Effects of Intrathecal κ-Opioid Receptor Agonist on Morphine-induced Itch and Antinociception in Mice

The m-opioid receptor agonist-induced itch is a common adverse effect associated with opioid pain treatment administered through systemic, spinal, and epidural routes. Studies have suggested that systemically administered k-opioid receptor (KOR) agonists alleviate intrathecal morphine-induced itch; moreover, systemic KOR agonists in combination with intrathecal morphine display additive antinociceptive effects against a thermal stimulus in primates. However, adverse effects, such as insomnia induced by systemically administered KOR agonists, may limit the usefulness of their antipruritic effects in patients. The aim of this study was to investigate the effects of intrathecal TRK820 a KOR agonist, on intrathecal morphine-induced itch, antinociception, and sedation. Intrathecal injections with the following drugs were administered to 108 mice: morphine (0.1 to 1.0 nmoL), the selective KOR agonist TRK-820 100 pmoL, the combination of morphine 0.3 nmoL+TRK-820 (10 to 100 pmoL), and 5mL of saline. Scratching behavior was then studied. An hour after intraperitoneal administration of the selective KOR antagonist nor-binaltorphimine 1.0 mmol, the effect of TRK-820 100 pmoL on intrathecal morphine 0.3 nmoLinduced scratching was tested. The animals’ sedation levels were evaluated subjectively. The tail immersion test with intrathecal injections of the following agents: morphine (0.1 to 1.0 nmoL), TRK-820 (10 to 100 pmoL), morphine 0.1 nmoL+TRK-820 10 pmoL, and 5mL of saline was used to determine nociceptive thresholds. Results of the study showed intrathecal TRK-820 dose-dependently inhibited intrathecal morphine-induced scratching compared with that in the saline group. Also, intraperitoneal nor-binaltorphimine completely inhibited the antipruritic effect of intrathecal TRK-820 100 pmoL. The study also found that the combination of morphine 0.3 nmoL and TRK-820 did not alter the sedation score compared with that in the morphine 0.3 nmoL group. A dose of morphine 0.1 nmoL+TRK-820 10 pmoL produced significantly greater thermal antinociceptive effects than morphine 0.1 nmoL. The study concluded that intrathecal TRK-820 reduced intrathecal morphine-evoked itch without elevating the sedation level. Furthermore, the combination of intrathecal morphine with intrathecal TRK-820 produced more potent antinociceptive effects against a thermal stimulus than those produced by morphine alone. Anesthesia and Analgesia Obstetric Anesthesia Digest Volume 36, Number 4, December 2016