Effects of baclofen on spinal reflexes and persistent inward currents in motoneurons of chronic spinal rats with spasticity.
In the months after spinal cord injury, motoneurons develop large voltage-dependent persistent inward currents (PICs) that cause sustained reflexes and associated muscle spasms. These muscle spasms are triggered by any excitatory postsynaptic potential (EPSP) that is long enough to activate the PICs, which take > 100 ms to activate. The PICs are composed of a persistent sodium current (Na PIC) and a persistent calcium current (Ca PIC). Considering that Ca PICs have been shown in other neurons to be inhibited by baclofen, we tested whether part of the antispastic action of baclofen was to reduce the motoneuron PICs as opposed to EPSPs. The whole sacrocaudal spinal cord from acute spinal rats and spastic chronic spinal rats (with sacral spinal transection 2 mo previously) was studied in vitro. Ventral root reflexes were recorded in response to dorsal root stimulation. Intracellular recordings were made from motoneurons, and slow voltage ramps were used to measure PICs. Chronic spinal rats exhibited large monosynaptic and long-lasting polysynaptic ventral root reflexes, and motoneurons had associated large EPSPs and PICs. Baclofen inhibited these reflexes at very low doses with a 50% inhibition (EC50) of the mono- and polysynaptic reflexes at 0.26 +/- 0.07 and 0.25 +/- 0.09 (SD) microM, respectively. Baclofen inhibited the monosynaptic reflex in acute spinal rats at even lower doses (EC50 = 0.18 +/- 0.02 microM). In chronic (and acute) spinal rats, all reflexes and EPSPs were eliminated with 1 microM baclofen with little change in motoneuron properties (PICs, input resistance, etc), suggesting that baclofen's antispastic action is presynaptic to the motoneuron. Unexpectedly, in chronic spinal rats higher doses of baclofen (20-30 microM) significantly increased the total motoneuron PIC by 31.6 +/- 12.4%. However, the Ca PIC component (measured in TTX to block the Na PIC) was significantly reduced by baclofen. Thus baclofen increased the Na PIC and decreased the Ca PIC with a net increase in total PIC. By contrast, when a PIC was induced by 5-HT (10-30 microM) in motoneurons of acute spinal rats, baclofen (20-30 microM) significantly decreased the PIC by 38.8 +/- 25.8%, primarily due to a reduction in the Ca PIC (measured in TTX), which dominated the total PIC in these acute spinal neurons. In summary, baclofen does not exert its antispastic action postsynaptically at clinically achievable doses (< 1 microM), and at higher doses (10-30 microM), baclofen unexpectedly increases motoneuron excitability (Na PIC) in chronic spinal rats.
Centre for Neuroscience, 513 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
Y
Y
Li
X
X
Li
P J
PJ
Harvey
D J
DJ
Bennett
D000208:Acute Disease; D000818:Animals; D001418:Baclofen / Q000494:pharmacology*; D002908:Chronic Disease; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005260:Female; D018755:GABA Agonists / Q000494:pharmacology; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology*; D009128:Muscle Spasticity / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012018:Reflex / Q000502:physiology*; D013116:Spinal Cord / Q000502:physiology* / Q000503:physiopathology; D013119:Spinal Cord Injuries / Q000503:physiopathology*; D013569:Synapses / Q000187:drug effects / Q000502:physiology*
D018755:GABA Agonists; D001418:Baclofen