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Oral presentation from 4th International Conference of cGMP Generators, Effectors and Therapeutic Implications ; Regensburg, Germany. 19–21 June 2009 Background: An exaggerated pain sensitivity is the dominant feature of inflammatory and neuropathic pain both in the clinical setting and in experimental animal models. It manifests as pain in response to normally innocuous stimuli (allodynia), increased response to noxious stimuli (hyperalgesia) or spontaneous pain, and can persist long after the initial injury is resolved. Research over the last decades has revealed that several signaling pathways in the spinal cord essentially contribute to the pain sensitization. To test the contribution of cGMP produced by NO-sensitive guanylyl cyclase (NO-GC) to pain sensitization, we investigated the localization of NO-GC in the spinal cord and in dorsal root ganglia, and we characterized the nociceptive behavior of mice deficient in NO-GC (GC-KO mice). Results: We show that NO-GC (β1 subunit) is distinctly expressed in neurons of the mouse spinal cord, while its distribution in dorsal root ganglia is restricted to non-neuronal cells. GC-KO mice exhibited a considerably reduced nociceptive behavior in models of inflammatory or neuropathic pain, but their responses to acute pain were not impaired. Moreover, GC-KO mice failed to develop pain sensitization induced by spinal administration of drugs releasing NO. Surprisingly, during spinal nociceptive processing cGMP produced by NO-GC may activate signaling pathways different from cGMP-dependent protein kinase I (cGKI), while cGKI can be activated by natriuretic peptide receptor-B (NPR-B) dependent cGMP production. Conclusion: Taken together, our results provide evidence that NO-GC has a dominant role in the development of exaggerated pain sensitivity during inflammatory and neuropathic pain. Furthermore, beside the NO-mediated cGMP synthesis, cGMP produced by NPR-B contributes to pain sensitization by activation of cGKI.
Although the Nobel Prize for the discovery of nitric oxide (NO) dates back almost 20 years now, the knowledge about cGMP signaling is still constantly increasing. It looks even so that our understanding of the role of the soluble guanylyl cyclase (sGC) and particulate guanylyl cyclase (pGC) in health and disease is in many aspects at the beginning and far from being understood. This holds even true for the therapeutic impact of innovative drugs acting on both the NO/sGC and the pGC pathways. Since cGMP, as second messenger, is involved in the pathogenesis of numerous diseases within the cardiovascular, pulmonary, renal, and endocrine systems and also plays a role in neuronal, sensory, and tumor processes, drug applications might be quite broad. On the 8th International Conference on cGMP, held in Bamberg, Germany, world leading experts came together to discuss these topics. All aspects of cGMP research from the basic understanding of cGMP signaling to clinical applicability were discussed in depth. In addition, present and future therapeutic applications of cGMP-modulating pharmacotherapy were presented (http://www.cyclicgmp.net/index.html).
Metabolic changes in summer active and anuric hibernating free-ranging brown bears (ursus arctos)
(2013)
The brown bear (Ursus arctos) hibernates for 5 to 6 months each winter and during this time ingests no food or water and remains anuric and inactive. Despite these extreme conditions, bears do not develop azotemia and preserve their muscle and bone strength. To date most renal studies have been limited to small numbers of bears, often in captive environments. Sixteen free-ranging bears were darted and had blood drawn both during hibernation in winter and summer. Samples were collected for measurement of creatinine and urea, markers of inflammation, the calcium-phosphate axis, and nutritional parameters including amino acids. In winter the bear serum creatinine increased 2.5 fold despite a 2-fold decrease in urea, indicating a remarkable ability to recycle urea nitrogen during hibernation. During hibernation serum calcium remained constant despite a decrease in serum phosphate and a rise in FGF23 levels. Despite prolonged inactivity and reduced renal function, inflammation does not ensue and bears seem to have enhanced antioxidant defense mechanisms during hibernation. Nutrition parameters showed high fat stores, preserved amino acids and mild hyperglycemia during hibernation. While total, essential, non-essential and branched chain amino acids concentrations do not change during hibernation anorexia, changes in individual amino acids ornithine, citrulline and arginine indicate an active, although reduced urea cycle and nitrogen recycling to proteins. Serum uric acid and serum fructose levels were elevated in summer and changes between seasons were positively correlated. Further studies to understand how bears can prevent the development of uremia despite minimal renal function during hibernation could provide new therapeutic avenues for the treatment of human kidney disease.
Knowledge of factors influencing the timing of reproduction is important for animal conservation and management. Brown bears (Ursus arctos) are able to vary the birth date of their cubs in response to their fat stores, but little information is available about the timing of implantation and parturition in free-ranging brown bears. Body temperature and activity of pregnant brown bears is higher during the gestation period than during the rest of hibernation and drops at parturition. We compared mean daily body temperature and activity levels of pregnant and nonpregnant females during preimplantation, gestation, and lactation. Additionally we tested whether age, litter size, primiparity, environmental conditions, and the start of hibernation influence the timing of parturition. The mean date of implantation was 1 December (SD = 12), the mean date of parturition was 26 January (SD = 12), and the mean duration of the gestation period was 56 days (SD = 2). The body temperature of pregnant females was higher during the gestation and lactation periods than that of nonpregnant bears. The body temperature of pregnant females decreased during the gestation period. Activity recordings were also used to determine the date of parturition. The parturition dates calculated with activity and body temperature data did not differ significantly and were the same in 50% of the females. Older females started hibernation earlier. The start of hibernation was earlier during years with favorable environmental conditions. Dates of parturition were later during years with good environmental conditions which was unexpected. We suggest that free-ranging pregnant brown bears in areas with high levels of human activities at the beginning of the denning period, as in our study area, might prioritize investing energy in early denning than in early parturition during years with favorable environmental conditions, as a strategy to prevent disturbances caused by human.
