Abstract
Spinal cord injury (SCI) results in not only the loss of voluntary muscle control, but also in the presence of involuntary movement or spasms. These spasms post-SCI involve hyperexcitability in the spinal motor system. Hyperactive motor commands post SCI result from enhanced excitatory postsynaptic potentials (EPSPs) and persistent inward currents in voltage-gated L-type calcium channels (LTCCs), which are reflected in evoked root reflexes with different timings. To further understand the contributions of these cellular mechanisms and to explore the involvement of LTCC subtypes in SCI-induced hyperexcitability, we measured root reflexes with ventral root recordings and motoneuron activities with intracellular recordings in an in vitro preparation using a mouse model of chronic SCI (cSCI). Specifically, we explored the effects of 1-(3-chlorophenethyl)-3-cyclopentylpyrimidine-2,4,6-(1H,3H,5H)-trione (CPT), a selective negative allosteric modulator of CaV1.3 LTCCs. Our results suggest a hyperexcitability in the spinal motor system in these SCI mice. Bath application of CPT displayed slow onset but dose-dependent inhibition of the root reflexes with the strongest effect on LLRs. However, the inhibitory effect of CPT is less potent in cSCI mice than in acute SCI (aSCI) mice, suggesting changes either in composition of CaV1.3 or other cellular mechanisms in cSCI mice. For intracellular recordings, the intrinsic plateau potentials, was observed in more motoneurons in cSCI mice than in aSCI mice. CPT inhibited the plateau potentials and reduced motoneuron firings evoked by intracellular current injection. These results suggest that the LLR is an important target and that CPT has potential in the therapy of SCI-induced muscle spasms.
Highlights
Spinal cord injury (SCI) is often associated with paralysis or the lack of volitional movement, but up to 80% of people with SCI develop involuntary muscle contractions, including spasms, which can severely impact function and safety (Maynard et al, 1990; Johnson et al, 1998; Noreau et al, 2000)
We first established a protocol for stable measurement of long lasting reflexes (LLRs) in both acute SCI (aSCI) and chronic SCI (cSCI) mice
After withdrawal of α-5-HT and citalopram at 10 min of the treatment, the stable and prolonged recordings were confirmed in three aSCI mice (Figure 1Bb), which could be the control to the effects of CPT as the drug had slow recovery especially at 200 μM
Summary
Spinal cord injury (SCI) is often associated with paralysis or the lack of volitional movement, but up to 80% of people with SCI develop involuntary muscle contractions, including spasms, which can severely impact function and safety (Maynard et al, 1990; Johnson et al, 1998; Noreau et al, 2000). CaV1.3 Channels in SCI Pathophysiology receptors to inhibit monosynaptic and polysynaptic spinal reflexes (Kita and Goodkin, 2000). Benzodiazepines, which target GABAA receptors, are prescribed to reduce spasms (Kita and Goodkin, 2000). The clinical applications of these medicines are limited by their considerable side effects, which include but are not limited to sedation, nausea, dizziness and even difficulty in breathing (Kita and Goodkin, 2000; Dario and Tomei, 2004). Benzodiazepines may have an additive effect when used in combination with baclofen (Kita and Goodkin, 2000). The search for better and more accurately targeted therapies with fewer side effects is necessary
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