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

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 non-benzodiazepine (BZ) site positive allosteric modulator (PAM) of α(4)β(3)δ GABA(A)Rs optimized to be non-sedative 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 following intraperitoneal administration. While 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 (CPP) and elevated dopamine levels in the nucleus accumbens of nerve-injured, but not sham-operated rats. Additionally, systemic pretreatment with 2–261 blocked CPP 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 since 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.