Spinal delivery of ampakine CX717 impacts phrenic motor output in adult rats

Abstract

Throughout the brainstem and spinal cord, α‐amino‐3‐hydroxy‐5‐methy‐4‐isoxazole propionate receptors (AMPARs) play an essential role in respiratory motor control. Ampakines are positive allosteric modulators of AMPARs which can enhance glutamatergic currents. Our laboratory recently reported that intravenous delivery of low‐dose ampakine CX717 can evoke increases in phrenic nerve inspiratory burst amplitude. However, this increased phrenic bursting could reflect an impact of the ampakine on pre‐motor brainstem circuits or a direct action on spinal neurons. In ongoing experiments, we are testing the hypothesis that delivery of ampakines to the cervical spinal cord is sufficient to evoke a sustained increase in phrenic nerve inspiratory burst amplitude. Phrenic motor output was measured in urethane‐anesthetized, mechanically ventilated, vagotomized adult male Sprague‐Dawley rats. Along with amplitude of inspiratory phrenic motor output, arterial blood pressure and end‐tidal CO2 were recorded. For intrathecal delivery of ampakine CX717 (15μl, 500μM, dissolved in 10% HPCD), the spinal cord was exposed via a dorsal approach followed by laminectomy and durotomy to enable drug administration over the mid‐cervical spinal cord. At least 15 min of stable phrenic burst amplitude was recorded as baseline after which intrathecal CX717 was applied. The initial results (n=3 sham, n=3 CX717) indicate that spinally directed CX717 causes a gradual and sustained increase in phrenic inspiratory burst amplitude lasting up to 60 min. Conversely, intrathecal delivery of 10% HPCD (sham) had no consistent impact on phrenic burst amplitude. These preliminary results are consistent with the hypothesis that allosteric modulation of spinal AMPA receptors can increase phrenic motor output. Phrenic motor neurons express AMPA receptors and are a likely candidate for the site of CX717 action.Support or Funding Information5 R01 HL139708 02 (DDF)