Spinorphin Attenuates Acute Experimental Seizures and Associated Neurochemical Alterations: Possible Involvement of Opioid Receptors.

Spinorphin, an endogenous enkephalinase inhibitor, enhances physiological opioid signaling by preventing the degradation of endogenous enkephalins, however, its anticonvulsant potential has not previously been investigated. This study evaluated the effects of spinorphin on seizure activity and associated neurochemical alterations in two complementary acute experimental seizure models. The effects of spinorphin on seizure activity were investigated in pentylenetetrazole (PTZ)- and penicillin-induced acute seizure rat models. Behavioral seizure parameters, passive avoidance memory, electrocorticographic activity, cortical and hippocampal glutamate, GABA, c-Fos, calcitonin gene-related peptide (CGRP), inflammatory cytokines, and oxidative stress biomarkers were evaluated. Nalmefene was used to determine the contribution of opioid receptor signaling. Spinorphin significantly attenuated behavioral seizures, reduced cortical epileptiform spike frequency, and improved passive avoidance retention performance. It attenuated PTZ-induced alterations in cortical and hippocampal glutamate and GABA concentrations and reduced tissue levels of c-Fos and CGRP, together with changes in inflammatory and oxidative stress-related biomarkers in both the cortex and hippocampus. These effects were substantially attenuated by nalmefene, suggesting a possible contribution of endogenous opioid signaling, although the incomplete reversal indicates that additional opioid-independent mechanisms may also be involved. Spinorphin attenuates seizure activity and associated biochemical alterations in experimental seizure models. By enhancing the regional availability of endogenous enkephalins rather than directly activating opioid receptors, spinorphin may exert its anticonvulsant effects partly through endogenous opioid signaling, while additional opioid-independent mechanisms may also contribute. These findings provide a basis for further investigation of enkephalinase inhibition in experimental seizure models.