Neuronal nitric oxide synthase deficiency decreases survival in bacterial peritonitis and sepsis.

OBJECTIVE: To investigate the role of neuronal nitric oxide synthase (NOS1) in murine polymicrobial peritonitis and sepsis. DESIGN: Randomized experimental trial. SETTING: Animal research facility. SUBJECTS: B6129S NOS1+/+ and B6;129S4 NOS-/- mice. INTERVENTIONS: NOS1+/+ and NOS1-/- animals underwent cecal ligation and puncture (CLP) or sham surgery and received the NOS1 inhibitor 7-nitroindazole (7-NI) or vehicle. MEASUREMENTS AND MAIN RESULTS: After CLP, genetic deficiency and pharmacologic inhibition of NOS1 significantly increased risk of mortality [8.69 (3.27, 23.1), p<0.0001 and 1.71 (1.00, 2.92) p=0.05, hazard ratio of death (95% confidence interval) for NOS1-/- and 7-NI-treated NOS1+/+ respectively] compared with NOS1+/+ animals. In 7-NI-treated NOS1+/+ animals, there were increases (6 h) and then decreases (24 h), whereas in NOS-/- animals persistent increases in blood bacteria counts (p=0.04 for differing effects of 7-NI and NOS1-/-) were seen compared with NOS1(+/+) animals. After CLP, NOS1(-/-) had upregulation of inducible NOS and proinflammatory cytokines and greater increases in serum tumor necrosis factor-alpha and interleukin-6 levels compared with NOS1+/+ mice (all p<0.05). Following CLP, there were similar significant decreases in circulating leukocytes and lung lavage cells (p

Effects of aging on current vocalization threshold in mice measured by a novel nociception assay.

BACKGROUND: Age-related changes in nociception have been extensively studied in the past decades. However, it remains unclear whether in addition to the increased incidence of chronic illness, age-related changes in nociception contribute to increased prevalence of pain in the elderly. Although a great deal of evidence suggests that nociception thresholds increase with aging, other studies yield disparate results. The aim of this investigation was to longitudinally determine the effect of aging on nociception. METHODS: The authors developed a nociception assay for mice using electrical stimuli at 2,000, 250, and 5 Hz that reportedly stimulate Abeta, Adelta, and C sensory nerve fibers, respectively. A system was designed to automate a method that elicits and detects pain-avoiding behavior in mice. Using a Latin square design, the authors measured current vocalization thresholds serially over the course of mice's life span. RESULTS: For 2,000-Hz (Abeta), 250-Hz (Adelta), and 5-Hz (C) electrical stimuli, current vocalization thresholds first decreases and then increases with aging following a U-shaped pattern (P < 0.001). In addition, average current vocalization thresholds at youth and senescence are significantly higher than those at middle age for the 250-Hz (Adelta) and 5-Hz (C fiber) electrical stimulus (P < 0.05). CONCLUSIONS: Using a novel and noninjurious nociception assay, the authors showed that over the life span of mice, current vocalization threshold to electrical stimuli changes in a U-shaped pattern. The findings support the notion that age-related changes in nociception are curvilinear, and to properly study and treat pain, the age of subjects should be considered.