Antinociceptive effects of α₂/α₃‐selective GABA_A receptor positive allosteric modulators on opioid‐induced hyperalgesia

Abstract

Opioids have been increasingly prescribed to treat chronic pain since the 1980s, despite evidence that long‐term use of opioids may lead to tolerance and pain sensitization called opioid‐induced hyperalgesia (OIH). OIH has been demonstrated in both preclinical models and healthy human volunteers, but is understudied and there is need for novel analgesics capable of mitigating OIH. α2/α3‐selective GABAA receptor positive allosteric modulators (PAMs) act specifically at subunits of the GABAA receptor found to mediate analgesia, and have demonstrated antinociceptive effects in models of chronic inflammatory and neuropathic pain. However, the efficacy of these compounds at relieving opioid‐induced pain hypersensitivity have not yet been investigated. This study systematically examined the antinociceptive effects of α2/α3‐selective GABAA receptor PAMs alone and in combination with acetaminophen in an OIH rat model wherein repeated treatment with the opioid fentanyl induces mechanical hyperalgesia. The von Frey test was used to measure mechanical nociception. Duration of actions of α2/α3‐selective GABAA receptor PAMs (KRM‐II‐81, NS16085, HZ‐166) alone were studied, and combinations of KRM‐II‐81 and acetaminophen were also studied at fixed ratios (1:1, 1:3, 3:1). Dose‐addition analysis was used to assess the antinociceptive interactions between KRM‐II‐81 and acetaminophen. α2/α3‐selective GABAA receptor PAMs were able to fully reverse mechanical sensitivity caused by OIH. Furthermore, KRM‐II‐81/acetaminophen combinations produced additive to supra‐additive interactions depending on the drug mixture ratios. These findings support the idea that α2/α3‐selective GABAA receptor PAMs could serve as novel analgesics for treating OIH, and may interact favorably with other non‐opioid analgesics.