Research Article: Chronic morphine exposure potentiates p-glycoprotein trafficking from nuclear reservoirs in cortical rat brain microvessels

Date Published: February 7, 2018

Publisher: Public Library of Science

Author(s): Charles P. Schaefer, Nathan B. Arkwright, Leigh M. Jacobs, Chelsea K. Jarvis, Kristen C. Hunn, Tally M. Largent-Milnes, Margaret E. Tome, Thomas P. Davis, Prasun K. Datta.


The rates of opioid prescription and use have continued to increase over the last few decades resulting in a greater number of opioid tolerant patients. Treatment of acute pain from surgery and injury is a clinical challenge for these patients. Several pain management strategies including prescribing increased opioids are used clinically with limited success; all currently available strategies have significant limitations. Many opioids are a substrate for p-glycoprotein (p-gp), an efflux transporter at the blood-brain barrier (BBB). Increased p-gp is associated with a decreased central nervous system uptake and analgesic efficacy of morphine. Our laboratory previously found that acute peripheral inflammatory pain (PIP) induces p-gp trafficking from the nucleus to the luminal surface of endothelial cells making up the BBB concomitant with increased p-gp activity and decreased morphine analgesic efficacy. In the current study, we tested whether PIP-induced p-gp trafficking could contribute to decreased opioid efficacy in morphine tolerant rats. A 6-day continuous dosing of morphine from osmotic minipumps was used to establish morphine tolerance in female rats. PIP induced p-gp trafficking away from nuclear stores showed a 2-fold increase in morphine tolerant rats. This observation suggests that p-gp trafficking contributes to the decreased morphine analgesic effects in morphine tolerant rats experiencing an acute pain stimulus. Attenuating p-gp trafficking during an acute pain stimulus could improve pain management by increasing the amount of opioid that could reach CNS analgesic targets and decrease the need for the dose escalation that is a serious challenge in pain management.

Partial Text

Long-term opioid use, even in a therapeutic setting, will lead to the development of opioid analgesic tolerance [1]. Opioid tolerance is a state in which a patient requires increasing doses of opioids to achieve the same analgesic effect. Addressing the problem of acute pain management for opioid-tolerant patients is an increasingly pressing clinical challenge. Improper pain management is costly to both patients and caregivers. Increased doses of opioids is one strategy used to overcome the issue of tolerance and manage acute pain, however, this approach has not worked well and has been partly responsible for our current opioid epidemic. Other strategies are also used including Non-Steroidal Anti-Inflammatory Drugs and local anesthetics to manage acute pain in these patients [2]. Treatment strategies involving NMDA receptor antagonists as a fast acting therapy for pain management in opioid tolerant patients have been attempted [3]. Ketamine is the drug that has been used clinically, but the interaction between ketamine and opioids is complex and not fully understood, leading to further complications [3–6]. Surgical patients can benefit from complex plans consisting of pre-operative opioid dose tapering with an increase in opioid dose after the procedure [2]. This strategy is only an option for planned procedures and cannot be used in an emergency, giving this strategy limited clinical application. All of these methods to treat pain in opioid-tolerant patients have significant limitations. There is a critical need for a better understanding of the biology and pharmacology underlying opioid tolerance and concurrent pain responses to devise more effective pain management strategies.

Long-term opioid exposure is sufficient to induce a 2-fold increase in PIP-mediated trafficking of p-gp away from the nucleus in rat brain microvessel isolates. PIP induces p-gp trafficking from nuclear reservoirs to the plasma membrane [21] concomitant with increased p-gp activity and decreased morphine analgesic efficacy [12]. In morphine tolerant rats, an acute dose of morphine is insufficient to suppress the mechanical and thermal sensitivity caused by the PIP stimulus. Increased trafficking of p-gp from nuclear reservoirs could contribute to increased drug efflux that reduces morphine analgesic efficacy. Fig 6 depicts the predicted consequences of increased p-gp trafficking due to long-term morphine exposure. These data suggest a potential role of p-gp trafficking in the clinical challenges associated with decreased opioid analgesic efficacy in patients with a history of long-term opioid use when there is a need for acute pain management [29,30].




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