Retigabine (N-(2-amino-4-(4-fluorobenzylamino)-phenyl) carbamic acid ethyl ester) has a broad anticonvulsant spectrum and is currently in clinical development for epilepsy. The compound has an opening effect on neuronal KCNQ channels. At higher concentrations an augmentation of gamma-aminobutyric acid (GABA) induced currents as well as a weak blocking effect on sodium and calcium currents were observed. The goal of this study was to characterise the activity of retigabine in models of acute and neuropathic pain and to investigate if the potassium channel opening effect of retigabine contributes to its activity. Retigabine was tested in mice and rats in the tail flick model of acute pain and in the nerve ligation model with tight ligation of the 5th spinal nerve (L5) using both thermal and tactile stimulation. While retigabine like gabapentin had almost no analgesic effect in mice it showed some analgesic effects in rats in the tail flick model. These effects could not be antagonised with linopirdine, a selective KCNQ potassium channel blocker, indicating a different mode of action for this activity. In L5-ligated rats retigabine significantly and dose-dependently elevated the pain threshold and prolonged the withdrawal latency after tactile and thermal stimulation, respectively. In the L5 ligation model with thermal stimulation retigabine 10 mg/kg p.o. was as effective as 100 mg/kg gabapentin or 10 mg/kg tramadol. The L5 model with tactile stimulation was used to test the role of the KCNQ potassium channel opening effect of retigabine. If retigabine 10 mg/kg p.o. was administered alone it was as effective as tramadol 10 mg/kg p.o. in elevating the pain threshold. Linopirdine (1 and 3 mg/kg i.p.) had nearly no influence on neuropathic pain response. If we administered both retigabine and linopirdine the effect of retigabine was abolished or diminished depending on the dose of linopirdine used.In summary, retigabine is effective in predictive models for neuropathic pain. The activity is comparable to tramadol and is present at lower doses compared with gabapentin. Since the anti-allodynic effect can be inhibited by linopirdine we can conclude that the potassium channel opening properties of retigabine are critically involved in its ability to reduce neuropathic pain response.

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Spontaneously hypertensive rats (SHR) and its counterpart, the Wistar-Kyoto rats (WKY), are probably the most often used animal model of ADHD. However, SHR as model of ADHD have also been criticised partly because of not differing to outbred rat strains. In the present study, adolescent SHR, WKY and Wistar rats from Charles River were tested in open-field, elevated plus maze and novel object recognition and on gastrointestinal transport to more intensively evaluate the strain characteristics. Non-habituated SHR and Wistar rats were more active than WKY rats but contrary to Wistar rats SHR stay hyperactive in a familiar environment. SHR were more sensitive to the alpha2-adrenoceptor agonist guanfacine and the dopamine D1 agonist A-68930 than WKY and Wistar rats, whereas amphetamine, the D1/D5 agonist ABT431 and the D2 agonist quinpirole, similarly affected open-field activity in all strains. In the elevated plus maze, SHR and Wistar rats showed less anxiety-related behaviour than WKY rats. Guanfacine and amphetamine induced an anxiolytic-like activity in SHR but not in WKY and Wistar rats. SHR showed the highest long-term memory in the novel object recognition. Gastrointestinal transport was similar and comparably affected by guanfacine in all rat strains. The present study shows clear differences in the behaviour of SHR and Wistar rats but also of WKY and Wistar rats. The use of SHR as animal model of ADHD is supported.

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The possibility to substitute PCP by MK-801 in this model indicates that the effect is mediated by their common mechanism of NMDA antagonism. PDE10A inhibitors similar to clozapine significantly antagonize the increase of immobility, suggesting a therapeutic potential for the treatment of negative symptoms. However, further validation of the model is necessary.