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IQM-PC332, a novel DREAM ligand with analgesic effect on experimental peripheral nerve injury- and diabetes-induced pain

AuthorsSocuéllamos, Paula G.; Cercós, Pilar ; Olivos-Oré, Luis Alcides; Barahona, María Victoria; Bosch, Gerardo; Naranjo, José Ramón; Valenzuela, Carmen ; Gutiérrez-Rodríguez, Marta ; Artalejo, Antonio R.
Neuropathic pain
Issue Date2019
CitationRECI VII (2019)
AbstractNeuropathic pain is a form of chronic pain arising from damage to the nerves that sense, transmit or process information about environmental stimuli. Given its growing prevalence and common refractoriness to conventional analgesics, the development of new drugs with pain relief effect constitute a prominent clinical need. In this respect, drugs that reduce activity of sensory neurons by modulating ion channels hold the promise to become effective analgesics. Here we have used two models of neuropathic pain, namely the chronic constriction injury of the sciatic nerve (CCI) and the streptozotocin-induced diabetic neuropathy, to evaluate the mechanical antiallodynic effect of IQM-PC332, a novel Downstream Regulatory Element Antagonist Modulator (DREAM)/KChIP3/calsenilin ligand potentially affecting DREAM modulated ionic currents like potassium IA and ICav. IQM-PC332 exerted a mechanical antiallodynic effect following intraperitoneal (I.P; DE50 of 0.06 μg/kg, Emax of 65%) and intraplantar (DE50 of 0.24 mg, Emax of 68%) administration in the CCI
model. Likewise, IQM-PC332 2 μg/kg I.P. significantly reduced mechanical allodynia in diabetic animals. Interestingly, no effect of IQM-PC332 on glucose levels from both CCI and diabetic animal could be observed at analgesic doses. The effects of IQM-PC332 on INav, ICav, IA, and the electrical excitability in neurons isolated from dorsal root ganglia (L4-L6; DRG) were also studied with the patch-clamp technique. IQM-PC332 reduced peak amplitudes of ICav from both Control and CCI animals with CI50 (@ +10 mV) of 78 μM y 40 μM, respectively. At variance, IQM-PC332 did not exert any effect on INav in the concentration range from 0.01 to 50 μM. PC332 10 μM also inhibited IA in DRG neurons from CCI animals, this effect being larger with membrane depolarization (≈ 50% inhibition at -10 mV). Interestingly, in about 55% of the neurons, IQM-PC332 slowed inactivation of IA. In accordance with its effects on ion currents, IQM-PC332 10 μM reduced the time to the first action potential (AP) evoked by current injection while decreasing the amplitude and duration of the after hyperpolarization that followed after APs within a train. However, no clear effect on instantaneous frequency of AP could be observed. It is suggested that inhibition of Ca2+ entry through Cav channels coupled to neurotransmitter release from peripheral and central terminals of nociceptive neurons may underlie the analgesic effect of IQM-PC332.
DescriptionResumen del trabajo presentado al VII Congreso Red Española Canales Iónicos, celebrado en Cáceres del 15 al 17 de mayo de 2019.
Appears in Collections:(IIBM) Comunicaciones congresos
(CNB) Comunicaciones congresos
(IQM) Comunicaciones congresos
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