Editors' ChoiceNeuroscience

Preventing Spasms After Spinal Cord Injury

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Science Signaling  22 Jun 2010:
Vol. 3, Issue 127, pp. ec187
DOI: 10.1126/scisignal.3127ec187

Counterintuitively, muscles can exhibit spastic contractions following a severe spinal cord injury. After an initial period of unexcitability due to the loss of brainstem-derived serotonin (5 hydroxytryptamine, 5-HT) signaling, later the motoneurons recover excitability (measured by persistent inward currents and long-lasting reflexes) despite ongoing absence of brainstem 5-HT signaling. Because the motoneurons still lack the normal modulatory inputs from the brain, the persistent inward currents fail to terminate properly, producing spasms. Murray et al. investigated the mechanism underlying these persistent inward currents and their role in recovery of motor function and spasticity. Serotonin receptors of the 5-HT2c type are produced from transcripts that undergo RNA editing, and the resultant proteins exhibit varying degrees of constitutive activity. Murray et al. first investigated the effect of spinal cord injury in rats and found that injection of a 5-HT2c antagonist failed to prevent tail muscle spasms, but injection of an inverse agonist (that blocks constitutive receptor activity) did. Additional pharmacological interventions that should either enhance or block ligand activation of the receptors failed to alter long-lasting reflexes of spinal cords isolated from regions below the resected area, whereas inverse agonists blocked the long-lasting reflexes. Intracellular recordings from motoneurons after spinal cord injury showed a persistent inward current that was blocked by the 5-HT2 inverse agonists. Following chronic spinal cord injury, the isoform (protein and edited mRNA) with the highest amount of constitutive activity increased in abundance in regions of the spinal cord below the injury. Injection of the inverse agonist into rats that had recovered some locomotor activity after spinal cord injury showed hindlimb support and locomotor ability. Treatment of human spinal cord injury patients with a 5-HT2c inverse agonist reduced spasms and eliminated the long-lasting reflexes. Unfortunately, this drug is not well tolerated due to side effects, but this work suggests that the development of new drugs that target the constitutive activity of 5-HT2c receptors would be valuable for treating spasticity in chronic spinal cord injury patients.

K. C. Murray, A. Nakae, M. J. Stephens, M. Rank, J. D’Amico, P. J. Harvey, X. Li, R. L. W. Harris, E. W. Ballou, R. Anelli, C. J. Heckman, T. Mashimo, R. Vavrek, L. Sanelli, M. A. Gorassini, D. J. Bennett, K. Fouad, Recovery of motoneuron and locomotor function after spinal cord injury depends on constitutive activity in 5-HT2c receptors. Nat. Med. 16, 694–700 (2010). [PubMed]