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The generation of transgenic 'knock-out' mice which lack genes relevant to pain is becoming increasing common. However, only one visceral pain model, the writhing test, is available in mice. The aim of this study was to adapt cyclophosphamide cystitis, a model of inflammatory visceral pain described in rats, for use in mice, and to characterise its behavioural effects. The toxic metabolites of systemically-administered cyclophosphamide are excreted in the urine, and induce bladder inflammation. We compared the effects of cyclophosphamide (100 and 300 mg/kg i.p., 4 h survival period) and vehicle (saline) in male mice on spontaneous behaviour (4 h continuous video-tape, and a 5-min Open Field test after 4 h). Involvement of the urinary bladder and other abdominal tissues was assessed by macroscopic examination and measurement of Evan's Blue plasma extravasation. Cyclophosphamide (300 mg/kg) produced significant changes in behaviour, including 22 +/- 6 min of 'crises' of visceral pain-related behaviour and a 53% reduction in activity, and also induced haemorrhage and substantial plasma extravasation in the bladder, but no change in other abdominal tissues. We conclude that cyclophosphamide cystitis has many advantages as a model of sub-acute, inflammatory visceral pain in mice. It does not require surgery or intubation, and we have found it to produce consistent, reproducible and quantifiable behavioural changes, which are significantly correlated with the degree of bladder inflammation in the absence of inflammation of other abdominal tissues. Copyright 1999 European Federation of Chapters of the International Association for the Study of Pain.

Retinitis pigmentosa (RP) is an inherited retinopathy that leads to photoreceptor loss. RP has been related to oxidative stress, autophagy, and inflammation. This study aimed to identify changes in the levels of oxidative stress and autophagy markers in the retina of control and rd10 mice during different phases of retinal development. Changes in the retinal oxidation system were investigated by measuring the levels of oxidized and reduced glutathione (GSH/GSSG), retinal avidin-positive cells, and 4-hydroxynonenal (4-HNE) staining intensity. Autophagy characterization was explored by measuring the levels of microtubule-associated protein 1 light chain 3 (LC3), beclin, autophagy-related proteins 5 and 7 (Atg5 and Atg7), and lysosomal associated membrane protein-2A (LAMP-2A). At P28 retinal GSH concentrations decreased in rd10 mice compared to the controls. No differences were found in retinal GSSG concentrations between the control and rd10 mice. There was an increase in retinal GSSG concentrations and a decrease in the GSH/GSSG ratio in the control and rd10 mice at P21 and P28 compared to P13. We observed an increase in avidin-positive cells in rd10 retinas. 4-HNE was increased in rd10 retinas at P13, and it also increased in control mice with age. We did not observe any differences in the retinal levels of LC3II/I ratio, Beclin, Atg5, or Atg7 in the rd10 mice compared to the controls. There was an increase in the LAMP-2A concentrations in the control and rd10 mice with development age (P28 concentrations vs. P13). Although only slight differences were found in the oxidative stress and autophagy markers between the control and rd10 mice, there were increases in the GSSG, 4-HNE, and LAMP-2A with age. This increase in the oxidative stress and chaperone-mediated autophagy has not been described before and occurred just after the mice opened their eyes, potentially indicating a retinal response to light exposure.

N-methyl-D-aspartate (NMDA) receptors appear to play little part in nociceptive responses evoked by acute stimulation of normal somatic tissues, but rather are involved in hyperalgesic responses after peripheral injury and inflammation. Previous studies from this laboratory have shown important differences in the neural organization of somatic and visceral nociceptive pathways. Here, we have explored the role of NMDA receptors in processing acute visceral noxious input, compared with somatic noxious input. The left ureter was cannulated close to the bladder in adult female Wistar rats anaesthetized with pentobarbitone (50 mg/kg i.p). Graded distentions of the ureter (30 s, 25-80 mmHg) evoked increases in blood pressure. These responses were dose-dependently inhibited by the NMDA receptor ion channel blockers ketamine and memantine (ID50 = 2.4+/-1.6 and 14.5+/-1.3 mg/kg, i.v.), and by the Merz glycine site antagonist Mrz 2/ 576 (ID50 = 0.2+/-0.2 mg/kg). Graded pinch stimuli (30 s, 2-4 N) of one hind-paw evoked similar pressor responses which were not affected by ketamine (up to 10 mg/kg). Similarly, Mrz 2/576 did not affect responses to noxious pinch, whereas memantine (ID50 = 17+/-12 mg/kg) did inhibit responses to pinch stimuli. However, in the dose range used neither ketamine nor Mrz 2/576 inhibited a pressor response of non-nociceptive origin (produced by bilateral carotid occlusion) whereas memantine did. Thus the effects of memantine are likely due to a non-specific cardiovascular effect. These results show that NMDA receptor antagonists inhibit nociceptive reflexes evoked from the normal ureter, and suggest that NMDA receptors are involved in the processing of acute nociceptive inputs from viscera. We conclude that acute stimulation of normal visceral tissue provokes intense responses that recruit neural mechanisms mediated by NMDA receptors. However, in somatic pathways, these mechanisms are recruited only by an enhanced peripheral input such as that produced after injury or inflammation.

Nitric oxide (NO) is a gas molecule with diverse physiological and cellular functions. In the eye, NO is used to maintain normal visual function as it is involved in photoreceptor light transduction. In addition, NO acts as a rapid vascular endothelial relaxant, is involved in the control of retinal blood flow under basal conditions and mediates the vasodilator responses of different substances such as acetylcholine, bradykinin, histamine, substance P or insulin. However, the retina is rich in polyunsaturated lipid membranes and is sensitive to the action of reactive oxygen and nitrogen species. Products generated from NO (i.e., dinitrogen trioxide (N2O3) and peroxynitrite) have great oxidative damaging effects. Oxygen and nitrogen species can react with biomolecules (lipids, proteins and DNA), potentially leading to cell death, and this is particularly important in the retina. This review focuses on the role of NO in several ocular diseases, including diabetic retinopathy, retinitis pigmentosa, glaucoma or age-related macular degeneration (AMD).

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When our data are compared to those from previous Spanish surveys carried out in 2003 and 2006, we can conclude that self-medication is increasing in Spain.

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