Mice with neuropathic pain exhibit morphine tolerance due to a decrease in the morphine concentration in the brain

• Published in: European journal of pharmaceutical sciences 2016-09, Vol.92, p.298-304
• Main Authors: Ochiai, Wataru, Kaneta, Mitsumasa, Nagae, Marina, yuzuhara, Ami, Li, Xin, Suzuki, Haruka, Hanagata, Mika, Kitaoka, Satoshi, Suto, Wataru, Kusunoki, Yoshiki, Kon, Risako, Miyashita, Kazuhiko, Masukawa, Daiki, Ikarashi, Nobutomo, Narita, Minoru, Suzuki, Tsutomu, Sugiyama, Kiyoshi
• Format: Article
• Language: English
• Subjects: Analgesics, Opioid - blood; Analgesics, Opioid - pharmacokinetics; Analgesics, Opioid - therapeutic use; Animals; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Brain - metabolism; Dose-Response Relationship, Drug; Drug Tolerance; Glucuronosyltransferase - metabolism; Intestine, Small - metabolism; Liver - metabolism; Male; Mice, Inbred ICR; Morphine; Morphine - blood; Morphine - pharmacokinetics; Morphine - therapeutic use; Morphine Derivatives - metabolism; Morphine-6-glucuronide; Neuralgia - drug therapy; Neuralgia - metabolism; P-gp; Sciatic Nerve - injuries; UGT
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/j.ejps.2016.03.019

The chronic administration of morphine to patients with neuropathic pain results in the development of a gradual tolerance to morphine. Although the detailed mechanism of this effect has not yet been elucidated, one of the known causes is a decrease in μ-opioid receptor function with regard to the active metabolite of morphine, M-6-G(morphine-6-glucuronide), in the ventrotegmental area of the midbrain. In this study, the relationship between the concentration of morphine in the brain and its analgesic effect was examined after the administration of morphine in the presence of neuropathic pain. Morphine was orally administered to mice with neuropathic pain, and the relationship between morphine's analgesic effect and its concentration in the brain was analysed. In addition, the expression levels of the conjugation enzyme, UGT2B (uridine diphosphate glucuronosyltransferase), which has morphine as its substrate, and P-gp, which is a transporter involved in morphine excretion, were examined. In mice with neuropathic pain, the concentration of morphine in the brain was significantly decreased, and a correlation was found between this decrease and the decrease in the analgesic effect. It was considered possible that this decrease in the brain morphine concentration may be due to an increase in the expression level of P-gp in the small intestine and to an increase in the expression level and binding activity of UGT2B in the liver. The results of this study suggest the possibility that a sufficient analgesic effect may not be obtained when morphine is administered in the presence of neuropathic pain due to a decrease in the total amount of morphine and M-6-G that reach the brain. The mechanism of the decrease in the morphine concentration in the brain in the presence of neuropathic pain. [Display omitted]