title: Development of GABA-sensitive spasticity and rigidity in rats after transient spinal cord ischemia: a qualitative and quantitative electrophysiological and histopathological study.
abstract: Transient spinal cord ischemia may lead to a progressive degeneration of spinal interneurons and subsequently to increased hind limb motor tone. In the present work we sought to characterize the rigidity and spasticity components of this altered motor function by: i) tonic electromyographic activity measured in gastrocnemius muscle before and after ischemia, ii) measurement of muscle resistance during the period of ankle flexion and corresponding changes in electromyographic activity, iii) changes in Hoffmann reflex, and, iv) motor evoked potentials. In addition the effect of intrathecal treatment with baclofen (GABAB receptor agonist; 1 microg), nipecotic acid (GABA uptake inhibitor; 300 microg) and dorsal L2-L5 rhizotomy on spasticity and rigidity was studied. Finally, the changes in spinal choline acetyltransferase (ChAT) and vesicular glutamate transporter 2 and 1 (VGLUT2 and VGLUT1) expression were characterized using immunofluorescence and confocal microscopy. At 3-7 days after ischemia an increase in tonic electromyographic activity with a variable degree of rigidity was seen. In animals with modest rigidity a velocity-dependent increase in muscle resistance and corresponding appearance in electromyographic activity (consistent with the presence of spasticity) was measured during ankle rotation (4-612 degrees /s rotation). Measurement of the H-reflex revealed a significant increase in Hmax/Mmax ratio and a significant loss of rate-dependent inhibition. In the same animals a potent increase in motor evoked potential amplitudes was measured and this change correlated positively with the increased H-reflex responses. Spasticity and rigidity were consistently present for a minimum of 3 months after ischemia. Intrathecal treatment with baclofen (GABA B receptor agonist) and nipecotic acid (GABA uptake inhibitor) provided a significant suppression of spasticity, rigidity, H-reflex or motor evoked potentials. Dorsal L2-L5 rhizotomy significantly decreased muscle resistance but had no effect on increased amplitudes of motor evoked potentials. Confocal analysis of spinal cord sections at 8 weeks-12 months after ischemia revealed a continuing presence of ChAT positive alpha-motoneurons, Ia afferents and VGLUT2 and VGLUT1-positive terminals but a selective loss of small presumably inhibitory interneurons between laminae V-VII. These data demonstrate that brief transient spinal cord ischemia in rat leads to a consistent development of spasticity and rigidity. The lack of significant suppressive effect of dorsal L2-L5 rhizotomy on motor evoked potentials response indicates that descending motor input into alpha-motoneurons is independent on Ia afferent couplings and can independently contribute to increased alpha-motoneuronal excitability. The pharmacology of this effect emphasizes the potent role of GABAergic type B receptors in regulating both the spasticity and rigidity.
authors.affiliation: Anesthesiology Research Laboratory-0818, University of California, San Diego 9500 Gilman Drive, San Diego, CA 92093-0818, USA.
authors.forename: O
authors.initials: O
authors.lastname: Kakinohana
authors.forename: M P
authors.initials: MP
authors.lastname: Hefferan
authors.forename: S
authors.initials: S
authors.lastname: Nakamura
authors.forename: M
authors.initials: M
authors.lastname: Kakinohana
authors.forename: J
authors.initials: J
authors.lastname: Galik
authors.forename: Z
authors.initials: Z
authors.lastname: Tomori
authors.forename: J
authors.initials: J
authors.lastname: Marsala
authors.forename: T L
authors.initials: TL
authors.lastname: Yaksh
authors.forename: M
authors.initials: M
authors.lastname: Marsala
mesh_terms: D000123:Acetyltransferases / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001418:Baclofen / Q000008:administration & dosage; D004307:Dose-Response Relationship, Radiation; D016503:Drug Delivery Systems / Q000379:methods; D004558:Electric Stimulation; D004576:Electromyography / Q000379:methods; D019054:Evoked Potentials, Motor / Q000502:physiology*; D018755:GABA Agonists / Q000008:administration & dosage; D015870:Gene Expression / Q000187:drug effects; D006181:H-Reflex / Q000187:drug effects / Q000502:physiology*; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D009127:Muscle Rigidity / Q000188:drug therapy / Q000209:etiology*; D009128:Muscle Spasticity / Q000188:drug therapy / Q000209:etiology*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000503:physiopathology; D009460:Neurologic Examination / Q000379:methods; D009557:Nipecotic Acids / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D019051:Rhizotomy / Q000379:methods; D020760:Spinal Cord Ischemia / Q000150:complications*; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism; D050599:Vesicular Glutamate Transport Protein 2 / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D018755:GABA Agonists; D009557:Nipecotic Acids; D050598:Vesicular Glutamate Transport Protein 1; D050599:Vesicular Glutamate Transport Protein 2; C030278:nipecotic acid; D005680:gamma-Aminobutyric Acid; D000123:Acetyltransferases; D001418:Baclofen