G. Horvath

Enhancement of fentanyl analgesia by clonidine plus verapamil in rats

An investigation was made of the analgesic effects of the subcutaneous coad ministration of fentanyl, an opioid μ- agonist (15 μg/kg), clonidine, an α2-agonist (100 μg/kg), and verapamil, a calcium channel blocker (10 mg/kg) in rats. Nociceptive sensitivity was assessed with hot-plate and tail-flick techniques. None of the three drugs alone was associated with appreciable analgesic effects in the doses used. The simultaneous administration of the three drugs resulted in marked analgesia superior to that of all binary combinations of these drugs. Two-way analysis of variance showed statistically significant differences in hot-plate and tail-flick latencies after drug treatments (P < 0.001). The significant differences in the area under the time-response curve values (P < 0.001) might indicate not only an increased analgesic effect, but also a prolongation of anti- nociception. These results suggest the existence of hitherto unreported interactions between drugs involved in the production of analgesia.

Sex-specific alterations in behavioral and cognitive functions in a "three hit" animal model of schizophrenia.

Whereas schizophrenia affects both human sexes, there are known sex-dependent disparities. We developed a chronic animal model that shows some schizophrenia-related deficits in rats by applying selective breeding after subchronic ketamine administration connected with postweaning social isolation (complex treatment). Our aim was to determine the sex-specific effects of these interventions on several processes. Sensory gating to acoustic stimulation, pain sensitivity, motor behavior, spatial learning and memory deficits on the hole-board test were assessed in the 17th generation of selectively bred Wistar rats compared to their naive counterparts with or without complex treatment. We found differences between the sexes: selectively bred males with complex treatment showed the lowest pain sensitivity; however, the results of the prepulse inhibition test indicated that female rats showed enhanced impairment of sensory gating and increased acoustic startle reaction. The cognitive performance, working and reference memory ratios were significantly decreased by selective breeding and showed sex-specific alterations, with the smallest value in male rats of the new substrain. Based on these results, the animals of the new substrain could be classified into the high-risk for schizophreniform phenotype with the highest sensitivity of males with complex treatment. Decreased cognitive performance highlighted spatial learning deficits in the selectively bred and treated rats that escalate the validity of our new and complex rat model of schizophrenia. The results indicate the same sex selectivity as observed in humans, with increased incidence of risk ratios for men to develop schizophrenia relative to women.

Inhibition of itch-related responses at spinal level in rats

The goal was to develop a rat model for determination of the effects of intrathecally administered drugs on the peripherally induced pruritic behaviors. After chronic intrathecal catheterization, a serotonin derivative (5-methoxytryptamine: MeOT, 200 μg on both sides) was injected into the lower leg skin. After the first period (phase 0: 0-30 min) MeOT injection was repeated and opioid antagonist naltrexone (10 μg), NMDA receptor antagonists ketamine (10-100 μg), kynurenic acid (1-10 μg) or their combinations were injected intrathecally. The second observational period lasted for 60 min (phases I and II, 30-60 and 60-90 min, respectively). MeOT produced pruritic behavior with high degree of interindividual differences. The second MeOT injection caused an enhanced pruritic behavior in Phase I. Naltrexone decreased the pruritic activity, while neither doses of ketamine influenced the effects of MeOT. The higher doses of kynurenic acid resulted in notable decreases in the pruritic behavior. The combinations of naltrexone with ketamine or kynurenic acid produced a prolonged antipruritic effect. Our data suggest an important direction for the development of a new itch model in rats that focuses on the spinal mechanism of itching. Besides, the results revealed the role of the spinal opioid and NMDA receptors in this process.

Telemetry monitoring for non-invasive assessment of changes in core temperature after spinal drug administration in freely moving rats.

INTRODUCTION There are no data available about the effects of spinally administered drugs on thermoregulation in freely moving animals. The first goal of the present study was to throw light on the consequences of intrathecally administered saline as a vehicle on core temperature and motor activity in unrestrained conditions. The second goal was to characterize the effects of morphine on these parameters as a widely used antinociceptive drug in spinal anesthesia, and reveal the potential role of the N-methyl-d-aspartate (NMDA) receptors in these processes. METHODS For these purposes, male Wistar rats were catheterized intrathecally, and E-Mitter battery-free transponders were implanted intraabdominally to continuously monitor core temperature and locomotor activity. RESULTS Saline induced a short-lasting hyperactivity accompanied by significant and prolonged hyperthermia that was blunted by systemic paracetamol administration. Morphine had no impact on motor activity; however, it caused high but equivalent degree hyperthermia in a wide dose range (1-15 μg), suggesting that it reached its peak effect. In the highest applied dose (25 μg), the NMDA receptor antagonist kynurenic acid blunted the saline-induced hyperthermia, and all doses caused higher hyperactivity compared to vehicle or morphine injections. In combination, kynurenic acid significantly inhibited the morphine-induced hyperthermia. DISCUSSION These data suggest that this method might be a valuable tool for investigating the thermoregulatory and locomotor effects of different drugs at spinal level; however, the prolonged effects of intrathecal vehicle injections should also be considered. The results point out that morphine is a very potent hyperthermic drug that may act primarily on the efferent limb of thermoregulation, at least partially, via an indirect NMDA-receptor mediated action mechanism.

