Morphine Tolerance in the Mouse Ileum and Colon

Abstract

Repeated administration of morphine is associated with tolerance to its antinociceptive properties. However, constipation remains the major side effect of chronic exposure to morphine. In contrast, previous studies suggest that tolerance to opioids develops in the ileum of several species. In this study, we provide evidence that constipation may arise due to a lack of tolerance development to morphine in the colon. Mice received implants with either placebo or 75 mg of morphine pellets, and they were examined for morphine tolerance to antinociception, defecation, and intestinal and colonic transit after 72 h. Tissues were obtained from the ileum and distal colon, and contractile responses were measured from longitudinal and circular muscle preparations. In morphine-pelleted mice, a 5.5-fold tolerance developed to antinociception after 72 h, and a 53.2-fold tolerance developed in mice that received an additional daily morphine injection. In both models, intestinal transit but not defecation or colonic transit developed tolerance. In isolated longitudinal muscles, electrical field stimulation-induced cholinergic contractions were dose-dependently inhibited by morphine in both the ileum and colon of placebo pelleted with a pD 2 of 7.1 Ϯ 0.4 and 7.8 Ϯ 0.4, respectively. However, the dose response to morphine inhibition was shifted to the right for the ileum from morphine-pelleted mice (pD 2 ϭ 5.1 Ϯ 0.4) but not the colon (pD 2 ϭ 6.9 Ϯ 0.4). In circular muscle preparations, morphine induced atropine-insensitive contractions in both tissue segments. Tolerance to morphine developed in the ileum but not the colon upon repeated administration of morphine. These findings indicate that a lack of tolerance development in the colon is the basis for opioid bowel dysfunction.

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

“…Similar to the results in previous studies (Koslo et al, 1986;Heyman et al, 1988;Pol et al, 1999;Ross et al, 2008), we showed that morphine can inhibit gastrointestinal transit mainly through peripheral, and in part through supraspinal as well as spinal, naloxonazine-insensitive sites of m-opioid receptors, whereas morphine inhibits colonic transit through peripheral naloxonazine-sensitive and -insensitive sites of m-opioid receptors. In the present study, we showed that oxycodone and fentanyl inhibit gastrointestinal transit mainly through peripheral m-opioid receptors.…”

“…Previous studies have demonstrated that intracentroventricular and intrathecal administration of morphine inhibits gastrointestinal and colonic function (Koslo et al, 1986;Heyman et al, 1988;Pol et al, 1999), whereas peripheral m-opioid receptors also contribute to morphine-induced intestinal movement in rodents (Gmerek et al, 1986;Pol et al, 1999;Ross et al, 2008). On the other hand, naloxonazine could not reverse the morphine-induced inhibition of gastrointestinal transit, even though it reversed the morphine-induced (intrathecally) inhibition of gastrointestinal transit (Heyman et al, 1988), and partially reversed the morphine-induced inhibition of colonic transit (Koslo et al, 1986).…”

“…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.…”

Morphine Tolerance and Physical Dependence Are Altered in Conditional HIV-1 Tat Transgenic Mice

“…Placebo or chronic morphine administration was achieved by the subcutaneous implantation of a placebo or 75-mg morphine pellet (National Institute on Drug Abuse, Rockville, MD) under aseptic conditions and 2.5% isoflurane anesthesia as previously described elsewhere (Ross et al, 2008). Using morphine pellets is a standard method for continuously administering morphine to prevent cycles of withdrawal in mice, and it produces brain drug levels considered to be similar to blood/tissue levels achieved in humans who are tolerant and dependent on opiates (Ozaita et al, 1998;Ghazi-Khansari et al, 2006), and therapeutic levels seen in patients maintained on chronic opiates/ opiate pumps for intractable pain (Balch and Trescot, 2010).…”

Enhanced Sensitivity of 3 4 Nicotinic Receptors in Enteric Neurons after Long-Term Morphine: Implication for Opioid-Induced Constipation

“…Pellets were implanted as previously described (Ross et al, 2008). Mice were anesthetized with 2.5% isoflurane, and the hair on the back of their neck was shaved.…”