Unilateral cervical spinal cord hemisection (i.e., C2Hx) usually interrupts the bulbospinal respiratory pathways and results in respiratory impairment. It has been demonstrated that activation of the serotonin system can promote locomotor recovery after spinal cord injury. The present study was designed to investigate whether serotonergic activation can improve respiratory function during the chronic injury state. Bilateral diaphragm electromyogram and tidal volume were measured in anesthetized and spontaneously breathing adult rats at 8 wk post-C2Hx or C2 laminectomy. A bolus intravenous injection of a serotonin precursor [5-hydroxytryptophan (5-HTP), 10 mg/kg], a serotonin reuptake inhibitor (fluoxetine, 10 mg/kg), or a potent agonist for serotonin 2A receptors (TCB-2, 0.05 mg/kg) was used to activate the serotonergic system. Present results demonstrated that 5-HTP and TCB-2, but not fluoxetine, significantly increased the inspiratory activity of the diaphragm electromyogram ipsilateral to the lesion for at least 30 min in C2Hx animals, but not in animals that received sham surgery. However, the tidal volume was not increased after administration of 5-HTP or TCB-2, indicating that the enhancement of ipsilateral diaphragm activity is not associated with improvement of the tidal volume. These results suggest that exogenous activation of the serotonergic system can specifically enhance the ipsilateral diaphragmatic motor outputs, but this approach may not be sufficient to improve respiratory functional recovery following chronic cervical spinal injury.

Unilateral high cervical spinal hemisection (i.e., C2Hx) interrupts the respiratory bulbospinal pathway and results in paralysis of the hemidiaphragm. The ipsilateral diaphragmatic activity can partially recover over weeks to months; however, its contribution to the tidal volume generation is less than 20%. Accordingly, we hypothesized that the contralateral diaphragm exerts a compensatory function to maintain the essential ventilation following C2Hx. The cardiorespiratory pattern and bilateral diaphragm electromyogram (EMG) signals were measured in urethane-anesthetized and spontaneously breathing adult rats at 1 day, and 2 or 8 weeks post-C2Hx or C2 laminectomy. The functional contribution of the diaphragm was assessed by measuring immediate changes of the tidal volume following phrenic nerve section. At 1 day post-injury, the tidal volume was significantly reduced after contralateral phrenicotomy in C2Hx animals (54 ± 3% decline) compared with uninjured controls (20 ± 2% decline). Moreover, the arterial carbon dioxide partial pressure was significantly elevated in C2Hx animals (from 76 ± 8 mmHg to 117 ± 5 mmHg) but not in uninjured animals (from 51 ± 4 mmHg to 55 ± 3 mmHg). By 2 and 8 weeks post-injury, contralateral phrenicotomy still caused a greater reduction in the tidal volume in C2Hx than in uninjured animals, and the percentage decline of the tidal volume was similar to the response at 1 day post-injury. These data suggested that unilateral cervical spinal cord injury induced a persistent compensatory plasticity in the contralateral diaphragm, which plays a critical role in maintenance of essential ventilation.

Unilateral cervical spinal cord hemisection (i.e., C2Hx) usually interrupts the bulbospinal respiratory pathways and results in attenuation of the phrenic motor output. It has been shown that activation of serotonergic system can induce partial recovery of phrenic activity after acute C2Hx. The purpose of present study was to examine whether manipulation of the serotonin system can still improve respiratory function during the chronic injury phase. Bilateral diaphragm electromyogram (EMG) and tidal volume were measured in anesthetized and spontaneously breathing adult rats at 8 weeks post‐C2Hx or C2 laminectomy. A bolus intravenous injection of a serotonin precursor (5‐Hydroxytryptophan; 5‐HTP, 10 mg/kg) or a potent agonist for serotonin 2A receptor agonist (TCB‐2, 0.05 mg/kg) was used to activate serotonergic system. Current results demonstrated that both 5‐HTP and TCB‐2 significantly induced a persistent increase in activity of the diaphragm EMG ipsilateral to the lesion but not contralateral diaphragm in C2Hx animals or bilateral diaphragm in uninjured animals. However, the tidal volume was not changed after administration of 5‐HTP or TCB‐2, indicating the enhancement of ipsilateral diaphragm activity is not associated with improvement of the tidal volume. These results suggest that activation of the serotonergic system can specifically increase the ipsilateral diaphragmatic motor output, but it is not sufficient to improve respiratory functional recovery following chronic cervical spinal injury.