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

The μ-opioid receptor (MOR) agonist-induced itch is a significant issue associated with analgesic therapies. Research suggested that systemically administered κ-opioid receptor (KOR) agonists inhibit intrathecal morphine-induced itch in primates. However, serious adverse effects induced by systemically administered KOR agonists may restrict their usefulness in humans. We investigated the effects of intrathecal KOR agonists on intrathecal morphine-mediated itch and antinociception in mice.Mice received intrathecal injections of one of the following drugs: morphine (0.1-1.0 nmol), the selective KOR agonist TRK-820 100 pmol, the combination of morphine 0.3 nmol + TRK-820 (10-100 pmol), and 5 μL of saline. One hour after intraperitoneal administration of the selective KOR antagonist nor-binaltorphimine 1.0 μmol, the effect of TRK-820 100 pmol on intrathecal morphine 0.3 nmol-induced scratching was tested. Total numbers of scratches after intrathecal injection were analyzed. After observing scratching behavior, sedation level was evaluated subjectively. Nociceptive threshold was determined by tail immersion test with intrathecal injections of the following agents: morphine (0.1-1.0 nmol), TRK-820 (10-100 pmol), morphine 0.1 nmol + TRK-820 10 pmol, and 5 μL of saline.Intrathecal TRK-820 dose-dependently inhibited intrathecal morphine-induced scratching compared with that in the saline group. Intraperitoneal nor-binaltorphimine completely inhibited the antiscratching effect of intrathecal TRK-820 100 pmol. 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. Morphine 0.1 nmol + TRK-820 10 pmol significantly produced greater thermal antinociceptive effects than morphine 0.1 nmol.We demonstrated that intrathecal KOR agonists exert antipruritic effects on intrathecal morphine-induced itch without affecting sedation. The combination of intrathecal morphine and intrathecal KOR agonists produces more potent antinociceptive effects against a thermal stimulus compared with morphine alone.