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.
Compound 2-261, a nonbenzodiazepine site positive allosteric modulator of α4β3δ GABAARs, was effective in reducing affective and sensory qualities of experimental neuropathic pain.
aDepartment of Pharmacology, School of Medicine, University of California, Irvine, Irvine, CA, United States
bDepartment of Basic Sciences, New York Institute of Technology, College of Osteopathic Medicine, Jonesboro, AR, United States
cUniversity of Nevada School of Medicine, Reno, NV, United States
dDepartment of Pharmacology, College of Medicine, University of Arizona Health Sciences Center, Tucson, AZ, United States
Corresponding author. Address: Department of Pharmacology, School of Medicine, University of California, Irvine, Irvine, 92697, CA, United States. Tel.: (949) 824-8009. E-mail address: firstname.lastname@example.org (K.W. Gee).
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
T.B.C. Johnstone and J.Y. Xie contributed equally to this manuscript.
Received May 15, 2018
Accepted August 29, 2018