Delta-aminovaleric acid antagonizes the pharmacological actions of baclofen in the central nervous system.
The action of delta-aminovaleric acid (AVA) on the muscle relaxant properties of baclofen, a GABAB receptor agonist, was investigated in two experimental models: (1) the pathologically increased muscle tone of the gastrocnemius muscle in spastic mutant Han-Wistar rats and (2) the Hoffmann (H)-reflex recorded from plantar foot muscles after electrical stimulation of the tibial nerve in barbiturate (60 mg/kg) anaesthetized rats. In both paradigms coadministration of AVA (500 nmol/5 microliter) antagonized the muscle relaxant action of intrathecally applied baclofen (0.2-2 nmol), but failed to affect the muscle relaxant effects of intrathecally injected muscimol (2-20 nmol). In contrast, coadministration of bicuculline (1 nmol) did block the muscle relaxant action of muscimol, but failed to alter the effects of baclofen. When administered alone, bicuculline (1 nmol), or AVA (500 nmol-2 mumol) were without intrinsic action in both paradigms. In an additional series of experiments we investigated the action of AVA on a supraspinal effect of baclofen. Coadministration of AVA (12.5 nmol/0.5 microliter) in the ventromedial thalamic nucleus antagonized the catalepsy induced by baclofen (ED50 10 pmol/0.5 microliter), as indicated by an increase in ED50 of baclofen by a factor of 4.835 and a parallel shift of the probit-log dosage regression line to the right. The parallel shift seems to be consistent with a competitive mechanism of action of AVA. This study presents evidence that AVA antagonizes central pharmacological actions of baclofen at both spinal and supraspinal sites without affecting the actions of a GABAA agonist, muscimol.
Schwarz
M
M
Max-Planck-Institute for Experimental Medicine, Göttingen, Federal Republic of Germany.
Klockgether
T
T
Wüllner
U
U
Turski
L
L
Sontag
K H
KH
D000818:Animals; D001418:Baclofen / Q000494:pharmacology*; D001640:Bicuculline / Q000494:pharmacology; D004336:Drug Antagonism; D004558:Electric Stimulation; D005260:Female; D006181:H-Reflex / Q000187:drug effects*; D008297:Male; D009118:Muscimol / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects*; D009128:Muscle Spasticity / Q000139:chemically induced; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D012023:Reflex, Monosynaptic / Q000187:drug effects*; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology; D014631:Valerates / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D014631:Valerates; D009118:Muscimol; D005680:gamma-Aminobutyric Acid; D001418:Baclofen; D001640:Bicuculline