Differential modulation of K+-evoked 3H-neurotransmitter release from human neocortex by gabapentin and pregabalin

Abstract

Anticonvulsant, analgesic, and anxiolytic effects have been observed both in preclinical and clinical studies with gabapentin (GBP) and pregabalin (PGB). These drugs appear to act by binding to the alpha(2)delta subunit of voltage-sensitive Ca(2+) channels (VSCC), resulting in the inhibition of neurotransmitter release. In this study, we examined the effects of GBP and PGB (mostly 100 microM, corresponding to relatively high preclinical/clinical plasma levels) on the release of neurotransmitters in human neocortical slices. These slices were prelabeled with (3)H-dopamine ((3)H-DA), (3)H-choline (to release (3)H-acetylcholine ((3)H-ACh)), (3)H-noradrenaline ((3)H-NA), and (3)H-serotonin ((3)H-5-HT), and stimulated twice in superfusion experiments by elevation of extracellular K(+) in the presence and absence of GBP and PGB. The alpha(2)delta ligands produced significant inhibitions of K(+)-evoked (3)H-ACh, (3)H-NA, and (3)H-5-HT release between 22% and 56% without affecting (3)H-DA release. Neither drug reduced (3)H-NA release in the presence of L: -isoleucine, a putative alpha(2)delta antagonist. Interestingly, this antagonism did not occur using the enantiomer, D: -isoleucine. These results suggest that GBP and PGB are not general inhibitors of VSCC and neurotransmitter release. Such alpha(2)delta ligands appear to be selective modulators of the release of certain, but not all, neurotransmitters. This differential modulation of neurotransmission presumably contributes to their clinical profile.

A Decade of Gabapentinoid Misuse: An Analysis of the European Medicines Agency’s ‘Suspected Adverse Drug Reactions’ Database

“…Indeed, pregabalin binding affinity for the a2-d subunit, and potency, is six times higher than that of gabapentin. The putative higher addiction potential of pregabalin in comparison with gabapentin may be owing to a range of factors, including more rapid absorption, faster onset of action/attainment of maximum plasma concentration [47], and higher bioavailability, which remains at [90 % irrespective of the dosage (for a review, see [48]). …”

Pregabalin Influences Insula and Amygdala Activation During Anticipation of Emotional Images

“…Research indicates PGB's primary mechanism of action involves binding at the a 2 d subunit of voltage-dependent calcium channels, subsequently leading to upregulation of GABA inhibitory activity and a reduction in the release of several neurotransmitters, including glutamate, noradrenaline, and substance P (Brawek et al, 2008;Dooley et al, 2007;Fink et al, 2002;Gee et al, 1996). Daily doses of 100-600 mg PGB have been shown to significantly reduce anxiety symptoms for 45-60% of generalized and social anxiety disorder patients (Feltner et al, , 2008Pande et al, 2003Pande et al, , 2004Pohl et al, 2005;Rickels et al, 2005).…”

Sympathetic Nervous System Dysfunction in Multiple Sclerosis, Linking Neurodegeneration to a Reduced Response to Therapy

“…Similar adverse effects are expected with GBP and the related compound PGB, which inhibit NE release in the brain [104]. These drugs are used by MS patients for their anticonvulsant, analgesic, anxiolytic, and antispastic characteristics [105,106].…”