Respiratory abnormalities resulting from midcervical spinal cord injury and their reversal by serotonin 1A agonists in conscious rats.
Respiratory dysfunction after cervical spinal cord injury (SCI) has not been examined experimentally using conscious animals, although clinical SCI most frequently occurs in midcervical segments. Here, we report a C5 hemicontusion SCI model in rats with abnormalities that emulate human post-SCI pathophysiology, including spontaneous recovery processes. Post-C5 SCI rats demonstrated deficits in minute ventilation (Ve) responses to a 7% CO2 challenge that correlated significantly with lesion severities (no injury or 12.5, 25, or 50 mm x 10 g weight drop; New York University impactor; p < 0.001) and ipsilateral motor neuron loss (p = 0.016). Importantly, C5 SCI resulted in at least 4 weeks of respiratory abnormalities that ultimately recovered afterward. Because serotonin is involved in respiration-related neuroplasticity, we investigated the impact of activating 5-HT1A receptors on post-C5 SCI respiratory dysfunction. Treatment with the 5-HT1A agonist 8-hydroxy-2-(di-n-propylmino)tetralin (8-OH DPAT) (250 microg/kg, i.p.) restored hypercapnic Ve at 2 and 4 weeks after injury (i.e., approximately 39.2% increase vs post-SCI baseline; p < or = 0.033). Improvements in hypercapnic Ve response after single administration of 8-OH DPAT were dose dependent and lasted for approximately 4 h(p < or = 0.038 and p < or = 0.024, respectively). Treatment with another 5-HT1A receptor agonist, buspirone (1.5 mg/kg, i.p.), replicated the results, whereas pretreatment with a 5-HT1A-specific antagonist, 4-iodo-N-[2-[4(methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-benzamide (3 mg/kg, i.p.) given 20 min before 8-OH DPAT negated the effect of 8-OH DPAT. These results imply a potential clinical use of 5-HT1A agonists for post-SCI respiratory disorders.
Choi
Howard
H
Department of Neurosurgery, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Liao
Wei-Lee
WL
Newton
Kimberly M
KM
Onario
Renna C
RC
King
Allyson M
AM
Desilets
Federico C
FC
Woodard
Eric J
EJ
Eichler
Marc E
ME
Frontera
Walter R
WR
Sabharwal
Sunil
S
Teng
Yang D
YD
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000627:therapeutic use*; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D002065:Buspirone / Q000627:therapeutic use*; D002574:Cervical Vertebrae; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D005552:Forelimb / Q000187:drug effects / Q000503:physiopathology; D007839:Functional Laterality; D006614:Hindlimb / Q000187:drug effects / Q000503:physiopathology; D010991:Plethysmography / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects; D012120:Respiration Disorders / Q000188:drug therapy* / Q000209:etiology; D017366:Serotonin Receptor Agonists / Q000627:therapeutic use*; D013119:Spinal Cord Injuries / Q000150:complications* / Q000473:pathology; D013997:Time Factors; D014851:Wakefulness
D017366:Serotonin Receptor Agonists; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D002065:Buspirone