The Role of β-Arrestin2 in the Mechanism of Morphine Tolerance in the Mouse and Guinea Pig Gastrointestinal Tract

Abstract

␤-Arrestin2 has been reported to play an essential role in analgesic tolerance. Analgesic tolerance without concomitant tolerance to constipation is a limiting side effect of chronic morphine treatment. Because tolerance to morphine develops in the mouse ileum but not the colon, we therefore examined whether the role of ␤-arrestin2 in the mechanism of morphine tolerance differs in the ileum and colon. In both guinea pig and mouse, chronic in vitro exposure (2 h, 10 M) to morphine resulted in tolerance development in the isolated ileum but not the colon. The IC 50 values for morphine-induced inhibition of electrical field stimulation contraction of guinea pig longitudinal muscle myenteric plexus shifted rightward in the ileum from 5.7 Ϯ 0.08 (n ϭ 9) to 5.45 Ϯ 0.09 (n ϭ 6) (p Ͻ 0.001) after morphine exposure. A significant shift was not observed in the colon. Similar differential tolerance was seen between the mouse ileum and the colon. However, tolerance developed in the colon from ␤-arrestin2 knockout mice. ␤-Arrestin2 and extracellular signal-regulated kinase 1/2 expression levels were determined further by Western blot analyses in guinea pig longitudinal muscle myenteric plexus. A time-dependent decrease in the expression of ␤-arrestin2 and extracellular signalregulated kinase 1/2 occurred in the ileum but not the colon after 2 h of morphine (10 M) exposure. Naloxone prevented the decrease in ␤-arrestin2. In the isolated ileum from guinea pigs chronically treated in vivo with morphine for 7 days, neither additional tolerance to in vitro exposure of morphine nor a decrease in ␤-arrestin2 occurred. We conclude that a decrease in ␤-arrestin2 is associated with tolerance development to morphine in the gastrointestinal tract.

The Impact of Opioid Treatment on Regional Gastrointestinal Transit

“…[34][35][36] Recent in vitro studies in rodents has demonstrated tolerance to opioids in the upper, but not the lower GI tract. 37,38 Therefore differences in tolerance may partly explain our findings although direct translation to human in vivo physiology is highly questionable. 39 No associations between questionnaire scores and transit times were found.…”

Distribution and trafficking of the μ-opioid receptor in enteric neurons of the guinea pig

“…Intractable constipation is a common side-effect of opiate analgesics, which persists for the duration of treatment (28). Recent studies demonstrate that morphine tolerance is developed in the colon of ␤arr2 Ϫ/Ϫ mice, suggesting that agonists that do not recruit ␤arr2 may be of therapeutic benefit (32). Herkinorin has been proposed as a potential alternative MOR-targeted analgesic (34).…”

Mechanisms That Underlie μ-Opioid Receptor Agonist–Induced Constipation: Differential Involvement of μ-Opioid Receptor Sites and Responsible Regions

“…Opioid rotation (switching) and the use of peripherally restricted opioid-receptor antagonists, such as methylnaltrexone, which has a limited ability to cross the blood-brain barrier, or oral naloxone administered in a prolonged-release manner, have been shown to reverse opioid-induced refractory constipation (Holzer et al, 2009;Leppert, 2010), which indicates that the stimulation of peripheral opioid receptors is important for the expression of m-opioid receptor agonist-induced constipation. In fact, peripheral m-opioid receptors contribute to intestinal function (Gmerek et al, 1986;Radbruch and Elsner, 2004;Ross et al, 2008;Kang et al, 2012). Animal studies have shown that both the i.c.v.…”