An electrophysiological study about the pharmacological manipulation of the immediate consequences of a spinal trauma reveals a crucial role for TRPV4 antagonism.

Abstract

A physical trauma to the spinal cord produces an immediate massive depolarizing injury potential accompanied both by a transient episode of spinal hypoxia, and an extensive cell loss at the level of injury, which interrupts conduction of longitudinal input along white matter tracts. Afterwards, the transient hypotonia and areflexia characterize the following spinal shock phase. The relationship between the extent of injury potentials and spinal cord injury (SCI) progression, as well as the potential pharmacological modulation of the immediate consequences of a trauma, have not yet been explored. To limit the peak of injury potentials and speed up recovery of reflex motor responses, we serially applied selective neurochemicals in the exact moment of an experimental physical trauma delivered through a calibrated device impacting the mid-thoracic cord of an entire CNS preparation of neonatal rats. Continuous lumbar root recordings monitored baseline DC-levels and reflex responses elicited by trains of electric pulses applied to sacrocaudal afferents. In uninjured preparations, each agent showed distinct effects on baseline polarization, modulation of synaptic responses, and appearance of bursting activity. Interestingly, neurochemicals acting on glutamatergic-, adenosinergic-, glycinergic- or GABAergic receptors, did not affect the monitored outcome when each parameter was normalized against pre-injury values. Conversely, the selective TRPV4 antagonist, RN1734, unlike the TRPA1 antagonist, AP18, reduced peak of injury potentials and speeded up full recovery of reflex responses within 1 min from trauma. Similarly, blockage of gap junctions quickly, yet partially, restored motor reflexes, while antagonism of GABAA receptors restored full reflexes, though slightly later. The current study indicates that both mechanosensitive TRPV4 receptors and GABAergic transmission reduce the immediate pathological consequences of a trauma when applied at the moment of impact, envisaging a clinical translation for preventing accidental spinal lesions during the most delicate spinal surgeries.