A mu-opioid receptor positive allosteric modulator provides opioid-sparing antinociception without enhancing opioid side effects.

Opioids that act at the mu-opioid receptor (MOR) are the gold standard for pain management, but can induce serious unwanted effects, including addiction liability and respiratory depression. 2-(3-bromo-4-methoxyphenyl)-3-[(4-chlorophenyl) sulfonyl]-thiazolidine is a positive allosteric modulator of MOR that increases the actions of small-molecule opioids and opioid peptides in vitro. In vivo, 2-(3-bromo-4-methoxyphenyl)-3-[(4-chlorophenyl) sulfonyl]-thiazolidine enhances the action of endogenously released opioid peptides to provide MOR-mediated antinociception, but not constipation, reward, or respiratory depression. However, the effects of positive allosteric modulators of MOR on the behavioral actions of opioid drugs such as morphine and fentanyl have not been studied. Here, we show that 2-(3-bromo-4-methoxyphenyl)-3-[(4-chlorophenyl) sulfonyl]-thiazolidine enhances opioid drug-induced antinociception in assays for acute and inflammatory pain but not the adverse effects of constipation, respiratory depression measured by blood oxygen levels and respiration rate, or reward as determined by conditioned place preference. These data support the potential of positive allosteric modulators of MOR as effective and safe opioid-sparing agents for pain management. SIGNIFICANCE STATEMENT: The undertreatment of pain and the addiction liability of opioids necessitate new strategies to improve pain management. Here, we demonstrate that the mu-opioid receptor modulator 2-(3-bromo-4-methoxyphenyl)-3-[(4-chlorophenyl) sulfonyl]-thiazolidine enhances opioid drug-mediated analgesia in mice without enhancing constipation, reward, or respiratory depression.