title: Respiratory abnormalities resulting from midcervical spinal cord injury and their reversal by serotonin 1A agonists in conscious rats.
abstract: 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.
authors.affiliation: Department of Neurosurgery, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Howard
authors.initials: H
authors.lastname: Choi
authors.forename: Wei-Lee
authors.initials: WL
authors.lastname: Liao
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Newton
authors.forename: Renna C
authors.initials: RC
authors.lastname: Onario
authors.forename: Allyson M
authors.initials: AM
authors.lastname: King
authors.forename: Federico C
authors.initials: FC
authors.lastname: Desilets
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Woodard
authors.forename: Marc E
authors.initials: ME
authors.lastname: Eichler
authors.forename: Walter R
authors.initials: WR
authors.lastname: Frontera
authors.forename: Sunil
authors.initials: S
authors.lastname: Sabharwal
authors.forename: Yang D
authors.initials: YD
authors.lastname: Teng
mesh_terms: 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
chemical_list: D017366:Serotonin Receptor Agonists; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D002065:Buspirone