergo surgery as part of their treatment of breast cancer. Importantly, an increasing number of studies suggest that individual variation in psychosocial factors such as catastrophizing, anxiety, depression, somatization and sleep quality play an important role in shaping an individual's risk of developing PPBCS. This review presents evidence for the importance of these factors and puts them within the context of other surgical, medical, psychophysical and demographic factors, which may also influence PPBCS risk, as well as discusses potential perioperative therapies to prevent PPBCS.

The only significant, unique predictors of both pain and opioid consumption were TSP, an index of central pain facilitatory processes, and BMI. Interestingly, psychosocial factors, such as catastrophizing and somatization, although correlated with postoperative pain scores and opioid consumption, generally did not independently explain substantial variance in these measures. This study suggests that BMI and quantitative sensory testing, specifically the temporal summation of pain, may provide value in the preoperative assessment of patients undergoing total knee arthroplasty and other surgeries via predicting their level of risk for adverse pain outcomes.

The severity and impact of acute pain after breast surgery varies markedly among individuals, underlining the importance of comprehensively identifying specific risk factors, including psychosocial and psychophysical traits. In this prospective observational study, women (n=234) undergoing breast-conserving surgery, mastectomy, or mastectomy with reconstruction completed a brief bedside quantitative sensory testing (QST) battery, along with measures of psychosocial characteristics. Postoperative pain severity, impact, and opioid use at 2 weeks were assessed using Brief Pain Inventory (BPI) and procedure-specific breast cancer pain questionnaires. Moderatesevere average pain (>3/10) was reported by 29% of patients at 2 weeks. Regression analysis of pain outcomes revealed that pain severity was independently predicted by axillary dissection, presurgical pain, temporal summation of pain (TSP), (−)positive affect, and behavioral coping style. Pain impact was predicted by age, education, axillary dissection, reconstruction, but also by negative affect and depression scores. Lastly, opioid use was predicted by age, education, axillary dissection, reconstruction, TSP and reinterpreting coping style. Our findings suggest that, individuals with certain phenotypic characteristics, including high TSP and negative affect may be at greater risk of significant pain and continued opioid use at 2 weeks after surgery, independent of known surgical risk factors.