Positive allosteric modulators of nonbenzodiazepine γ-aminobutyric acid A receptor subtypes for the treatment of chronic pain

Timothy B.C. Johnstone, Jennifer Y. Xie, Chaoling Qu, David J. Wasiak, Derk J. Hogenkamp, Frank Porreca, Kelvin W. Gee

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

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 GABA A R-mediated currents by agonist ligands for δ subunit-containing GABA A Rs. However, typical ligands that target δ subunit-containing GABA A Rs 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 α 4 β 3 δ GABA A Rs optimized to be nonsedative by selective activation of β 2/3 -subunit-containing GABA A Rs over receptor subtypes incorporating β 1 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 GABA A R-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 α 4 β 3 δ GABA A R 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 β 2/3 -subunit-containing extrasynaptic GABA A Rs.

Original languageEnglish (US)
Pages (from-to)198-209
Number of pages12
JournalPain
Volume160
Issue number1
DOIs
StatePublished - Jan 1 2019

    Fingerprint

Keywords

  • Conditioned place preference
  • Dopamine release
  • GABA receptors
  • Neuropathic pain
  • Positive allosteric modulation
  • β subunits

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Anesthesiology and Pain Medicine

Cite this