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Background The function of brain networks can be changed in a maladaptive manner in response to chronic neuropathic pain. Analgesics can reduce pain by acting on such networks via direct or indirect (peripheral or spinal) mechanisms. This investigation aimed to map gabapentin's pharmacodynamics ( PD) in the rodent brain following induction of neuropathic pain in order to further understand its PD profile. Methods Pharmacological magnetic resonance imaging ( phMRI) and a novel functional connectivity analysis procedure were performed following vehicle or gabapentin treatment in the rat spinal nerve ligation ( SNL) model of neuropathic pain as well as sham animals. Results phMRI performed in SNL animals revealed robust gabapentin-induced responses throughout the hippocampal formation, yet significant ( p < 0.05, corrected for multiple comparisons) responses were also measured in other limbic structures and the sensorimotor system. In comparison, sham animals displayed weaker and less widespread phMRI signal changes subsequent to gabapentin treatment. Next, communities of networks possessing strong functional connectivity were elucidated in vehicle-treated SNL and sham animals. We observed that SNL and sham animals possessed distinct functional connectivity signatures. When measuring how gabapentin altered the behaviour of the discovered networks, a decrease in functional connectivity driven by gabapentin was not only observed, but the magnitude of this PD effect was greater in SNL animals. Conclusions Using phMRI and functional connectivity analysis approaches, the PD effects of gabapentin in a preclinical neuropathic pain state were characterized. Furthermore, the current results offer insights on which brain systems gabapentin directly or indirectly acts upon. [ABSTRACT FROM AUTHOR]

Aim: To examine whether the velocity of saccadic eye movements in internuclear ophthalmoparesis (INO) improves with fampridine treatment in patients with multiple sclerosis (MS)., Methods: Randomized, double-blind, placebo-controlled, cross-over trial with fampridine in patients with MS and INO. Horizontal saccades were recorded at baseline and at multiple time points post-dose. Main outcome measures were the change of peak velocity versional dysconjugacy index (PV-VDI) and first-pass amplitude VDI (FPA-VDI). Both parameters were compared between fampridine and placebo using a mixed model analysis of variance taking patients as their own control. Pharmacokinetics was determined by serial blood sampling., Results: Thirteen patients had a bilateral and 10 had a unilateral INO. One patient had an INO of abduction (posterior INO of Lutz) and was excluded. Fampridine significantly reduced both PV-VDI (-17.4%, 95% CI: -22.4%, -12.1%; P < 0.0001) and FPA-VDI (-12.5%, 95% CI: -18.9%, -5.5%; P < 0.01). Pharmacokinetics demonstrated that testing coincided with the average t max at 2.08 hours (SD 45 minutes). The main adverse event reported after administration of fampridine was dizziness (61%)., Conclusion: Fampridine improves saccadic eye movements due to INO in MS. Treatment response to fampridine may gauge patient selection for inclusion to remyelination strategies in MS using saccadic eye movements as primary outcome measure., (© 2019 The Authors CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.)