title: Potent suppression of stretch reflex activity after systemic or spinal delivery of tizanidine in rats with spinal ischemia-induced chronic spastic paraplegia.
abstract: 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 α2-adrenoreceptors (AR) but also to imidazoline (I) receptors. Both receptor systems (AR+I) are present in the spinal cord interneurons and α-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.
  
  
  METHODS
  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°/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 μg or 50 μg 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), α2A AR antagonist; BRL44408 (BRL), α2B 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 α2A 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 μg) was reversed by IT injection of Ati (50 μg). 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 α2A receptor in activated astrocytes.
  
  
  CONCLUSIONS
  These data suggest that α2A AR and I receptors, but not α2B AR, primarily mediate the Tiz-induced antispasticity effect. This effect involves spinal and potentially supraspinal sites and likely targets α2A 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.
authors.affiliation: Department of Anesthesiology, University of the Ryukyus, Okinawa, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Fuchigami
authors.forename: O
authors.initials: O
authors.lastname: Kakinohana
authors.forename: M P
authors.initials: MP
authors.lastname: Hefferan
authors.forename: N
authors.initials: N
authors.lastname: Lukacova
authors.forename: S
authors.initials: S
authors.lastname: Marsala
authors.forename: O
authors.initials: O
authors.lastname: Platoshyn
authors.forename: K
authors.initials: K
authors.lastname: Sugahara
authors.forename: T L
authors.initials: TL
authors.lastname: Yaksh
authors.forename: M
authors.initials: M
authors.lastname: Marsala
mesh_terms: D000818:Animals; D002908:Chronic Disease; D003000:Clonidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D008297:Male; D009125:Muscle Relaxants, Central / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D010264:Paraplegia / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012026:Reflex, Stretch / Q000187:drug effects* / Q000502:physiology; D020760:Spinal Cord Ischemia / Q000150:complications / Q000503:physiopathology*
chemical_list: D009125:Muscle Relaxants, Central; C023754:tizanidine; D003000:Clonidine