Gabapentin Inhibits γ-Amino Butyric Acid Release in the Locus Coeruleus but Not in the Spinal Dorsal Horn after Peripheral Nerve Injury in Rats

Abstract

Background Gabapentin reduces acute postoperative and chronic neuropathic pain, but its sites and mechanisms of action are unclear. Based on previous electrophysiologic studies, we tested whether gabapentin reduced γ-Amino butyric acid (GABA) release in the locus coeruleus (LC), a major site of descending inhibition, rather than in the spinal cord. Methods Male Sprague-Dawley rats with or without L5-L6 spinal nerve ligation (SNL) were used. Immunostaining for glutamic acid decarboxylase and GABA release in synaptosomes and microdialysates were examined in the LC and spinal dorsal horn. Results Basal GABA release and expression of glutamic acid decarboxylase increased in the LC but decreased in the spinal dorsal horn following SNL. In microdialysates from the LC, intravenously administered gabapentin decreased extracellular GABA concentration in normal and SNL rats. In synaptosomes prepared from the LC, gabapentin and other α2δ ligands inhibited KCl-evoked GABA release in normal and SNL rats. In microdialysates from the spinal dorsal horn, intravenous gabapentin did not alter GABA concentrations in normal rats but slightly increased them in SNL rats. In synaptosomes from the spinal dorsal horn, neither gabapentin nor other α2δ ligands affected KCl-evoked GABA release in normal and SNL rats. Discussion These results suggest that peripheral nerve injury induces plasticity of GABAergic neurons differently in the LC and spinal dorsal horn, and that gabapentin reduces pre-synaptic GABA release in the LC but spinal dorsal horn. The present study supports the idea that gabapentin activates descending noradrenergic inhibition via disinhibition of LC neurons.

Social stress exacerbates the aversion to painful experiences in rats exposed to chronic pain: The role of the locus coeruleus

“…Although several neurotransmitters have been shown to modulate tonic and sensory-evoked LC activity (eg, excitatory amino acids, GABA, corticotropin-release-factor), our data as well as previous data point to an enhanced GABAergic neurotransmission in the LC in neuropathic pain [38,44]. Thus, we explored the effect of GABA-A receptors blockade in the contralateral LC because GABA signals mainly through these receptors [14,30].…”

“…Neuropathic pain was previously shown to be associated with higher glutamic acid decarboxylase expression and GABA release in the LC [44]. Accordingly, gephyrin expression was slightly enhanced by nerve injury, but this expression was significantly robust when nerve injury was associated with stress, and it was accompanied by functional changes such as lower and irregular tonic discharge.…”

Relief of Hypersensitivity after Nerve Injury from Systemic Donepezil Involves Spinal Cholinergic and γ-Aminobutyric Acid Mechanisms

“…[37][38][39][40][41] Electrophysiologic studies confirmed that primary afferent-evoked inhibitory postsynaptic currents in the spinal dorsal horn were reduced after nerve injury. 40,42,43 Although controversy exists with regard to the actual loss of GABAergic interneurons, [44][45][46][47] the dysfunction of GABAergic inhibition in the spinal cord likely contributes to neuropathic pain, 48,49 and several lines of evidence suggest that stimulation of the spinal GABAergic system produces analgesia in neuropathic pain.…”

Alterations in the cholinergic system of brain stem neurons in a mouse model of Rett syndrome

“…Norepinephrine (NE) is a major neuromodulator in the central nervous system (CNS), which acts on breathing (56 -58), cognition (6,25,41,55), motor movement, pain (7,8,12,65), and paradoxical sleep (14,23,46,53). The NE concentration is low in RTT patients and mouse models of RTT (47,50,73,74).…”