Systemic Administration of Rolipram Increases Medullary and Spinal cAMP and Activates a Latent Respiratory Motor Pathway After High Cervical Spinal Cord Injury

Abstract

Background/Objective: High cervical spinal cord hemisection interrupts descending respiratory drive from the rostral ventral respiratory group in the medulla to the ipsilateral phrenic motoneurons. Hemisection results in the paralysis of the ipsilateral hemidiaphragm. Chronic administration of rolipram, a specific phosphodiesterase-IV inhibitor, promotes synaptic plasticity and restores phrenic nerve function after a high cervical spinal cord lesion. Here, we test the hypothesis that an acute administration of rolipram will increase spinal and medullary levels of 3 0 ,5 0 -cyclic adenosine monophosphate (cAMP) and induce phrenic nerve recovery after cervical (C2) spinal cord hemisection. Methods: Male Sprague-Dawley rats were subjected to left C2 hemisection surgery 1 week before experimentation. Bilateral phrenic nerve activity was recorded in anesthetized, vagotomized, and pancuronium paralyzed rats, and rolipram was intravenously applied (2 mg/kg). Results: Intravenous administration of rolipram increased phrenic nerve output in uninjured control and left C2 spinal cord-hemisected rats. In addition, rolipram restored respiratory-related activity to the left phrenic nerve made quiescent by the hemisection. In both uninjured and hemisected rats, rolipram significantly enhanced phrenic inspiratory burst amplitude and burst area compared with predrug values. Also, rolipram concomitantly increased spinal and medullary cAMP. Conclusions: These results suggest that a phosphodiesterase inhibitor capable of elevating cAMP levels can enhance phrenic nerve output and restore respiratory-related phrenic nerve function after high cervical spinal cord injury. Thus, targeting the cAMP signaling cascade can be a useful therapeutic approach in promoting synaptic efficacy and respiratory recovery after cervical spinal cord injury.

Spinal 5-HT7 receptors and protein kinase A constrain intermittent hypoxia-induced phrenic long-term facilitation

“…Conversely, A 2A or 5-HT 7 receptor agonists may be useful to restore respiratory and non-respiratory (somatic) motor function following spinal injury (Golder et al 2008) or motor neuron disease by eliciting spinal plasticity. Factors that activate cAMP-PKA may trigger functional recovery (Kajana et al 2008; 2009). …”

The crossed phrenic phenomenon and recovery of function following spinal cord injury

“…Rather, theophylline causes a specific change in the respiratory circuitry that allows for a persistent expression of the CPP after the animal is weaned from the drug. The underlying mechanisms for this drug-induced plasticity in the respiratory circuitry have been the subject of recent investigations in the Goshgarian laboratory (Kajana and Goshgarian, 2008a, 2008b, 2009). …”

Blockade of phosphodiesterase 4 reverses morphine-induced ventilatory disturbance without loss of analgesia

“…It has been demonstrated that rolipram (2.0 mg/kg, i.v.) activated the phrenic nerve discharge by increasing the cAMP content in the medulla oblongata and cervical spinal cord after high cervical spinal cord injury in rats [16]. Moreover, rolipram (0.1-5 μM) recovered depression of the respiratory-related rhythm induced by opioids in vitro [32,33].…”