RGD Reference Report - Potent suppression of stretch reflex activity after systemic or spinal delivery of tizanidine in rats with spinal ischemia-induced chronic spastic paraplegia. - Rat Genome Database

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Potent suppression of stretch reflex activity after systemic or spinal delivery of tizanidine in rats with spinal ischemia-induced chronic spastic paraplegia.

Authors: Fuchigami, T  Kakinohana, O  Hefferan, MP  Lukacova, N  Marsala, S  Platoshyn, O  Sugahara, K  Yaksh, TL  Marsala, M 
Citation: Fuchigami T, etal., Neuroscience. 2011 Oct 27;194:160-9. Epub 2011 Aug 16.
RGD ID: 6480106
Pubmed: PMID:21871540   (View Abstract at PubMed)
PMCID: PMC3192017   (View Article at PubMed Central)
DOI: DOI:10.1016/j.neuroscience.2011.08.022   (Journal Full-text)

BACKGROUND: Spasticity and rigidity are serious complications associated with spinal traumatic or ischemic injury. Clinical studies show that tizanidine (Tiz) is an effective antispasticity agent; however, the mechanism of this effect is still not clear. Tiz binds not only to alpha2-adrenoreceptors (AR) but also to imidazoline (I) receptors. Both receptor systems (AR+I) are present in the spinal cord interneurons and alpha-motoneurons. The aim of the present study was to evaluate the therapeutic potency of systematically or spinally (intrathecally [IT]) delivered Tiz on stretch reflex activity (SRA) in animals with ischemic spasticity, and to delineate supraspinal or spinal sites of Tiz action. EXPERIMENTAL PROCEDURES: Animals were exposed to 10 min of spinal ischemia to induce an increase in SRA. Increase in SRA was identified by simultaneous increase in recorded electromyography (EMG) activity and ankle resistance measured during computer-controlled ankle dorsiflexion (40 degrees /3 s) in fully awake animals. Animals with increased SRA were divided into several experimental subgroups and treated as follows: (i) Tiz administered systemically at the dose of 1 mg kg(-1), or IT at 10 mug or 50 mug delivered as a single dose; (ii) treatment with systemic Tiz was followed by the systemic injection of vehicle, or by nonselective AR antagonist without affinity for I receptors; yohimbine (Yoh), alpha2A AR antagonist; BRL44408 (BRL), alpha2B AR antagonist; ARC239 (ARC), nonselective AR and I(1) receptor antagonist; efaroxan (Efa), or nonselective AR and I(2) receptor antagonist; idazoxan (Ida); (iii) treatment with IT Tiz was followed by the IT injection of selective alpha2A AR antagonist; atipamezole (Ati). In a separate group of spastic animals the effect of systemic Tiz treatment (1 mg/kg) or isoflurane anesthesia on H-reflex activity was also studied. RESULTS: Systemic and/or IT treatment with Tiz significantly suppressed SRA. This Tiz-mediated anti-SRA effect was reversed by BRL (5 mg kg(-1)), Efa (1 mg kg(-1)), and Ida (1 mg kg(-1)). No reversal was seen after Yoh (3 mg kg(-1)) or ARC (5 mg kg(-1)) treatment. Anti-SRA induced by IT Tiz (50 mug) was reversed by IT injection of Ati (50 mug). Significant suppression of H-reflex was measured after systemic Tiz treatment (1 mg/kg) or isoflurane (2%) anesthesia, respectively. Immunofluorescence staining of spinal cord sections taken from animals with spasticity showed upregulation of alpha2A receptor in activated astrocytes. CONCLUSIONS: These data suggest that alpha2A AR and I receptors, but not alpha2B AR, primarily mediate the Tiz-induced antispasticity effect. This effect involves spinal and potentially supraspinal sites and likely targets alpha2A receptor present on spinal neurons, primary afferents, and activated astrocytes. Further studies using highly selective antagonists are needed to elucidate the involvement of specific subtypes of the AR and I receptors in the antispasticity effect seen after Tiz treatment.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
ADRA2AHumanMuscle Spasticity  ISOAdra2a (Rattus norvegicus) RGD 
Adra2aRatMuscle Spasticity  IEP  RGD 
Adra2aMouseMuscle Spasticity  ISOAdra2a (Rattus norvegicus) RGD 

Objects Annotated

Genes (Rattus norvegicus)
Adra2a  (adrenoceptor alpha 2A)

Genes (Mus musculus)
Adra2a  (adrenergic receptor, alpha 2a)

Genes (Homo sapiens)
ADRA2A  (adrenoceptor alpha 2A)


Additional Information