Comparison of ex vivo and in vitro actions of gabapentin in superficial dorsal horn and the role of extra-spinal sites of drug action. (16th February 2019)

• Record Type: Journal Article
• Authors: Alles, Sascha R.A.; Smith, Peter A.
• Is Part Of: Neuroscience letters. Volume 694(2019)
• Page Start: 148
• Page End: 153
• Publication Date: 2019-02-16
• Subjects: Neuropathic pain -- alpha-2-delta -- Substantia gelatinosa -- Descending modulation -- Top down pain modulation; Neurology -- Periodicals; Neurology -- Periodicals; Research -- Periodicals; Neurologie -- Périodiques; Neuroanatomie -- Périodiques; Neuropharmacologie -- Périodiques; Neurophysiologie -- Périodiques; Neurology; Periodicals; Electronic journals; 617.48
• DOI: 10.1016/j.neulet.2018.11.050
• Languages: English
• ISSNs: 0304-3940

Abstract

Highlights: Spinal actions of gabapentin studied ex vivo differ from those seen in vitro. Gabapentin increases sEPSC frequency in inhibitory neurons ex vivo. Gabapentin decreases sEPSC frequency in inhibitory neurons in vitro. This difference may relate to absence of descending pain control in vitro. Extraspinal actions are involved in gabapentin attenuation of allodynia. Abstract: Although gabapentin (GBP) is a first-line treatment in the management of neuropathic pain, its mechanism of action is incompletely understood. We have previously shown, in rats made neuropathic following sciatic chronic constriction injury, that IP injection of 100 mg/kg GBP decreases overall excitability of spinal cord slices obtained ex vivo. Excitability was assessed using confocal imaging to monitor the amplitude of K + - induced increases in cytoplasmic Ca 2+ . This decrease in excitability involved a reduction in the frequency and amplitude of spontaneous EPSC's (sEPSC) in putative excitatory substantia gelatinosa neurons and an increase in sEPSC frequency in putative inhibitory neurons. We used have whole-cell recording to compare these ex vivo actions of GBP with its acute in vitro effects on spinal cord slices obtained from neuropathic but drug-free rats. While GBP (100μM) decreased sEPSC amplitude and frequency in excitatory neurons in vitro in a similar fashion to effects observed ex vivo, sEPSC frequency in inhibitory neurons was decreased in vitro rather than increased. Acute in vitro application of GBP also failed to decrease the overall excitability of slices from neuropathic animals as monitored by confocal Ca 2+ imaging. Since spinal cord slices in vitro are disconnected from the periphery and higher brain centres, the GBP-induced increase in sEPSC frequency in inhibitory neurons previously reported and seen ex vivo must result from extra-spinal actions. It may be attributable to alterations in descending neurotrophic control of dorsal horn circuitry.