Chronic
neuropathic pain may be caused, in part, by loss of inhibition in spinal
pain processing pathways due to attenuation of local GABAergic tone. Nociception and nocifensive behaviors are reduced after enhancement of tonically activated extrasynaptic GABAAR-mediated currents by agonist
ligands for δ subunit-containing GABAARs. However, typical
ligands that target δ subunit-containing GABAARs are limited due to
sedative effects at higher doses. We used the spinal nerve
ligation (SNL) and gp120 models of experimental
neuropathic pain to evaluate compound 2-261, a nonbenzodiazepine site positive allosteric modulator of α4β3δ GABAARs optimized to be nonsedative by selective activation of β2/3-subunit-containing GABAARs over receptor subtypes incorporating β1 subunits. Similar levels of 2-261 were detected in the brain and plasma after intraperitoneal administration. Although systemic 2-261 did not alter sensory thresholds in
sham-operated animals, it significantly reversed SNL-induced thermal and tactile
hypersensitivity in a GABAAR-dependent fashion. Intrathecal 2-261 produced conditioned place preference and elevated
dopamine levels in the nucleus accumbens of nerve-injured, but not
sham-operated, rats. In addition, systemic pretreatment with 2-261 blocked conditioned place preference from spinal
clonidine in SNL rats. Moreover, 2-261 reversed
thermal hyperalgesia and partially reversed
tactile allodynia in the gp120 model of HIV-related
neuropathic pain. The effects of 2-261 likely required interaction with the α4β3δ GABAAR because 2-301, a close structural analog of 2-261 with limited extrasynaptic receptor efficacy, was not active. Thus, 2-261 may produce
pain relief with diminished side effects through selective modulation of β2/3-subunit-containing extrasynaptic GABAARs.