Interocular amplitude differences of multifocal electroretinograms obtained under monocular and binocular stimulation conditions

PURPOSE To compare the interocular amplitude differences of the multifocal electroretinograms (mfERGs) evoked by either monocular or binocular stimulation in healthy subjects with good vision. METHODS Thirty-five subjects were included in the study. A Roland Consult RETIscan system was used. DTL electrodes were employed. First, the right and left eyes were stimulated separately, then, binocular stimulation was applied. The amplitudes of the scalar products were averaged over five concentric retinal regions (rings). RESULTS The interocular amplitude differences were 21.55% (SD: ±12.72) under monocular conditions and 18.69% (SD: ±11.64) under binocular conditions. No significant differences were found between the amplitudes and variability values obtained under either monocular or binocular stimulation. CONCLUSIONS Our results provided no evidence for the advantage of either binocular or monocular stimulating conditions in obtaining mfERGs. A considerable side difference was found between the mfERGs of the two eyes in almost all individual cases.

Impaired GAD1 expression in schizophrenia-related WISKET rat model with sex-dependent aggressive behavior and motivational deficit

After peri‐adolescence isolation rearing (IS) and subchronic ketamine (KET) treatment, adult, selectively bred Wistar rats (named WISKET) mimic abnormal behaviors reminiscent of human schizophrenia, including reduced prepulse‐inhibition of startle reflex, disturbances in cognition, locomotor activity and thermoregulation, decreased pain sensitivity and electrophysiological alterations. To further validate our WISKET rat line, regarding its translational utility in schizophrenia research, we examined their social behavior and introduced a short and simple holeboard (HB)‐like test to investigate their motivational deficit that predicts the cognitive disturbance. Sex‐dependent alterations in schizophrenia may yield important insights into its etiology; thus, male and female WISKET rats were also investigated and compared with their naive Wistar counterparts. Considering the contribution of the hippocampal and cortical GABAergic inhibitory circuitry in these behavioral alterations, molecular‐biology studies were also performed regarding the GAD1 gene products. Impaired social activity with increased aggression, stress‐related behavior, active social withdrawal, motivation deficit and decreased exploration were observed, especially in male WISKET rats, compared with Wistar ones and their corresponding females. These alterations were accompanied by sex‐dependent alterations regarding GAD67 mRNA and protein expression in the prefrontal cortex and hippocampus. In conclusion, the WISKET animals are valuable tools for animal‐based preclinical drug discovery studies for predictive screening of novel compounds improving negative symptoms with potential antipsychotic efficacy.

VEP and PERG in patients with multiple sclerosis, with and without a history of optic neuritis

PurposeVisual electrophysiology is routinely used to detect the visual complications of multiple sclerosis, but the analysis mostly focuses on visual evoked potential (VEP) and especially the P100 component. Our goal was to analyze the components and waveform alterations of VEPs and pattern electroretinograms (PERGs) in patients with multiple sclerosis (MS) with good vision.MethodsThe main VEP and PERG components of 85 patients with MS were analyzed in two groups: 38 patients who had optic neuritis in their history (ON group) and 47 patients who had never had optic neuritis (MS group). The results were compared against a control group of 47 healthy subjects.ResultsBoth VEP and PERG alterations occurred in a greater number of patients than expected, and these alterations were not necessarily linked to ON in the history or a deterioration of visual acuity.ConclusionsBoth VEP and PERG can detect dysfunction in the visual system in MS, even if the patient has no subjective symptoms. Even if PERG is not routinely used in neuro-ophthalmology, the results suggest that PERG assessment may provide useful information describing the retinal defect in MS.

171 POTENCY OF SPINALLY ADMINISTERED ENDOCANNABINOIDS ON MECHANICAL ALLODYNIA

168 N-ACYLETHANOLAMINES IN MICRODIALYSATE FROM MYALGIC HUMAN TRAPEZIUS MUSCLE B. Ghafouri, N. Ghafouri *, M. Turkina, B. Larsson, B.A.G. Jönsson, C. Fowler, B. Gerdle. Rehabilitation Medicine, Department of Clinical and Experimental Medicine, Linköping University, and Pain and Rehabilitation Centre, University Hospital, Linköping, Sweden; Department of Occupational and Environmental Medicine, Institute of Laboratory Medicine, University Hospital, Lund, Sweden; Department of pharmacology and Clinical neuroscience, Umeå university, Umeå, Sweden; Occupational and Environmental Medicine, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; Division of Cell Biology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden