The role of GSK-3β in the pathogenesis of pain has recently emerged. It has been reported that inhibition of GSK-3β activity can prevent the development and reverse the existence of neuropathic pain. The aim of the project is to evaluate the therapeutic potential of AF3581, an Angelini GSK-3β inhibitor, in pain conditions.
The chronic constriction injury model (CCI) is one a widely used animal model of neuropathic pain. Nerve injury in rats induced by loose ligatures around the sciatic nerve produces a characteristic behaviour with the appearance of allodynia, hyperalgesia and spontaneous pain, often accompanied by sensory deficits.
CCI was induced in SD rats by loosely constrictive ligatures around the sciatic nerve trunk at mid-thigh level. Mechanical allodynia and mechanical hyperalgesia were measured following oral administration of AF3581 (10mg/kg) and tramadol (10mg/kg), used as reference drug. Sections of spinal cord were used for immunohistochemistry studies. All procedures conformed to the guidelines of the European Community’s Council for Animal Experiments.
AF3581 administration induces a significant antiallodynic effect comparable to that of tramadol. Differently from tramadol, AF3581 treatment produces a significant inhibition also of mechanical hyperalgesia. The immunohistochemistry study suggests a possible target engagement of GSK-3β since a significant increase in the phospho-GSK-3β/GSK-3β ratio was observed following AF3581 administration.
These results provide experimental evidence that AF3581 produces marked antihyperalgesic effects in neuropathic pain in rats, possibly linked to a down-regulation of GSK-3β activation. The study support GSK-3β as pharmacological target for the treatment of neuropathic pain.

GLYCOGEN SYNTHASE KINASE 3 INHIBITOR AF3581 DECREASES NEUROPATHIC PAIN IN RATS