Trigeminal neuropathic pain development and maintenance in rats are suppressed by a positive modulator of α6 GABA_A receptors

Abstract

γ‐Aminobutyric acid type A (GABAA) 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 GABAA 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 GABAA 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 GABAA receptors is appropriate for repeated administration and thus may represent a novel treatment option against the development and maintenance of trigeminal neuropathic pain.

Two Distinct Populations of α1α6-Containing GABAA-Receptors in Rat Cerebellum

“…α6-containing GABAA receptors have been reported to contribute to the alleviation of sensorimotor gating deficits (Chiou et al, 2018 ) and orofacial pain and migraine (Fan et al, 2018 ) in animal and cell models. Moreover, models of essential tremor and trigeminal neuropathic pain also have been demonstrated to benefit from drugs that act on α6-containing GABAA receptors (Handforth et al, 2018 ; Vasović et al, 2019 ). α6βγ2-containing receptors can be discriminated from α1βγ2, α2βγ2, α3βγ2, and α5βγ2 since they are not sensitive to diazepam.…”

“…It was suggested that α6 subunits are recruited for the strengthening of synapses and added to α1 subunit containing postsynaptic densities (Accardi et al, 2015 ). Recent research has identified a number of putative pathophysiological roles which involve α6-containing receptors, and targeting these is considered an interesting strategy for disorders with sensorimotor gating deficits (Chiou et al, 2018 ), essential tremor (Handforth et al, 2018 ), and by way of receptors thought to be localized in the trigeminal ganglia, trigeminal neuropathic pain states (Puri et al, 2012 ; Vasović et al, 2019 ) and migraine (Fan et al, 2018 ).…”

Gut microbiota regulates neuropathic pain: potential mechanisms and therapeutic strategy

“…Both host and bacteria can convert glutamate to GABA [ 71 ]. Some previous studies reported that agents promote the release of GABA by activating GABA receptors, thus effectively relieving trigeminal and diabetic-related NP [ 72 , 73 ]. Braz et al demonstrated that GABAergic precursor cell transplantation can reverse allodynia in a mouse NP model and propose transplantation as a therapeutic option in various NP-related models [ 74 , 75 ].…”

Psychotropic Drugs for the Management of Chronic Pain and Itch

“…In the paper [93], the α6 subunit of the GABAARs located in trigeminal ganglia was tested as a possible target for management of trigeminal neuropathic pain. The effect of two pyrazoloquinolinone compounds, DK-I-56-1 and DK-I-87-1 was studied, and one of them, DK-I-56-1, was shown to have a therapeutic potential.…”