GABA, glutamate and substance P-like immunoreactivity release: effects of novel GABAB antagonists.
1. The effects of various GABA receptor ligands on the electrically-evoked release of endogenous GABA, glutamate and substance P-like immunoreactivity from the dorsal horn of rat isolated spinal cord were examined. 2. Exogenous GABA (10-300 microM) significantly decreased the evoked, but not basal, release of endogenous glutamate in a concentration-dependent manner. The GABAA agonist, isoguvacine (1-100 microM), failed to decrease the release of glutamate although it did reduce the release of GABA. Baclofen (0.1-1000 microM), the GABAB agonist, reduced the release of GABA and glutamate in a stereospecific and concentration-dependent manner. 3. The actions of five GABAB antagonists on these release systems were compared. CGP36742, CGP52432, CGP55845A and CGP57250A significantly increased the evoked release of GABA and glutamate. They also reversed the effects of (-)-baclofen in a concentration-dependent manner. On the other hand, while CGP56999A had no effect on glutamate release, it was an effective antagonist of the baclofen-induced inhibition of GABA and substance P release. 4. These results suggest that GABAB receptors on nerve terminals within the dorsal horn spinal cord may be heterogeneous. However, this is based solely on the data obtained with CGP56999A which affected only GABA and substance P, but not glutamate, release.
Teoh
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Department of Pharmacology, School of Pharmacy, London, United Kingdom.
Malcangio
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Bowery
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D000818:Animals; D001418:Baclofen / Q000037:antagonists & inhibitors*; D001565:Benzoates / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism*; D007539:Isonicotinic Acids / Q000494:pharmacology; D008297:Male; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010721:Phosphinic Acids / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018080:Receptors, GABA-B / Q000187:drug effects / Q000378:metabolism; D013126:Spinal Nerve Roots / Q000187:drug effects / Q000378:metabolism; D013237:Stereoisomerism; D013373:Substance P / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism* / Q000502:physiology
D001565:Benzoates; D001596:Benzylamines; C102659:CGP 56999A; C102658:CGP 57250A; D018755:GABA Agonists; D018756:GABA Antagonists; D007539:Isonicotinic Acids; D009943:Organophosphorus Compounds; D010721:Phosphinic Acids; D011412:Propanolamines; D018080:Receptors, GABA-B; C083008:CGP 52432; C079148:(3-aminopropyl)(n-butyl)phosphinic acid; C085075:CGP 55845A; D013373:Substance P; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D001418:Baclofen; C015300:isoguvacine