HZ166, a novel GABAA receptor subtype-selective benzodiazepine site ligand, is antihyperalgesic in mouse models of inflammatory and neuropathic pain

Abstract

a b s t r a c tDiminished GABAergic and glycinergic inhibition in the spinal dorsal horn contributes significantly to chronic pain of different origins. Accordingly, pharmacological facilitation of GABAergic inhibition by spinal benzodiazepines (BDZs) has been shown to reverse pathological pain in animals as well as in human patients. Previous studies in GABA A receptor point-mutated mice have demonstrated that the spinal anti-hyperalgesic effect of classical BDZs is mainly mediated by GABA A receptors containing the a2 subunit (a2-GABA A receptors), while a1-GABA A receptors, which mediate the sedative effects, do not contribute. Here, we investigated the potential analgesic profile of HZ166, a new partial BDZ-site agonist with preferential activity at a2-and a3-GABA A receptors. HZ166 showed a dose-dependent antihyperalgesic effect in mouse models of neuropathic and inflammatory pain, triggered by chronic constriction injury (CCI) of the sciatic nerve and by subcutaneous injection of the yeast extract zymosan A, respectively. This antihyperalgesic activity was antagonized by flumazenil and hence mediated via the BDZ-binding site of GABA A receptors. A central site of action of HZ166 was consistent with its pharmacokinetics in the CNS. When non-sedative doses of HZ166 and gabapentin, a drug widely used in the clinical management of neuropathic pain, were compared, the efficacies of both drugs against CCI-induced pain were similar. At doses producing already maximal antihyperalgesia, HZ166 was devoid of sedation and motor impairment, and showed no loss of analgesic activity during a 9-day chronic treatment period (i.e. no tolerance development). These findings provide further evidence that compounds selective for a2-and a3-GABA A receptors might constitute a novel class of analgesics suitable for the treatment of chronic pain.

Current and Future Issues in the development of spinal agents for the management of pain

“…Intrathecal benzodiazepines and neurosteroids have been shown precliincally in rodent models to attenuate tissue and nerve injury hyperpathic states [218,[222][223][224][225][226]. In dogs, intrathecal benzodiazepines have been shown to depress nociceptive reflexes [227].…”

Restoring the Spinal Pain Gate

“…Both questions were addressed with conditional GABA A R deficient mice (hoxb8-α2 À/À mice), which lack the GABA A R α2 subunit specifically from the spinal cord and dorsal root ganglia (DRGs) (up to about segment C4). In these experiments, a recently developed benzodiazepine site agonists (HZ166; Rivas et al, 2009) was employed which exerts antihyperalgesic actions similar to systemic diazepam but with reduced sedative and muscle relaxant properties (Di Lio et al, 2011). Antihyperalgesia was assessed as the change in heat and pin-prick induced withdrawal responses.…”

“…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.…”

GABAA receptor modulation: Potential to deliver novel pain medicines?

“…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 .…”

“…However, the agents differ with respect to absolute efficacy at each subtype of GABA A receptor (e.g., even though most compounds have greater selectivity at GABA A α2 and/ or α3 receptors than at GABA A α1 receptors, they differ with respect to the level of efficacy at GABA A α1 receptors per se (see Munro et al, 2009 α3β3γ2 and α5β3γ2, respectively), Di Lio et al, 2011). In keeping with these specific facets, HZ166 displayed flumazenil-reversible anti-hyperalgesic efficacy in mice with zymosan A-induced inflammation and CCI induced mechanical hypersensitivity (Di Lio et al, 2011), (Table 1). Importantly, the efficacy obtained in chronic constriction injury mice was comparable to the standard of care compound gabapentin, and as shown previously for L-838,417 did not tolerate out with repeated administration.…”