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Trigeminal neuropathic pain development and maintenance in rats are suppressed by a positive modulator of α6 GABA A receptors
Author(s) -
Vasović Dina,
Divović Branka,
Treven Marco,
Knutson Daniel E.,
Steudle Friederike,
Scholze Petra,
Obradović Aleksandar,
Fabjan Jure,
Brković Božidar,
Sieghart Werner,
Ernst Margot,
Cook James M.,
Savić Miroslav M.
Publication year - 2019
Publication title -
european journal of pain
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.305
H-Index - 109
eISSN - 1532-2149
pISSN - 1090-3801
DOI - 10.1002/ejp.1365
Subject(s) - neuropathic pain , infraorbital nerve , trigeminal ganglion , receptor , trigeminal nerve , gabaa receptor , trigeminal neuralgia , glutamate receptor , nociception , chemistry , pharmacology , medicine , anesthesia , endocrinology , neuroscience , biology , sensory system
γ‐Aminobutyric acid type A (GABA A ) receptors containing the α6 subunit are located in trigeminal ganglia, and their reduction by small interfering RNA increases inflammatory temporomandibular and myofascial pain in rats. We thus hypothesized that enhancing their activity may help in neuropathic syndromes originating from the trigeminal system. Here, we performed a detailed electrophysiological and pharmacokinetic analysis of two recently developed deuterated structurally similar pyrazoloquinolinone compounds. DK‐I‐56‐1 at concentrations below 1 µM enhanced γ‐aminobutyric acid (GABA) currents at recombinant rat α6β3γ2, α6β3δ and α6β3 receptors, whereas it was inactive at most GABA A receptor subtypes containing other α subunits. DK‐I‐87‐1 at concentrations below 1 µM was inactive at α6‐containing receptors and only weakly modulated other GABA A receptors investigated. Both plasma and brain tissue kinetics of DK‐I‐56‐1 were relatively slow, with half‐lives of 6 and 13 hr, respectively, enabling the persistence of estimated free brain concentrations in the range 10–300 nM throughout a 24‐hr period. Results obtained in two protocols of chronic constriction injury of the infraorbital nerve in rats dosed intraperitoneally with DK‐I‐56‐1 during 14 days after surgery or with DK‐I‐56‐1 or DK‐I‐87‐1 during 14 days after trigeminal neuropathy were already established, demonstrated that DK‐I‐56‐1 but not DK‐I‐87‐1 significantly reduced the hypersensitivity response to von Frey filaments. Significance Neuropathic pain induced by trigeminal nerve damage is poorly controlled by current treatments. DK‐I‐56‐1 that positively modulates α6 GABA A receptors is appropriate for repeated administration and thus may represent a novel treatment option against the development and maintenance of trigeminal neuropathic pain.