Modulation of the release of norepinephrine by gamma-aminobutyric acid and morphine in the frontal cerebral cortex of the rat

Robert William Peoples, Purdue University

Abstract

Agents that enhance gamma-aminobutyric acid, or GABA, neurotransmission modulate certain effects of opioids, such as analgesia. Opioid analgesia is mediated in part by norepinephrine in the forebrain. In this study, the interactions between morphine and GABAergic agents on release of ($\sp3$H) norepinephrine from rat frontal cerebral cortical slices were examined. GABA, 5 $\times$ 10$\sp{-5}$-10$\sp{-3}$ M, enhanced potassium-stimulated ($\sp3$H) norepinephrine release and reversed the inhibitory effect of morphine in a noncompetitive manner. GABA did not enhance release of ($\sp3$H) norepinephrine stimulated by the calcium ionophore A23187. The effect of GABA was reduced by the GABA$\sb{\rm A}$ receptor antagonists bicuculline methiodide or picrotoxin, and by the selective inhibitor of GABA uptake SKF 89976A, but was blocked completely only when bicuculline methiodide and SKF 89976A were used in combination. The GABA$\sb{\rm A}$ agonist muscimol, 10$\sp{-4}$ M, mimicked the effect of GABA, but the GABA$\sb{\rm B}$ agonist ($\pm$)baclofen, 10$\sp{-4}$ M, did not affect the release of ($\sp3$H) norepinephrine in the absence or the presence of morphine. Thus GABA appears to produce this effect by stimulating GABA uptake and GABA$\sb{\rm A}$, but not GABA$\sb{\rm B}$, receptors. In contrast to the results that would be predicted for an event involving GABA$\sb{\rm A}$ receptors, however, the effect of GABA did not desensitize, and benzodiazepine agonists did not enhance the effect of GABA at any concentration tested between 10$\sp{-8}$ and 10$\sp{-4}$ M. Thus these receptors may constitute a subclass of GABA$\sb{\rm A}$ receptors. These results support a role of GABA uptake and GABA$\sb{\rm A}$ receptors in enhancing the release of norepinephrine and modulating its inhibition by opioids in the frontal cortex of the rat, which may account for the in vivo modulation of opioid analgesia by GABAergic agents.

Degree

Ph.D.

Advisors

Isom, Purdue University.

Subject Area

Pharmacology

COinS