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Acute anti-allodynic action of gabapentin in dorsal horn and primary somatosensory cortex: Correlation of behavioural and physiological data

Alles, SRA; Bandet, MV; Eppler, K; Noh, M-C; Winship, IR; Baker, G; Ballanyi, K; (2017) Acute anti-allodynic action of gabapentin in dorsal horn and primary somatosensory cortex: Correlation of behavioural and physiological data. Neuropharmacology , 113 (Part A) pp. 576-590. 10.1016/j.neuropharm.2016.11.011. Green open access

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Abstract

Neuropathic pain is a debilitating consequence of neuronal injury or disease. Although first line treatments include the alpha-2-delta (a2d)-ligands, pregabalin and gabapentin (GBP), the mechanism of their anti-allodynic action is poorly understood. One specific paradox is that GBP relieves signs of neuropathic pain in animal models within 30min of an intraperitoneal (IP) injection yet its actions in vitro on spinal dorsal horn or primary afferent neurons take hours to develop. We found, using confocal Ca2þ imaging, that substantia gelatinosa neurons obtained ex vivo from rats subjected to sciatic chronic constriction injury (CCI) were more excitable than controls. We confirmed that GBP (100 mg/kg) attenuated mechanical allodynia in animals subject to CCI within 30min of IP injection.Substantia gelatinosa neurons obtained ex vivo from these animals no longer displayed CCI-induced increased excitability. Electrophysiological analysis of substantia gelatinosa neurons ex vivo suggest that rapidly developing in vivo anti-allodynic effects of GBP i) are mediated intracellularly, ii) involve actions on the neurotransmitter release machinery and iii) depend on decreased excitatory synaptic drive to excitatory neurons without major actions on inhibitory neurons or on intrinsic neuronal excitability. Experiments using in vivo Ca2þ imaging showed that 100 mg/kg GBP also suppressed the response of the S1 somatosensory cortex of CCI rats, but not that of control rats, to vibrotactile stimulation. Since the level of a2d1 protein is increased in primary afferent fibres after sciatic CCI, we suggest this dictates the rate of GBP action; rapidly developing actions can only be seen when a2d1 levels are elevated.

Type: Article
Title: Acute anti-allodynic action of gabapentin in dorsal horn and primary somatosensory cortex: Correlation of behavioural and physiological data
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.neuropharm.2016.11.011
Publisher version: http://doi.org/10.1016/j.neuropharm.2016.11.011
Language: English
Additional information: © 2016 Elsevier Ltd. All rights reserved. This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Science & Technology, Life Sciences & Biomedicine, Neurosciences, Pharmacology & Pharmacy, Neurosciences & Neurology, Neuropathic pain, Electrophysiology: In vivo calcium imaging, Alpha 2 delta, Substantia gelatinosa, Synaptic transmission, ANTERIOR CINGULATE CORTEX, GATED CALCIUM-CHANNELS, CHRONIC CONSTRICTION INJURY, RAT SUBSTANTIA-GELATINOSA, NEUROPATHIC PAIN MODELS, SUBUNIT UP-REGULATION, NERVE INJURY, ROOT GANGLION, IN-VIVO, LAMINAE-I
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10042806
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