Abstract
Pruritus is the most common complication of intrathecal morphine; however, its exact molecular mechanism is unclear, and treatment is challenging. The analgesic effect of N-methyl-D-aspartate (NMDA) receptor antagonists and the morphine-associated increase in NMDA receptor activation suggest potential role of NMDA receptor in the spinal itch sensation. Male C57BL/6 mice were given intrathecal morphine to induce scratching behavior. The effects of NMDA, ketamine, ifenprodil and U0126 on morphine-induced pruritus and analgesia were evaluated also. The number of scratching responses was counted for 30 min post-injection to evaluate pruritus. A warm-water tail immersion assay was conducted before and until 120 min post-injection at 30-min intervals. Percent of maximal possible effect (%MPE) and area under curve (AUC) were calculated based on tail-flick latency to evaluate analgesic efficacy. Compared with control treatment, intrathecal morphine elicited an obvious scratching response and analgesic effect in a dose dependent manner. Ketamine (1 μg), ifenprodil (0.1 μg) and U0126 (0.1 μg and 1.0 μg) all significantly attenuated morphine induced scratches. Ifenprodil (0.1 μg) injection significantly prolonged the analgesic effect of intrathecal morphine. The ERK1/2 phosphorylation induced by intrathecal morphine was inhibited by ketamine, ifenprodil and U0126 as well. U0126 inhibited morphine-induced pruritus with no effect on its analgesia. Therefore, intrathecal coadministration of morphine with NMDA receptor antagonists ketamine and ifenprodil alleviated morphine-induced scratching. Intrathecal morphine increased ERK phosphorylation in the lumbar spinal dorsal horn, which may be related with morphine-induced pruritus, and was counteracted by NMDA receptor antagonists.
Highlights
Pruritus is the most common complication of intrathecal morphine analgesia
Since extracellular signal-regulated kinase (ERK) activation is required for itch sensation in the spinal cord, in this study, we explored whether ERK1/2 activation is related to morphine-induced pruritus at the molecular level
Morphine-induced pruritus Mice were randomly assigned to the naïve group, which received no injection, the normal saline (NS) group, which received an intrathecal injection of NS, and intrathecal morphine groups, which received morphine injections from 0.1 μg to 1.0 μg
Summary
Various kinds of medications with different mechanisms of action have been used for the prevention and treatment of morphine-induced pruritus. The effects are variable and have failed to lead to the identification of a consistent mechanism of action [1, 2]. Neurons expressing gastrin-releasing peptide receptor (GRPR) have been suggested to be responsible for itch sensation in the spinal cord. The μ-opioid receptor (MOR) isoform, MOR1D, which is heterodimerized with. GRPR in the spinal cord, relays itch information induced by intrathecal morphine [3, 4]. Another isoform, MOR1, is required for the analgesic effect of morphine [4]
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