CHRONIC AND INTERVENTIONAL PAIN

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 morphineinduced 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. (Reg Anesth Pain Med 2016;41: 69–74) The μ-opioid receptor (MOR) agonist–induced itch is a serious adverse effect associated with pain treatment administered through systemic, spinal, and epidural routes. The opioid receptor antagonist naloxone can inhibit MOR agonist–induced itch, whereas antihistamine drugs are ineffective as antipruritics. Therefore, it is thought that MOR agonists induce itch mainly through MORs. However, opioid receptor antagonists are unavailable in the clinical setting because they attenuate the From the Department of Anesthesiology, Shimane University Faculty of Medicine, Shimane, Japan. Accepted for publication August 12, 2015. Address correspondence to: Noritaka Imamachi, MD, PhD, Department of Anesthesiology, Shimane University Faculty of Medicine, 89-1 Enyacho Izumo, Shimane, Japan (e‐mail: imamachi@med.shimane-u.ac.jp). The authors declare no conflict of interest. This work was supported by the Japan Society for the Promotion of Science KAKENHI grant no. 26460697. Copyright © 2015 by American Society of Regional Anesthesia and Pain Medicine ISSN: 1098-7339 DOI: 10.1097/AAP.0000000000000326 Regional Anesthesia and Pain Medicine • Volume 41, Number 1, Januar Copyright © 2015 American Society of Regional Anesthesia and Pain antinociceptive effects of MOR agonists. Ko and Husbands suggested that systemically administered κ-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. In recent years, the orally administered KOR agonist TRK-820 has been applied to treat itch in patients undergoing hemodialysis in a clinical setting. However, adverse effects, such as insomnia, induced by systemically administered KOR agonists, may limit the usefulness of their antipruritic effects in patients. No report is available regarding the effects of the combination of intrathecally administered KOR and MOR agonists. We therefore investigated the effects of intrathecal TRK-820 on intrathecal morphine–induced itch, antinociception, and sedation.