title: Polysynaptic excitatory postsynaptic potentials that trigger spasms after spinal cord injury in rats are inhibited by 5-HT1B and 5-HT1F receptors.
abstract: Sensory afferent transmission and associated spinal reflexes are normally inhibited by serotonin (5-HT) derived from the brain stem. Spinal cord injury (SCI) that eliminates this 5-HT innervation leads to a disinhibition of sensory transmission and a consequent emergence of unusually long polysynaptic excitatory postsynaptic potentials (EPSPs) in motoneurons. These EPSPs play a critical role in triggering long polysynaptic reflexes (LPRs) that initiate muscles spasms. In the present study we examined which 5-HT receptors modulate the EPSPs and whether these receptors adapt to a loss of 5-HT after chronic spinal transection in rats. The EPSPs and associated LPRs recorded in vitro in spinal cords from chronic spinal rats were consistently inhibited by 5-HT(1B) or 5-HT(1F) receptor agonists, including zolmitriptan (5-HT(1B/1D/1F)) and LY344864 (5-HT(1F)), with a sigmoidal dose-response relation, from which we computed the 50% inhibition (EC(50)) and potency (-log EC(50)). The potencies of 5-HT receptor agonists were highly correlated with their binding affinity to 5-HT(1B) and 5-HT(1F) receptors, and not to other 5-HT receptors. Zolmitriptan also inhibited the LPRs and general muscle spasms recorded in vivo in the awake chronic spinal rat. The 5-HT(1B) receptor antagonists SB216641 and GR127935 and the inverse agonist SB224289 reduced the inhibition of LPRs by 5-HT(1B) agonists (zolmitriptan). However, when applied alone, SB224289, SB216641, and GR127935 had no effect on the LPRs, indicating that 5-HT(1B) receptors do not adapt to chronic injury, remaining silent, without constitutive activity. The reduction in EPSPs with zolmitriptan unmasked a large glycine-mediated inhibitory postsynaptic current (IPSC) after SCI. This IPSC and associated chloride current reversed at -73 mV, slightly below the resting membrane potential. Zolmitriptan did not change motoneuron properties. Our results demonstrate that 5-HT(1B/1F) agonists, such as zolmitriptan, can restore inhibition of sensory transmission after SCI without affecting general motoneuron function and thus may serve as a novel class of antispastic drugs.
authors.affiliation: Centre for Neuroscience, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Katherine C
authors.initials: KC
authors.lastname: Murray
authors.forename: Marilee J
authors.initials: MJ
authors.lastname: Stephens
authors.forename: Michelle
authors.initials: M
authors.lastname: Rank
authors.forename: Jessica
authors.initials: J
authors.lastname: D'Amico
authors.forename: Monica A
authors.initials: MA
authors.lastname: Gorassini
authors.forename: David J
authors.initials: DJ
authors.lastname: Bennett
mesh_terms: D000818:Animals; D004558:Electric Stimulation / Q000379:methods; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D005260:Female; D009433:Neural Inhibition / Q000502:physiology*; D051381:Rats; D044302:Receptor, Serotonin, 5-HT1B / Q000502:physiology*; D011985:Receptors, Serotonin / Q000502:physiology*; D012447:Sacrum; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology / Q000627:therapeutic use; D013035:Spasm / Q000503:physiopathology* / Q000517:prevention & control; D013119:Spinal Cord Injuries / Q000503:physiopathology*; D000096642:Receptor, Serotonin, 5-HT1F
chemical_list: D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin; D058825:Serotonin 5-HT1 Receptor Agonists; D000096642:Receptor, Serotonin, 5-HT1F