A Comparison of the 2/3/5 Selective Positive Allosteric Modulators L-838,417 and TPA023 in Preclinical Models of Inflammatory and Neuropathic Pain

Abstract

GABAA receptors containing α2/3 subunits are current targets in the battle to develop new pain medications, as they are expressed in the spinal cord where increasing inhibitory drive should result in analgesia. However, this approach is prone to a range of side effects including sedation, cognitive impairment, and abuse as a consequence of the widespread influence of GABA. The ability to make subtype selective low-efficacy benzodiazepine compounds, which potentiate the action of GABA at specific α subunits, has the potential to reduce this side effect profile. In this study, we have investigated the effects of the medium-efficacy positive allosteric modulator (PAM) L-838,417 and the low-efficacy PAM TPA023 in a number of preclinical inflammatory and neuropathic pain models. We conclude that either the higher level of efficacy at α2/3 or efficacy at α5 is required for compounds to have a significant analgesic effect in a range of models, and, therefore, although the side-effect profile of compounds can be reduced compared to typical benzodiazepines, it is unlikely that it can be completely eliminated.

GABAA receptor modulation: Potential to deliver novel pain medicines?

“…Moreover, in chronic constriction injury rats whereas tolerance develops to the antiallodynic actions of morphine after repeated administration, efficacy is maintained for L-838,417 after chronic treatment (Knabl et al, 2008). L-838,417 also attenuates high threshold mechanical activity of electrophysiologically identified spinal wide dynamic range neurones recorded from chronic constriction injury rats (Nickolls et al, 2011). Unfortunately, any effects of L-838,417 on spontaneous electrical activity of sensitized spinal dorsal horn neurones were not reported, as this might have provided useful information as the utility of subtypeselective GABA A receptor modulators to affect a surrogate marker of spontaneous pain, one of the most commonly reported clinical signs of chronic pain.…”

“…Although other subtype-selective GABA A receptor modulators have since been reported to possess similar analgesic properties in rodent models of pathological pain (Di Lio et al, 2011;Nickolls et al, 2011;Munro et al, 2011) little was known at this time about the efficacy profile required to mediate preferential analgesia. In pursuit of this goal NS11394 was compared to other known positive allosteric modulators (PAMs) that included the nonselective full allosteric modulator diazepam, the GABA A -α1-selective modulator zolpidem, the partial nonselective modulator bretazenil and the α4 preferring agonist gaboxadol .…”

“…Whilst these in vitro properties for each compound have managed to translate into nonsedating anxiolytic profiles in rodents and primates (McKernan et al, 2000;Atack, 2009), they revealed a number of interesting facets when tested in animal models of experimental pain. A number of independent investigators have shown that systemic L-838,417 robustly reverses thermal hyperalgesia in CFA-inflamed rats, and mechanical and thermal hypersensitivity in rats with postoperative incisional pain and peripheral nerve injury, at doses corresponding with 100% receptor occupancy (Knabl et al, 2008;Nickolls et al, 2011;Reichl et al, 2012), (Table 1) Accordingly, reversal of inflammatory hyperalgesia by L-838,417 is blocked by flumazenil confirming that this efficacy is mediated via GABA A receptors (Knabl et al, 2008). Moreover, in chronic constriction injury rats whereas tolerance develops to the antiallodynic actions of morphine after repeated administration, efficacy is maintained for L-838,417 after chronic treatment (Knabl et al, 2008).…”

Restoring the Spinal Pain Gate

“…The analgesic effect in the formalin test was blocked by the benzodiazepine site antagonist flumazenil confirming that it occurred through GABA A Rs. L-838,417, which completely lacks intrinsic activity at α1-GABA A Rs and possesses partial agonistic activity at α2-, α3-, and α5-GABA A Rs (15-32%, relative to diazepam; McKernan et al, 2000), was tested in several rodent pain models where it was not sedative but active against inflammatory and neuropathic hyperalgesia (Knabl et al, 2008;Nickolls et al, 2011) and formalin-induced nociception (Hofmann et al, 2012). In addition, L-838,417 was active against hyperalgesia evoked by skin incision, a model of postoperative hyperalgesia (Reichl et al, 2012), and against capsaicin-induced central pain sensitization (Hansen et al, 2012).…”

“…Other benzodiazepines with low sedative propensities include HZ166 (Rivas et al, 2009) and TPA023 (Atack et al, 2006). HZ166, which exerts rather high intrinsic activity, was antihyperalgesic in inflammatory and neuropathic mouse models (Di Lio et al, 2011), while TPA023, which is a low intrinsic activity partial agonist, showed comparatively weak anti-allodynic or antihyperalgesic effects (Munro et al, 2011;Nickolls et al, 2011). Other compounds, which have higher intrinsic activities at α1-GABA A Rs than at α2-, α3-, and α5-GABA A Rs, did not exhibit antihyperalgesic activity at non-sedative doses.…”