Pharmacological disinhibition enhances paced breathing following complete spinal cord injury in rats

• Published in: Respiratory physiology & neurobiology 2020-11, Vol.282, p.103514-103514, Article 103514
• Main Authors: Bezdudnaya, T., Lane, M.A., Marchenko, V.
• Format: Article
• Language: English
• Subjects: Animals; Breathing; Cervical Cord - injuries; Combined Modality Therapy; Complete spinal cord injury; Diaphragm - physiology; Disease Models, Animal; Disinhibition; Epidural Space; Epidural stimulation; GABA Antagonists - administration & dosage; GABA Antagonists - pharmacology; Glycine Agents - administration & dosage; Glycine Agents - pharmacology; Injections, Spinal; Phrenic Nerve - physiology; Rat; Rats; Rats, Sprague-Dawley; Respiration; Respiration Disorders - drug therapy; Respiration Disorders - etiology; Respiration Disorders - therapy; Spinal Cord Injuries - complications; Spinal Cord Stimulation
• ISSN: 1569-9048; 1878-1519
• DOI: 10.1016/j.resp.2020.103514

•Epidural stimulation and intrathecal drug delivery were performed at C4 cervical spinal segment post- complete C1 spinal transection.•Low doses of GABAzine and strychnine were intrathecally delivered to disinhibit phrenic spinal circuits.•Phrenic nerve responses, diaphragm electromyography amplitudes, and tidal volume were assessed during experiments.•Combination of high-frequency EDS and pharmacological disinhibition of phrenic spinal circuits significantly improved paced breathing. Respiratory dysfunction is one of the most devastating and life-threatening deficits that occurs following cervical spinal cord injury (SCI). Assisted breathing with mechanical ventilators is a necessary part of care for many cervical injured individuals, but it is also associated with increased risk of secondary complications such as infection, muscle atrophy and maladaptive plasticity. Pre-clinical studies with epidural stimulation (EDS) have identified it as an alternative/additional method to support adequate lung ventilation without mechanical assistance. The full potential of EDS, however, may be limited by spinal inhibitory mechanisms within the injured spinal cord. The goal of the present work is to assess the potential improvement for EDS in combination with pharmacological disinhibition of spinal circuits following complete high cervical SCI. All experiments were performed in decerebrate, unanesthetized, non-paralyzed (n = 13) and paralyzed (n = 8) adult Sprague-Dawley rats 6 h following a complete C1 transection. The combination of high-frequency EDS (HF-EDS) at the C4 spinal segment with intrathecal delivery of GABA and glycine receptors antagonists (GABAzine and strychnine, respectively) resulted in significantly increased phrenic motor output, tidal volume and amplitude of diaphragm electrical activity compared to HF-EDS alone. Thus, it appears that spinal fast inhibitory mechanisms limit phrenic motor output and present a new neuropharmacological target to improve paced breathing in individuals with cervical SCI.