GRIN2B gain of function mutations are sensitive to radiprodil, a negative allosteric modulator of GluN2B-containing NMDA receptors.

De novo gain of function mutations in GRIN2B encoding the GluN2B subunit of the N-methyl-d-aspartate (NMDA) receptor have been linked with epileptic encephalopathies, including infantile spasms. We investigated the effects of radiprodil, a selective GluN2B negative allosteric modulator and other non-selective NMDA receptor inhibitors on glutamate currents mediated by NMDA receptors containing mutated GluN2B subunits. The experiments were performed in Xenopus oocytes co-injected with the following human mRNAs: GRIN1/GRIN2B, GRIN1/GRIN2B-R540H, GRIN1/GRIN2B-N615I and GRIN1/GRIN2B-V618G. Glutamate displayed slightly increased potency in the R540H variant, but not in N615I and V618G variants. However, the inhibition by Mg2+ was completely abolished in N615I and V618G variants. In fact, Mg2+ enhanced glutamate responses in those variants. The potency of radiprodil to block glutamate-evoked currents was not affected in any of the variants, while the effects by non-selective NMDA inhibitors were greatly reduced in some of the variants. Additionally, in the Mg2+ insensitive variants, radiprodil blocked glutamate-activated currents with the same potency as in the absence of Mg2+. The gain of function observed in the reported GRIN2B variants could be a key pathophysiological factor leading to neuronal hyper-excitability in epileptic encephalopathies. The GluN2B-selective inhibitor radiprodil fully retained its pharmacological profile under these conditions, while other non-selective NMDA receptor antagonists lost their potency. Consequently, our data suggest that radiprodil may be a valuable therapeutic option for treatment of pediatric epileptic encephalopathies associated with GRIN2B mutations.

Fibromyalgia syndrome: novel therapeutic targets.

Fibromyalgia syndrome (FMS) is a chronic disorder characterized by widespread pain and tenderness, accompanied by disturbed sleep, chronic fatigue and multiple additional functional symptoms. FMS continues to pose an unmet need regarding pharmacological treatment and many patients fail to achieve sufficient relief from existing treatments. As FMS is considered to be a condition in which pain amplification occurs within the CNS, therapeutic interventions, both pharmacological and otherwise, have revolved around attempts to influence pain processing in the CNS. In the current review, we present an update on novel targets in the search for effective treatment of FMS.

Ketamina endovenosa preoperatoria mejora la analgesia postoperatoria de colecistectomías laparoscópicas / Preoperative intravenous ketamine improves analgesia alter laparoscopic cholecystectomy

El adecuado tratamiento del dolor agudo postoperatorio es un desafío actual y real. La utilización de analgesia preventiva con ketamina puede ser de alta utilidad, ya que prevendría la sensibilización central mediada por receptores n-metil-diaspartato (NMDA). Objetivo: evaluar el uso preincisión de colecistectomías laparoscópicas de 0,15 mg/kg de ketamina EV. Resultados: en 84 pacientes adultos con edad promedio de 52 +/- 9 años se logró una disminución significativa del dolor postoperatorio con el uso de ketamina EV preoperatoria. La evaluación visual análoga (EVA) de dolor fue significativamente menor en las 72 horas postoperatorias estudiadas. La cantidad de analgésico de rescate (morfina) consumida fue significativamente menor en el grupo que recibió ketamina siendo en promedio de 1,7 mg/por paciente en 24 horas versus el grupo que recibió placebo, que fue de 4,2 mg/por paciente en 24 horas (p<0.01). No se registraron episodios de malos recuerdos intraoperatorios y agitación en el despertar anestésico en ninguno de los grupos. La incidencia de náuseas y vómitos no tuvo diferencias estadísticamente significativas entre los enfermos. El grado de satisfacción fue en general muy bueno y bueno en ambos grupos y no se evidenció diferencias entre ambos, pero los únicos dos casos que evaluaron su analgesia como mala se ubicaron en el grupo que recibió placebo. Con respecto a incidencia de pesadillas o alucinaciones, ningún paciente refirió haberlas presentado hasta 14 días postoperatorios. Conclusión: el uso de dosis bajas de ketamina EV en el preoperatorio de colecistectomías laparoscópicas es altamente recomendable, ya que proporciona una buena calidad analgésica, disminuyendo la necesidad de utilizar fármacos de rescate.

Backround: Treating acute postoperative pain is challenging. Preemptive analgesia with ketamine can be useful as it prevents central sensibilitation inhibiting NMDA receptors. Objective: To test a pre insision dose of 0.15 mg/kg ketamine during laparoscopic cholecystectomy. Results: 84 patients were studied divided in two groups; group ketamine and group placebo. Acute postoperative pain was significantely lower in the ketamine group. VAS scores were lower for the 72 postoperative hours studied in patients receiving ketamine. Rescue analgesia (morphine) was 1.7 mg/patient for 24 hours in the ketamine group comparing it with the control group which was 4.2 mg/patient in 24 hours (p<0.01). Postoperative agitation, bad recalls or nightmares were absent in both groups. Postoperative nausea or vomiting had no difference comparing the groups. Patient satisfaction was evaluated good and very good by the mayority of them. There were two cases evaluating analgesic treatment as not good. Both received placebo. Conclusion: Preoperative ketamine was useful because it prometed good analgesia and because it lower the use of rescue analgesia.